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1. Processes and outcomes from a clinical genetics e-consultation service managed by a primary care physician champion

Author: Benjamin J. Kerman, Carrie B.L. Zawatsky, Elizabeth Fieg, Natasha Y. Frank, Roseann S. Donnelly, Robert C. Green, John C. Kennedy, Neal Lakdawala, Adam M. Licurse, Emma F. Perez, Charlene L. Preys, Joel B. Krier, Huma Q. Rana, Bethany Zettler, and Jason L. Vassy
Subjects: Clinical genetics, e-consultation, Outcomes, Primary care, Genetics, QH426-470, Medicine
Abstract: Purpose: Timely access to clinical genetics consultations remains a barrier to timely genomic medicine services, which new service delivery models might help address. Methods: We implemented a genetics electronic consultation (eConsult) service staffed by a primary care physician (PCP) champion, supervised by genetics specialists. Chart reviews from July 2018 to January 2022 examined categories of questions received, e-consultant’s recommendations, and outcomes of any conventional genetics referrals. Providers were surveyed on likelihood of ordering a conventional genetics consultation before eConsult and satisfaction with eConsult responses. Results: Conventional genetics consultation was recommended for 338 out of 462 (73%) eConsults received, among whom 254 out of 338 (75%) had an order placed for a conventional consult by the provider requesting the eConsult. Among all 462 eConsults, including in cases which conventional consult was not recommended, 279 (60%) were referred for conventional genetics consultation, of which 171 out of 279 (61%) completed a consult. Of these, 122 out of 171 (71%) were recommended for genetic testing, and 84 out of 122 (69%) completed testing. The genetic testing of 23 out of 84 (27%) patients identified informative actionable findings. Supervising genetics specialists made substantive revisions to PCP draft responses for only 8% (36/462) of eConsults. Conclusion: This case series demonstrates that a PCP champion eConsult model can feasibly triage and respond to genetics questions with PCP-relevant content and yield high provider satisfaction. Such a model warrants further evaluation as an addition to the genetic services of health care systems.
Published: 2024
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2. A novel variant in the GNAS complex locus causes Albright hereditary osteodystrophy with pseudopseudohypoparathyroidism

Author: Jeffrey S. Smith, MD, PhD, Abdulrahman A. Aldeeri, MD, Scott A. Elman, MD, Joel B. Krier, MD, and Joseph F. Merola, MD, MMSc
Subjects: Albright hereditary osteodystrophy, genodermatoses, G protein, GNAS, GPCR, pseudopseudohypoparathyroidism, Dermatology, RL1-803
Published: 2022
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3. Clinical utility of brain MRS imaging of patients with adult-onset non-cirrhotic hyperammonemia

Author: Andrew B. Stergachis, Joel B. Krier, Sai K. Merugumala, Gerard T. Berry, and Alexander P. Lin
Subjects: Non-cirrhotic hyperammonemia, Urea cycle disorder, Magnetic resonance spectroscopy, Cerebral myo-inositol, Cerebral glutamine, Medicine (General), R5-920, Biology (General), QH301-705.5
Abstract: Adult-onset non-cirrhotic hyperammonemia (NCH) is a rare, but often fatal condition that can result in both reversible and irreversible neurological defects. Here we present five cases of adult-onset non-cirrhotic hyperammonemia wherein brain magnetic resonance spectroscopy (MRS) scans for cerebral glutamine (Gln) and myo-inositol (mI) levels helped guide clinical management. Specifically, we demonstrate that when combined with traditional brain magnetic resonance imaging (MRI) scans, cerebral Gln and mI MRS can help disentangle the reversible from irreversible neurological defects associated with hyperammonemic crisis. Specifically, we demonstrate that whereas an elevated brain MRS Gln level is associated with reversible neurological defects, markedly low mI levels are associated with a risk for irreversible neurological defects such as central pontine myelinolysis. Overall, our findings indicate the utility of brain MRS in guiding clinical care and prognosis in patients with adult-onset non-cirrhotic hyperammonemia.
Published: 2021
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4. The BabySeq project: implementing genomic sequencing in newborns

Author: Ingrid A. Holm, Pankaj B. Agrawal, Ozge Ceyhan-Birsoy, Kurt D. Christensen, Shawn Fayer, Leslie A. Frankel, Casie A. Genetti, Joel B. Krier, Rebecca C. LaMay, Harvey L. Levy, Amy L. McGuire, Richard B. Parad, Peter J. Park, Stacey Pereira, Heidi L. Rehm, Talia S. Schwartz, Susan E. Waisbren, Timothy W. Yu, The BabySeq Project Team, Robert C. Green, and Alan H. Beggs
Subjects: Newborn screening, Newborn sequencing, Whole exome sequencing, Methods, Randomized trial, Ethical, legal, social implications, Pediatrics, RJ1-570
Abstract: Abstract Background The greatest opportunity for lifelong impact of genomic sequencing is during the newborn period. The “BabySeq Project” is a randomized trial that explores the medical, behavioral, and economic impacts of integrating genomic sequencing into the care of healthy and sick newborns. Methods Families of newborns are enrolled from Boston Children’s Hospital and Brigham and Women’s Hospital nurseries, and half are randomized to receive genomic sequencing and a report that includes monogenic disease variants, recessive carrier variants for childhood onset or actionable disorders, and pharmacogenomic variants. All families participate in a disclosure session, which includes the return of results for those in the sequencing arm. Outcomes are collected through review of medical records and surveys of parents and health care providers and include the rationale for choice of genes and variants to report; what genomic data adds to the medical management of sick and healthy babies; and the medical, behavioral, and economic impacts of integrating genomic sequencing into the care of healthy and sick newborns. Discussion The BabySeq Project will provide empirical data about the risks, benefits and costs of newborn genomic sequencing and will inform policy decisions related to universal genomic screening of newborns. Trial registration The study is registered in ClinicalTrials.gov Identifier: NCT02422511. Registration date: 10 April 2015.
Published: 2018
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5. Heterozygous loss-of-function variants significantly expand the phenotypes associated with loss of GDF11

Author: Thomas A. Ravenscroft, Jennifer B. Phillips, Elizabeth Fieg, Sameer S. Bajikar, Judy Peirce, Jeremy Wegner, Alia A. Luna, Eric J. Fox, Yi-Lin Yan, Jill A. Rosenfeld, Jonathan Zirin, Oguz Kanca, Maria T. Acosta, Margaret Adam, David R. Adams, Pankaj B. Agrawal, Mercedes E. Alejandro, Justin Alvey, Laura Amendola, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanya, Dustin Baldridge, Jim Bale, Michael Bamshad, Deborah Barbouth, Pinar Bayrak-Toydemir, Anita Beck, Alan H. Beggs, Edward Behrens, Gill Bejerano, Jimmy Bennet, Beverly Berg-Rood, Jonathan A. Bernstein, Gerard T. Berry, Anna Bican, Stephanie Bivona, Elizabeth Blue, John Bohnsack, Carsten Bonnenmann, Devon Bonner, Lorenzo Botto, Brenna Boyd, Lauren C. Briere, Elly Brokamp, Gabrielle Brown, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, Peter Byers, William E. Byrd, John Carey, Olveen Carrasquillo, Ta Chen Peter Chang, Sirisak Chanprasert, Hsiao-Tuan Chao, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, Matthew Coggins, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Andrew B. Crouse, Michael Cunningham, Precilla D’Souza, Hongzheng Dai, Surendra Dasari, Joie Davis, Jyoti G. Dayal, Matthew Deardorff, Esteban C. Dell’Angelica, Shweta U. Dhar, Katrina Dipple, Daniel Doherty, Naghmeh Dorrani, Argenia L. Doss, Emilie D. Douine, David D. Draper, Laura Duncan, Dawn Earl, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Cecilia Esteves, Marni Falk, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Laurie C. Findley, Paul G. Fisher, Brent L. Fogel, Irman Forghani, Laure Fresard, William A. Gahl, Ian Glass, Bernadette Gochuico, Rena A. Godfrey, Katie Golden-Grant, Alica M. Goldman, Madison P. Goldrich, David B. Goldstein, Alana Grajewski, Catherine A. Groden, Irma Gutierrez, Sihoun Hahn, Rizwan Hamid, Neil A. Hanchard, Kelly Hassey, Nichole Hayes, Frances High, Anne Hing, Fuki M. Hisama, Ingrid A. Holm, Jason Hom, Martha Horike-Pyne, Alden Huang, Yong Huang, Laryssa Huryn, Rosario Isasi, Fariha Jamal, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Lefkothea Karaviti, Jennifer Kennedy, Dana Kiley, Isaac S. Kohane, Jennefer N. Kohler, Deborah Krakow, Donna M. Krasnewich, Elijah Kravets, Susan Korrick, Mary Koziura, Joel B. Krier, Seema R. Lalani, Byron Lam, Christina Lam, Grace L. LaMoure, Brendan C. Lanpher, Ian R. Lanza, Lea Latham, Kimberly LeBlanc, Brendan H. Lee, Hane Lee, Roy Levitt, Richard A. Lewis, Sharyn A. Lincoln, Pengfei Liu, Xue Zhong Liu, Nicola Longo, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, John MacDowall, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Marta M. Majcherska, Bryan C. Mak, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Kenneth Maravilla, Thomas C. Markello, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Julian A. Martínez-Agosto, Shruti Marwaha, Jacob McCauley, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Elisabeth McGee, Heather Mefford, J. Lawrence Merritt, Matthew Might, Ghayda Mirzaa, Eva Morava, Paolo Moretti, Paolo M. Moretti, Deborah Mosbrook-Davis, John J. Mulvihill, David R. Murdock, Anna Nagy, Mariko Nakano-Okuno, Avi Nath, Stan F. Nelson, John H. Newman, Sarah K. Nicholas, Deborah Nickerson, Shirley Nieves-Rodriguez, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, Stephen Pak, J. Carl Pallais, Christina GS. Palmer, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, Lorraine Potocki, Bradley Power, Barbara N. Pusey, Aaron Quinlan, Wendy Raskind, Archana N. Raja, Deepak A. Rao, Genecee Renteria, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Natalie Rosenwasser, Francis Rossignol, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Susan L. Samson, Mario Saporta, C. Ron Scott, Judy Schaechter, Timothy Schedl, Kelly Schoch, Daryl A. Scott, Vandana Shashi, Jimann Shin, Rebecca Signer, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Edward C. Smith, Kevin S. Smith, Emily Solem, Lilianna Solnica-Krezel, Ben Solomon, Rebecca C. Spillmann, Joan M. Stoler, Jennifer A. Sullivan, Kathleen Sullivan, Angela Sun, Shirley Sutton, David A. Sweetser, Virginia Sybert, Holly K. Tabor, Amelia L.M. Tan, Queenie K.-G. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Audrey Thurm, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Brianna M. Tucker, Tiina K. Urv, Adeline Vanderver, Matt Velinder, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Stephanie Wallace, Nicole M. Walley, Chris A. Walsh, Melissa Walker, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Daniel Wegner, Mark Wener, Tara Wenger, Katherine Wesseling Perry, Monte Westerfield, Matthew T. Wheeler, Jordan Whitlock, Lynne A. Wolfe, Jeremy D. Woods, Shinya Yamamoto, John Yang, Muhammad Yousef, Diane B. Zastrow, Wadih Zein, Chunli Zhao, Stephan Zuchner, Paul J. Benke, Eric S. Cameron, Vincent Strehlow, Konrad Platzer, Rami Abou Jamra, Chiara Klöckner, Matthew Osmond, Thomas Licata, Samantha Rojas, David Dyment, Josephine S.C. Chong, Sharyn Lincoln, John H. Postlethwait, Joel Krier, and Hugo J. Bellen
Subjects: 0301 basic medicine, Craniofacial abnormality, Mutation, Missense, 030105 genetics & heredity, Biology, Article, Frameshift mutation, Craniofacial Abnormalities, 03 medical and health sciences, medicine, Animals, Humans, Missense mutation, Craniofacial, Allele, Zebrafish, Genetics (clinical), Loss function, Genetics, medicine.disease, biology.organism_classification, Phenotype, Spine, Growth Differentiation Factors, 030104 developmental biology, Bone Morphogenetic Proteins
Abstract: Purpose Growth differentiation factor 11 (GDF11) is a key signaling protein required for proper development of many organ systems. Only one prior study has associated an inherited GDF11 variant with a dominant human disease in a family with variable craniofacial and vertebral abnormalities. Here, we expand the phenotypic spectrum associated with GDF11 variants and document the nature of the variants. Methods We present a cohort of six probands with de novo and inherited nonsense/frameshift (4/6 patients) and missense (2/6) variants in GDF11. We generated gdf11 mutant zebrafish to model loss of gdf11 phenotypes and used an overexpression screen in Drosophila to test variant functionality. Results Patients with variants in GDF11 presented with craniofacial (5/6) , vertebral (5/6), neurological (6/6), visual (4/6), cardiac (3/6), auditory (3/6) and connective tissue abnormalities (3/6). gdf11 mutant zebrafish show craniofacial abnormalities and body segmentation defects that match some patient phenotypes. Expression of the patients’ variants in the fly showed that one nonsense variant in GDF11 is a severe loss-of-function (LOF) alleles whereas the missense variants in our cohort are partial LOF variants. Conclusion GDF11 is needed for human development, particularly neuronal development, and LOF GDF11 alleles can affect the development of numerous organs and tissues.
Published: 2021
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6. Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain

Author: Felix Marbach, Georgi Stoyanov, Florian Erger, Constantine A. Stratakis, Nikolaos Settas, Edra London, Jill A. Rosenfeld, Erin Torti, Chad Haldeman-Englert, Evgenia Sklirou, Elena Kessler, Sophia Ceulemans, Stanley F. Nelson, Julian A. Martinez-Agosto, Christina G.S. Palmer, Rebecca H. Signer, Maria T. Acosta, Margaret Adam, David R. Adams, Pankaj B. Agrawal, Mercedes E. Alejandro, Justin Alvey, Laura Amendola, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanyam, Dustin Baldridge, Jim Bale, Michael Bamshad, Deborah Barbouth, Pinar Bayrak-Toydemir, Anita Beck, Alan H. Beggs, Edward Behrens, Gill Bejerano, Jimmy Bennett, Beverly Berg-Rood, Jonathan A. Bernstein, Gerard T. Berry, Anna Bican, Stephanie Bivona, Elizabeth Blue, John Bohnsack, Carsten Bonnenmann, Devon Bonner, Lorenzo Botto, Brenna Boyd, Lauren C. Briere, Elly Brokamp, Gabrielle Brown, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, Peter Byers, William E. Byrd, John Carey, Olveen Carrasquillo, Ta Chen Peter Chang, Sirisak Chanprasert, Hsiao-Tuan Chao, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, Matthew Coggins, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Andrew B. Crouse, Michael Cunningham, Precilla D’Souza, Hongzheng Dai, Surendra Dasari, Joie Davis, Jyoti G. Daya, Matthew Deardorff, Esteban C. Dell’Angelica, Shweta U. Dhar, Katrina Dipple, Daniel Doherty, Naghmeh Dorrani, Argenia L. Doss, Emilie D. Douine, David D. Draper, Laura Duncan, Dawn Earl, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Cecilia Esteves, Marni Falk, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Laurie C. Findley, Paul G. Fisher, Brent L. Fogel, Irman Forghani, Laure Fresard, William A. Gahl, Ian Glass, Bernadette Gochuico, Rena A. Godfrey, Katie Golden-Grant, Alica M. Goldman, Madison P. Goldrich, David B. Goldstein, Alana Grajewski, Catherine A. Groden, Irma Gutierrez, Sihoun Hahn, Rizwan Hamid, Neil A. Hanchard, Kelly Hassey, Nichole Hayes, Frances High, Anne Hing, Fuki M. Hisama, Ingrid A. Holm, Jason Hom, Martha Horike-Pyne, Alden Huang, Yong Huang, Laryssa Huryn, Rosario Isasi, Fariha Jamal, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Lefkothea Karaviti, Jennifer Kennedy, Dana Kiley, Isaac S. Kohane, Jennefer N. Kohler, Susan Korrick, Mary Kozuira, Deborah Krakow, Donna M. Krasnewich, Elijah Kravets, Joel B. Krier, Grace L. LaMoure, Seema R. Lalani, Byron Lam, Christina Lam, Brendan C. Lanpher, Ian R. Lanza, Lea Latham, Kimberly LeBlanc, Brendan H. Lee, Hane Lee, Roy Levitt, Richard A. Lewis, Sharyn A. Lincoln, Pengfei Liu, Xue Zhong Liu, Nicola Longo, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, John MacDowall, Calum A. MacRae, Ellen F. Macnamara, Valerie V. Maduro, Marta M. Majcherska, Bryan C. Mak, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Kenneth Maravilla, Thomas C. Markello, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Shruti Marwaha, Jacob McCauley, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Elisabeth McGee, Heather Mefford, J. Lawrence Merritt, Matthew Might, Ghayda Mirzaa, Eva Morava, Paolo M. Moretti, Paolo Moretti, Deborah Mosbrook-Davis, John J. Mulvihill, David R. Murdock, Anna Nagy, Mariko Nakano-Okuno, Avi Nath, John H. Newman, Sarah K. Nicholas, Deborah Nickerson, Shirley Nieves-Rodriguez, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, Stephen Pak, J. Carl Pallais, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, Lorraine Potocki, Bradley Power, Barbara N. Pusey, Aaron Quinlan, Archana N. Raja, Deepak A. Rao, Wendy Raskind, Genecee Renteria, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Natalie Rosenwasser, Francis Rossignol, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Susan L. Samson, Mario Saporta, Judy Schaechter, Timothy Schedl, Kelly Schoch, C. Ron Scott, Daryl A. Scott, Vandana Shashi, Jimann Shin, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Edward C. Smith, Kevin S. Smith, Emily Solem, Lilianna Solnica-Krezel, null Ben Solomon, Rebecca C. Spillmann, Joan M. Stoler, Jennifer A. Sullivan, Kathleen Sullivan, Angela Sun, Shirley Sutton, David A. Sweetser, Virginia Sybert, Holly K. Tabor, Amelia L.M. Tan, Queenie K.-G. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Audrey Thurm, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Brianna M. Tucker, Tiina K. Urv, Adeline Vanderver, Matt Velinder, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Melissa Walker, Stephanie Wallace, Nicole M. Walley, Chris A. Walsh, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Daniel Wegner, Mark Wener, Tara Wenger, Katherine Wesseling Perry, Monte Westerfield, Matthew T. Wheeler, Jordan Whitlock, Lynne A. Wolfe, Jeremy D. Woods, Shinya Yamamoto, John Yang, Muhammad Yousef, Diane B. Zastrow, Wadih Zein, Chunli Zhao, Stephan Zuchner, Marisa V. Andrews, Dorothy K. Grange, Rebecca Willaert, Richard Person, Aida Telegrafi, Aaron Sievers, Magdalena Laugsch, Susanne Theiß, YuZhu Cheng, Olivier Lichtarge, Panagiotis Katsonis, Amber Stocco, and Christian P. Schaaf
Subjects: 0301 basic medicine, Apraxias, Autism Spectrum Disorder, Pain, Biology, Apraxia, Article, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, Pregnancy, Intellectual Disability, Intellectual disability, medicine, Humans, Missense mutation, Global developmental delay, Genetics (clinical), Genetics, medicine.disease, Phenotype, Human genetics, 030104 developmental biology, Neurodevelopmental Disorders, Autism spectrum disorder, Cyclic AMP-Dependent Protein Kinase RIbeta Subunit, Female, 030217 neurology & neurosurgery
Abstract: Purpose We characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA). Methods Variants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development. Results Recent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs. Conclusion Our study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder.
Published: 2021
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7. Commonalities across computational workflows for uncovering explanatory variants in undiagnosed cases

Author: Shilpa Nadimpalli Kobren, Dustin Baldridge, Matt Velinder, Joel B. Krier, Kimberly LeBlanc, Cecilia Esteves, Barbara N. Pusey, Stephan Züchner, Elizabeth Blue, Hane Lee, Alden Huang, Lisa Bastarache, Anna Bican, Joy Cogan, Shruti Marwaha, Anna Alkelai, David R. Murdock, Pengfei Liu, Daniel J. Wegner, Alexander J. Paul, Maria T. Acosta, Margaret Adam, David R. Adams, Pankaj B. Agrawal, Mercedes E. Alejandro, Justin Alvey, Laura Amendola, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanyam, Jim Bale, Michael Bamshad, Deborah Barbouth, Pinar Bayrak-Toydemir, Anita Beck, Alan H. Beggs, Edward Behrens, Gill Bejerano, Jimmy Bennett, Beverly Berg-Rood, Jonathan A. Bernstein, Gerard T. Berry, Stephanie Bivona, John Bohnsack, Carsten Bonnenmann, Devon Bonner, Lorenzo Botto, Brenna Boyd, Lauren C. Briere, Elly Brokamp, Gabrielle Brown, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, Peter Byers, William E. Byrd, John Carey, Olveen Carrasquillo, Ta Chen Peter Chang, Sirisak Chanprasert, Hsiao-Tuan Chao, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, Matthew Coggins, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Andrew B. Crouse, Michael Cunningham, Precilla D’Souza, Hongzheng Dai, Surendra Dasari, Joie Davis, Jyoti G. Daya, Matthew Deardorff, Esteban C. Dell’Angelica, Shweta U. Dhar, Katrina Dipple, Daniel Doherty, Naghmeh Dorrani, Argenia L. Doss, Emilie D. Douine, David D. Draper, Laura Duncan, Dawn Earl, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Marni Falk, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Laurie C. Findley, Paul G. Fisher, Brent L. Fogel, Irman Forghani, Laure Fresard, William A. Gahl, Ian Glass, Bernadette Gochuico, Rena A. Godfrey, Katie Golden-Grant, Alica M. Goldman, Madison P. Goldrich, David B. Goldstein, Alana Grajewski, Catherine A. Groden, Irma Gutierrez, Sihoun Hahn, Rizwan Hamid, Neil A. Hanchard, Kelly Hassey, Nichole Hayes, Frances High, Anne Hing, Fuki M. Hisama, Ingrid A. Holm, Jason Hom, Martha Horike-Pyne, Yong Huang, Laryssa Huryn, Rosario Isasi, Fariha Jamal, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Lefkothea Karaviti, Jennifer Kennedy, Dana Kiley, Isaac S. Kohane, Jennefer N. Kohler, Susan Korrick, Mary Kozuira, Deborah Krakow, Donna M. Krasnewich, Elijah Kravets, Grace L. LaMoure, Seema R. Lalani, Byron Lam, Christina Lam, Brendan C. Lanpher, Ian R. Lanza, Lea Latham, Brendan H. Lee, Roy Levitt, Richard A. Lewis, Sharyn A. Lincoln, Xue Zhong Liu, Nicola Longo, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, John MacDowall, Calum A. MacRae, Ellen F. Macnamara, Valerie V. Maduro, Marta M. Majcherska, Bryan C. Mak, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Kenneth Maravilla, Thomas C. Markello, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Julian A. Martinez-Agosto, Jacob McCauley, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Elisabeth McGee, Heather Mefford, J. Lawrence Merritt, Matthew Might, Ghayda Mirzaa, Eva Morava, Paolo M. Moretti, Paolo Moretti, Deborah Mosbrook-Davis, John J. Mulvihill, Anna Nagy, Mariko Nakano-Okuno, Avi Nath, Stanley F. Nelson, John H. Newman, Sarah K. Nicholas, Deborah Nickerson, Shirley Nieves-Rodriguez, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, Stephen Pak, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, Lorraine Potocki, Bradley Power, Aaron Quinlan, Archana N. Raja, Deepak A. Rao, Wendy Raskind, Genecee Renteria, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Jill A. Rosenfeld, Natalie Rosenwasser, Francis Rossignol, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Susan L. Samson, Mario Saporta, Judy Schaechter, Timothy Schedl, Kelly Schoch, C. Ron Scott, Daryl A. Scott, Vandana Shashi, Jimann Shin, Rebecca H. Signer, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Edward C. Smith, Kevin S. Smith, Emily Solem, Lilianna Solnica-Krezel, null Ben Solomon, Rebecca C. Spillmann, Joan M. Stoler, Jennifer A. Sullivan, Kathleen Sullivan, Angela Sun, Shirley Sutton, David A. Sweetser, Virginia Sybert, Holly K. Tabor, Amelia L.M. Tan, Queenie K.-G. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Audrey Thurm, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Brianna M. Tucker, Tiina K. Urv, Adeline Vanderver, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Melissa Walker, Stephanie Wallace, Nicole M. Walley, Chris A. Walsh, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Daniel Wegner, Mark Wener, Tara Wenger, Katherine Wesseling Perry, Monte Westerfield, Matthew T. Wheeler, Jordan Whitlock, Lynne A. Wolfe, Jeremy D. Woods, Shinya Yamamoto, John Yang, Muhammad Yousef, Diane B. Zastrow, Wadih Zein, Chunli Zhao, Stephan Zuchner, and Shamil R. Sunyaev
Subjects: Prioritization, Genome, medicine.diagnostic_test, Genomic sequencing, Multimodal data, Computational Biology, Structural variant, Genomics, Undiagnosed Diseases, Data science, Shruti, Article, Workflow, Biomedical data, medicine, Humans, Genetic Testing, Psychology, Software, Genetics (clinical), Genetic testing
Abstract: Author(s): Kobren, Shilpa Nadimpalli; Baldridge, Dustin; Velinder, Matt; Krier, Joel B; LeBlanc, Kimberly; Esteves, Cecilia; Pusey, Barbara N; Zuchner, Stephan; Blue, Elizabeth; Lee, Hane; Huang, Alden; Bastarache, Lisa; Bican, Anna; Cogan, Joy; Marwaha, Shruti; Alkelai, Anna; Murdock, David R; Liu, Pengfei; Wegner, Daniel J; Paul, Alexander J; Undiagnosed Diseases Network; Sunyaev, Shamil R; Kohane, Isaac S | Abstract: PurposeGenomic sequencing has become an increasingly powerful and relevant tool to be leveraged for the discovery of genetic aberrations underlying rare, Mendelian conditions. Although the computational tools incorporated into diagnostic workflows for this task are continually evolving and improving, we nevertheless sought to investigate commonalities across sequencing processing workflows to reveal consensus and standard practice tools and highlight exploratory analyses where technical and theoretical method improvements would be most impactful.MethodsWe collected details regarding the computational approaches used by a genetic testing laboratory and 11 clinical research sites in the United States participating in the Undiagnosed Diseases Network via meetings with bioinformaticians, online survey forms, and analyses of internal protocols.ResultsWe found that tools for processing genomic sequencing data can be grouped into four distinct categories. Whereas well-established practices exist for initial variant calling and quality control steps, there is substantial divergence across sites in later stages for variant prioritization and multimodal data integration, demonstrating a diversity of approaches for solving the most mysterious undiagnosed cases.ConclusionThe largest differences across diagnostic workflows suggest that advances in structural variant detection, noncoding variant interpretation, and integration of additional biomedical data may be especially promising for solving chronically undiagnosed cases.
Published: 2021
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8. One is the loneliest number: genotypic matchmaking using the electronic health record

Author: Nichole Hayes, Euan A. Ashley, Laura A. Mamounas, Allyn McConkie-Rosell, Shirley Sutton, John J.E. Mulvihill, John H. Postlethwait, Richard L. Maas, Jennefer N. Kohler, Dana Kiley, Joel B. Krier, Pankaj B. Agrawal, Xue Zhong Liu, Josh F. Peterson, Jill A. Rosenfeld, Thomas May, Jennifer E. Kyle, David A. Sweetser, Neil H. Parker, Jeanette C. Papp, Manish J. Butte, Calum A. MacRae, Rong Mao, Vandana Shashi, Christopher A. Walsh, Alica M. Goldman, Gabor T. Marth, Sharyn A. Lincoln, David Goldstein, Colleen E. McCormack, Byron L. Lam, Elly Brokamp, Lynette Rives, Lee-kai Wang, Lorraine Potocki, Mary Koziura, Matthew T. Wheeler, Teri A. Manolio, Camille L. Birch, Moretti Paolo, Willa Thorson, Fariha Jamal, Cynthia M. Cooper, Yong Huang, Matt Velinder, Catherine H. Sillari, Archana Raja, Andrea L. Gropman, J. Carl Pallais, Amy K. Robertson, Dave Viskochil, William J. Craigen, Thomas C. Markello, Devin Oglesbee, Olveen Carrasquillo, Precilla D'Souza, Lorenzo D. Botto, Hugo J. Bellen, Susan L. Samson, Jim Bale, Lisa Shakachite, Catherine Groden, Kathleen Shields, Jimann Shin, Carlos Ferreira, Lynne A. Wolfe, Melissa A. Haendel, Brent L. Fogel, Joan M. Stoler, Rebecca C. Spillmann, Roy C. Levitt, Gary D. Clark, Daniel J. Wegner, Gill Bejerano, Deborah Krakow, Ashok Balasubramanyam, J. Scott Newberry, Heidi Cope, Jijun Wan, Sandra K. Loo, Laura Duncan, Elizabeth A. Worthey, Leigh Anne Tang, Mercedes E. Alejandro, Matthew Might, Cecelia P. Tamburro, Patrick Allard, Joseph Loscalzo, Bret L. Bostwick, Lisa Emrick, Sarah K. Nicholas, David R. Murdock, Jeremy D. Woods, Alana L. Grajewski, Eva H. Baker, Lindsay C. Burrage, Stephen Pak, Camilo Toro, Ashley Andrews, James P. Orengo, Shawn Levy, Lance H. Rodan, Kelly Schoch, Jyoti G. Dayal, Thomas O. Metz, Kathy Sisco, Stephanie Bivona, Paolo Moretti, Braden E. Boone, Mahshid S. Azamian, Nicole M. Walley, Esteban C. Dell'Angelica, Rosario Isasi, Jacinda B. Sampson, F. Sessions Cole, Guoyun Yu, Rena A. Godfrey, John F. Bohnsack, Elizabeth A. Burke, John H. Newman, Alden Y. Huang, Patricia A. Ward, Barbara N. Pusey, Maria T. Acosta, Alan H. Beggs, Melissa A. Walker, Shweta U. Dhar, Edwin K. Silverman, Stephan Züchner, Ian R. Lanza, Bobbie-Jo M. Webb-Robertson, Anastasia L. Wise, Angela Jones, Nicholas Stong, Irman Forghani, Matthew H. Brush, Michael F. Wangler, Jonathan A. Bernstein, Aaron R. Quinlan, David D. Draper, Pinar Bayrak-Toydemir, Diane B. Zastrow, Daniel C. Dorset, Anna Bican, David J. Eckstein, Janet S. Sinsheimer, Isaac S. Kohane, Hsiao-Tuan Chao, May Christine V. Malicdan, C. Christopher Lau, Mariska Davids, Eva Morava-Kozicz, Beth A. Martin, Daryl A. Scott, Prashant Sharma, Elizabeth L. Fieg, Lauren C. Briere, Shinya Yamamoto, Devon Bonner, Ralph L. Sacco, Amanda J. Yoon, John Yang, Katrina M. Waters, Carlos A. Bacino, Pengfei Liu, Brendan Lee, Lisa Bastarache, Emily G. Kelley, Tiphanie P. Vogel, Jason Hom, Marta M. Majcherska, Robb Rowley, Liliana Fernandez, Carsten Bonnenmann, Stanley F. Nelson, Colleen E. Wahl, Guney Bademci, Justin Alvey, Naghmeh Dorrani, Hane Lee, Lefkothea P. Karaviti, Monte Westerfield, John A. Phillips, Laurel A. Cobban, Chunli Zhao, Nicola Longo, Donna M. Krasnewich, Ta Chen Peter Chang, Tiina K. Urv, Christine M. Eng, Chloe M. Reuter, Ingrid A. Holm, Jozef Lazar, Emilie D. Douine, Susan A. Korrick, Alexa T. McCray, Richard A. Lewis, Ronit Marom, Kimberly LeBlanc, Cynthia J. Tifft, Cecilia Esteves, David R. Adams, Donna M. Brown, Avi Nath, Rebecca Signer, Martin G. Martin, Julian A. Martinez-Agosto, Jacob L. McCauley, Alyssa A. Tran, Jennifer A. Sullivan, William A. Gahl, Brendan C. Lanpher, Marie Morimoto, Donna Novacic, Jean-Philippe F. Gourdine, Paul G. Fisher, Fred F. Telischi, Shruti Marwaha, Heather A. Colley, Queenie K.-G. Tan, Seema R. Lalani, Deborah Barbouth, Jennifer E. Posey, Yong-hui Jiang, Jennifer Wambach, Mario Saporta, Jean M. Johnston, Dustin Baldridge, Timothy Schedl, Pace Laura, Ellen Macnamara, Joy D. Cogan, Kevin S. Smith, David M. Koeller, Genecee Renteria, Maura R.Z. Ruzhnikov, Christina G.S. Palmer, Valerie Maduro, Frances A. High, Gerard T. Berry, Holly K. Tabor, Terra R. Coakley, Surendra Dasari, Neil A. Hanchard, David P. Bick, Laure Fresard, Rizwan Hamid, Lilianna Solnica-Krezel, Gabriel F. Batzli, Judy Schaechter, John C. Carey, Tyra Estwick, and Mustafa Tekin
Subjects: World Wide Web, Electronic health record, Biology, Genetics (clinical)
Published: 2021
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9. Clinical Utility of Pharmacogenomic Data Collected by a Health-System Biobank to Predict and Prevent Adverse Drug Events

Author: Dariel Delos Reyes, Mary G. Amato, Diane L. Seger, Joel B. Krier, Maryam Alobaidly, Sarah Hasan, Sonam N. Shah, Roseann S. Gammal, and David W. Bates
Subjects: Pharmacology, medicine.medical_specialty, Thiopurine methyltransferase, biology, business.industry, Warfarin, Toxicology, 030226 pharmacology & pharmacy, Rash, 03 medical and health sciences, Patient safety, 0302 clinical medicine, Internal medicine, Pharmacogenomics, medicine, biology.protein, Pharmacology (medical), 030212 general & internal medicine, VKORC1, medicine.symptom, business, Oxcarbazepine, Pharmacogenetics, medicine.drug
Abstract: Medication-related harm represents a significant issue for patient safety and quality of care. One strategy to avoid preventable adverse drug events is to utilize patient-specific factors such as pharmacogenomics (PGx) to individualize therapy. We measured the number of patients enrolled in a health-system biobank with actionable PGx results who received relevant medications and assessed the incidence of adverse drug events (ADEs) that might have been prevented had the PGx results been used to inform prescribing. Patients with actionable PGx results in the following four genes with Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines were identified: HLA-A*31:01, HLA-B*15:02, TPMT, and VKORC1. The patients who received interacting medications (carbamazepine, oxcarbazepine, thiopurines, or warfarin) were identified, and electronic health records were reviewed to determine the incidence of potentially preventable ADEs. Of 36,424 patients with PGx results, 2327 (6.4%) were HLA-A*31:01 positive; 3543 (9.7%) were HLA-B*15:02 positive; 2893 (7.9%) were TPMT intermediate metabolizers; and 4249 (11.7%) were homozygous for the VKORC1 c.1639 G>A variant. Among patients positive for one of the HLA variants who received carbamazepine or oxcarbazepine (n = 92), four (4.3%) experienced a rash that warranted drug discontinuation. Among the TPMT intermediate metabolizers who received a thiopurine (n = 56), 11 (19.6%) experienced severe myelosuppression that warranted drug discontinuation. Among patients homozygous for the VKORC1 c.1639 G>A variant who received warfarin (n = 379), 85 (22.4%) experienced active bleeding and/or international normalized ratio (INR) > 5 that warranted drug discontinuation or dose reduction. Patients with actionable PGx results from a health-system biobank who received relevant medications experienced predictable ADEs. These ADEs may have been prevented if the patients’ PGx results were available in the electronic health record with clinical decision support prior to prescribing.
Published: 2021
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10. Clinical sites of the Undiagnosed Diseases Network: unique contributions to genomic medicine and science

Author: Kelly Schoch, Cecilia Esteves, Anna Bican, Rebecca Spillmann, Heidi Cope, Allyn McConkie-Rosell, Nicole Walley, Liliana Fernandez, Jennefer N. Kohler, Devon Bonner, Chloe Reuter, Nicholas Stong, John J. Mulvihill, Donna Novacic, Lynne Wolfe, Ayat Abdelbaki, Camilo Toro, Cyndi Tifft, May Malicdan, William Gahl, Pengfei Liu, John Newman, David B. Goldstein, Jason Hom, Jacinda Sampson, Matthew T. Wheeler, Mercedes E. Alejandro, Mahshid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Lindsay C. Burrage, Hsiao-Tuan Chao, Gary D. Clark, William J. Craigen, Hongzheng Dai, Shweta U. Dhar, Lisa T. Emrick, Alica M. Goldman, Neil A. Hanchard, Fariha Jamal, Lefkothea Karaviti, Seema R. Lalani, Brendan H. Lee, Richard A. Lewis, Ronit Marom, Paolo M. Moretti, David R. Murdock, Sarah K. Nicholas, James P. Orengo, Jennifer E. Posey, Lorraine Potocki, Jill A. Rosenfeld, Susan L. Samson, Daryl A. Scott, Alyssa A. Tran, Tiphanie P. Vogel, Michael F. Wangler, Shinya Yamamoto, Christine M. Eng, Patricia A. Ward, Edward Behrens, Matthew Deardorff, Marni Falk, Kelly Hassey, Kathleen Sullivan, Adeline Vanderver, Vandana Shashi, Edward C. Smith, Rebecca C. Spillmann, Jennifer A. Sullivan, Queenie K.-G. Tan, Nicole M. Walley, Pankaj B. Agrawal, Alan H. Beggs, Gerard T. Berry, Lauren C. Briere, Laurel A. Cobban, Matthew Coggins, Cynthia M. Cooper, Elizabeth L. Fieg, Frances High, Ingrid A. Holm, Susan Korrick, Joel B. Krier, Sharyn A. Lincoln, Joseph Loscalzo, Richard L. Maas, Calum A. MacRae, J.Carl Pallais, Deepak A. Rao, Lance H. Rodan, Edwin K. Silverman, Joan M. Stoler, David A. Sweetser, Melissa Walker, Chris A. Walsh, Emily G. Kelley, Isaac S. Kohane, Kimberly LeBlanc, Alexa T. McCray, Anna Nagy, Surendra Dasari, Brendan C. Lanpher, Ian R. Lanza, Eva Morava, Devin Oglesbee, Guney Bademci, Deborah Barbouth, Stephanie Bivona, Olveen Carrasquillo, Ta Chen Peter Chang, Irman Forghani, Alana Grajewski, Rosario Isasi, Byron Lam, Roy Levitt, Xue Zhong Liu, Jacob McCauley, Ralph Sacco, Mario Saporta, Judy Schaechter, Mustafa Tekin, Fred Telischi, Willa Thorson, Stephan Zuchner, Heather A. Colley, Jyoti G. Dayal, David J. Eckstein, Laurie C. Findley, Donna M. Krasnewich, Laura A. Mamounas, Teri A. Manolio, Grace L. LaMoure, Madison P. Goldrich, Tiina K. Urv, Argenia L. Doss, Maria T. Acosta, Carsten Bonnenmann, Precilla D’Souza, David D. Draper, Carlos Ferreira, Rena A. Godfrey, Catherine A. Groden, Ellen F. Macnamara, Valerie V. Maduro, Thomas C. Markello, Avi Nath, Barbara N. Pusey, Colleen E. Wahl, Eva Baker, Elizabeth A. Burke, David R. Adams, William A. Gahl, May Christine V. Malicdan, Cynthia J. Tifft, Lynne A. Wolfe, John Yang, Bradley Power, Bernadette Gochuico, Laryssa Huryn, Lea Latham, Joie Davis, Deborah Mosbrook-Davis, Francis Rossignol, Ben Solomon, John MacDowall, Audrey Thurm, Wadih Zein, Muhammad Yousef, Margaret Adam, Laura Amendola, Michael Bamshad, Anita Beck, Jimmy Bennett, Beverly Berg-Rood, Elizabeth Blue, Brenna Boyd, Peter Byers, Sirisak Chanprasert, Michael Cunningham, Katrina Dipple, Daniel Doherty, Dawn Earl, Ian Glass, Katie Golden-Grant, Sihoun Hahn, Anne Hing, Fuki M. Hisama, Martha Horike-Pyne, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Christina Lam, Kenneth Maravilla, Heather Mefford, J.Lawrence Merritt, Ghayda Mirzaa, Deborah Nickerson, Wendy Raskind, Natalie Rosenwasser, C.Ron Scott, Angela Sun, Virginia Sybert, Stephanie Wallace, Mark Wener, Tara Wenger, Euan A. Ashley, Gill Bejerano, Jonathan A. Bernstein, Terra R. Coakley, Paul G. Fisher, Laure Fresard, Yong Huang, Elijah Kravets, Marta M. Majcherska, Beth A. Martin, Shruti Marwaha, Colleen E. McCormack, Archana N. Raja, Chloe M. Reuter, Maura Ruzhnikov, Jacinda B. Sampson, Kevin S. Smith, Shirley Sutton, Holly K. Tabor, Brianna M. Tucker, Diane B. Zastrow, Chunli Zhao, William E. Byrd, Andrew B. Crouse, Matthew Might, Mariko Nakano-Okuno, Jordan Whitlock, Gabrielle Brown, Manish J. Butte, Esteban C. Dell’Angelica, Naghmeh Dorrani, Emilie D. Douine, Brent L. Fogel, Irma Gutierrez, Alden Huang, Deborah Krakow, Hane Lee, Sandra K. Loo, Bryan C. Mak, Martin G. Martin, Julian A. Martínez-Agosto, Elisabeth McGee, Stanley F. Nelson, Shirley Nieves-Rodriguez, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, Genecee Renteria, Rebecca H. Signer, Janet S. Sinsheimer, Jijun Wan, Lee-kai Wang, Katherine Wesseling Perry, Jeremy D. Woods, Justin Alvey, Ashley Andrews, Jim Bale, John Bohnsack, Lorenzo Botto, John Carey, Laura Pace, Nicola Longo, Gabor Marth, Paolo Moretti, Aaron Quinlan, Matt Velinder, Dave Viskochil, Pinar Bayrak-Toydemir, Rong Mao, Monte Westerfield, Elly Brokamp, Laura Duncan, Rizwan Hamid, Jennifer Kennedy, Mary Kozuira, John H. Newman, John A. Phillips, Lynette Rives, Amy K. Robertson, Emily Solem, Joy D. Cogan, F. Sessions Cole, Nichole Hayes, Dana Kiley, Kathy Sisco, Jennifer Wambach, Daniel Wegner, Dustin Baldridge, Stephen Pak, Timothy Schedl, Jimann Shin, Lilianna Solnica-Krezel, and Joy Cogan
Subjects: Exome sequencing, 0301 basic medicine, Computational biology, 030105 genetics & heredity, Genome sequencing, Article, DNA sequencing, Retrospective data, 03 medical and health sciences, Rare Diseases, Animals, Humans, Genomic medicine, Medicine, Medical diagnosis, Exome, Genetics (clinical), Retrospective Studies, Disease gene, business.industry, Genomics, 030104 developmental biology, Phenotyping, New disease, Undiagnosed diseases, Ultra-rare diseases, business
Abstract: Purpose The NIH Undiagnosed Diseases Network (UDN) evaluates participants with disorders that have defied diagnosis, applying personalized clinical and genomic evaluations and innovative research. The clinical sites of the UDN are essential to advancing the UDN mission; this study assesses their contributions relative to standard clinical practices. Methods We analyzed retrospective data from four UDN clinical sites, from July 2015 to September 2019, for diagnoses, new disease gene discoveries and the underlying investigative methods. Results Of 791 evaluated individuals, 231 received 240 diagnoses and 17 new disease-gene associations were recognized. Straightforward diagnoses on UDN exome and genome sequencing occurred in 35% (84/240). We considered these tractable in standard clinical practice, although genome sequencing is not yet widely available clinically. The majority (156/240, 65%) required additional UDN-driven investigations, including 90 diagnoses that occurred after prior nondiagnostic exome sequencing and 45 diagnoses (19%) that were nongenetic. The UDN-driven investigations included complementary/supplementary phenotyping, innovative analyses of genomic variants, and collaborative science for functional assays and animal modeling. Conclusion Investigations driven by the clinical sites identified diagnostic and research paradigms that surpass standard diagnostic processes. The new diagnoses, disease gene discoveries, and delineation of novel disorders represent a model for genomic medicine and science.
Published: 2021
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11. Airmen and health-care providers’ attitudes toward the use of genomic sequencing in the US Air Force: findings from the MilSeq Project

Author: Stacey Pereira, Rebecca L. Hsu, Rubaiya Islam, Jill Oliver Robinson, Rishab Ramapriyan, Emily Sirotich, Megan D. Maxwell, Mary Majumder, Carrie L. Blout, Kurt D. Christensen, Maxwell Mehlman, Efthimios Parasidis, Cubby L. Gardner, Jacqueline M. Killian, Mauricio De Castro, Robert C. Green, Rebecca Hsu, Jacqueline Killian, Joel B. Krier, William Lane, Matthew S. Lebo, Amy L. McGuire, Maxwell J. Mehlman, Jill O. Robinson, Jason L. Vassy, Jameson Voss, and Bethany Zettler
Subjects: 0301 basic medicine, medicine.medical_specialty, Active duty, Attitude of Health Personnel, media_common.quotation_subject, education, 030105 genetics & heredity, Health benefits, Article, 03 medical and health sciences, Healthy Populations, Military, Exome Sequencing, Health care, medicine, Humans, Duty, Genetics (clinical), Exome sequencing, media_common, business.industry, Genomic sequencing, Genomics, Service member, United States, Military Personnel, 030104 developmental biology, ELSI, Software deployment, Family medicine, business
Abstract: PURPOSE The use of genomic sequencing (GS) in military settings poses unique considerations, including the potential for GS to impact service members' careers. The MilSeq Project investigated the use of GS in clinical care of active duty Airmen in the United States Air Force (USAF). METHODS We assessed perceived risks, benefits, and attitudes toward use of GS in the USAF among patient participants (n = 93) and health-care provider participants (HCPs) (n = 12) prior to receiving or disclosing GS results. RESULTS Participants agreed that there are health benefits associated with GS (90% patients, 75% HCPs), though more HCPs (75%) than patients (40%) agreed that there are risks (p = 0.048). The majority of both groups (67% HCPs, 77% patients) agreed that they trust the USAF with genetic information, but far fewer agreed that genetic information should be used to make decisions about deployment (5% patients, 17% HCPs) or duty assignments (3% patients, 17% HCPs). Despite their hesitancy, patients were supportive of the USAF testing for nondisease traits that could impact their duty performance. Eighty-seven percent of patients did not think their GS results would influence their career. CONCLUSION Results suggest favorable attitudes toward the use of GS in the USAF when not used for deployment or assignment decisions.
Published: 2020
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12. A retrospective study of adult patients with noncirrhotic hyperammonemia

Author: David A. Sweetser, Joshua Baker, Roy W A Peake, Alexander P. Lin, Kris M. Mogensen, Joel B. Krier, Andrew B. Stergachis, Inderneel Sahai, Gerard T. Berry, Charbel C. Khoury, and Ebrahim Barkoudah
Subjects: Adult, Male, medicine.medical_specialty, medicine.drug_class, medicine.medical_treatment, Antibiotics, Gastroenterology, Young Adult, Ammonia, Seizures, Internal medicine, Genetics, Humans, Hyperammonemia, Urea, Medicine, Renal replacement therapy, Age of Onset, Risk factor, Urea Cycle Disorders, Inborn, Genetics (clinical), Aged, Retrospective Studies, business.industry, Retrospective cohort study, Middle Aged, medicine.disease, Survival Analysis, Urea cycle, Cohort, Etiology, Female, business
Abstract: Adult-onset noncirrhotic hyperammonemia (NCH) is poorly understood and has a high morbidity and mortality. To elucidate the etiology and management of NCH, we performed a retrospective analysis of 23 adults (median age 51) with NCH treated between 2014 and 2020 at two academic medical centers. Hyperammonemia was diagnosed in all cases during the evaluation of altered mental status, with 22% presenting with seizures. Peak ammonia levels were >200 μmol/L in 70% of cases. Defects in ammonia metabolism were assessed using urea cycle biochemical testing, germline genetic testing, and testing for urease-producing infectious agents. Ammonia metabolism defects in these cases appear attributable to four major sources: (a) infection with urease-producing organism (n = 5); (b) previously undiagnosed inborn errors of metabolism (IEMs) (n = 4); (c) clinical exposures causing acquired urea cycle dysfunction (n = 6); and (d) unexplained acquired urea cycle dysfunction (uaUCD) (n = 8), as evidenced by biochemical signatures of urea cycle dysfunction without a genetic or clinical exposure. Severe protein malnutrition appeared to be a reversible risk factor for uaUCD. Overall, 13% of our cohort died prior to resolution of hyperammonemia, 26% died after hyperammonemia resolution, 57% survived after having reversible neurological changes, and 4% survived with irreversible neurological changes. Renal replacement therapy for ammonia clearance was often utilized for patients with an ammonia level above 250 μmol/L and patients were frequently empirically treated with antibiotics targeting urea-splitting organisms. Our study demonstrates that acquired urea cycle dysfunction, IEMs and urease-producing infections are major sources of adult-onset NCH and highlights successful management strategies for adult-onset NCH.
Published: 2020
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13. Biallelic MADD variants cause a phenotypic spectrum ranging from developmental delay to a multisystem disorder

Author: Katherine Wesseling Perry, Archana Raja, Emilie D. Douine, Xue Zhong Liu, Brent L. Fogel, Stan F. Nelson, Kenneth R. Maravilla, Eva H. Baker, Dave Viskochil, Kerstin Kutsche, Jordan H. Whitlock, Susan L. Samson, Christine M. Eng, Chloe M. Reuter, Suman Jayadev, David R. Adams, Sihoun Hahn, Rebecca C. Spillmann, Margaret Adam, Heather C Mefford, John C. Carey, Ehsan Ghayoor Karimiani, Donna M. Krasnewich, David Goldstein, Susan A. Korrick, Guoyun Yu, Tomas Honzik, Henry Houlden, Andrea L. Gropman, David A. Sweetser, Anna Bican, Carlos A. Bacino, Liliana Fernandez, Gabrielle Brown, Justin Alvey, Hane Lee, Emanuele G. Coci, Hongzheng Dai, Mario Saporta, Laurel A. Cobban, John F. Bohnsack, Stephanie Fox, Heidi Cope, Tyra Estwick, Lorraine Potocki, Nichole Hayes, Elizabeth A. Burke, Rizwan Hamid, Aaron R. Quinlan, Kelly Hassey, Lindsay C. Burrage, Jane Juusola, Adeline Vanderver, Malik Alawi, Teri A. Manolio, Maja Hempel, Esther M. Maier, Jennifer Kennedy, Bruce D. Gelb, Martha Horike-Pyne, Amarilis Sanchez-Valle, Euan A. Ashley, Surendra Dasari, Elizabeth Blue, Eva Morava-Kozicz, Natalie Rosenwasser, Alan H. Beggs, Bryn D. Webb, Isaac S. Kohane, Kelly Schoch, C. Christopher Lau, Nicole M. Walley, Laura M. Amendola, Genecee Renteria, Catherine H. Sillari, Jonathan A. Bernstein, Pinar Bayrak-Toydemir, R. Frank Kooy, Mariko Nakano-Okuno, Manuela Siekmeyer, Marije E. C. Meuwissen, Stephanie Bivona, Mark Wener, Precilla D'Souza, Olveen Carrasquillo, Paolo Moretti, Diane B. Zastrow, David J. Eckstein, Janet S. Sinsheimer, Kathy Sisco, Holly K. Tabor, William E. Byrd, Esteban C. Dell'Angelica, Rosario Isasi, Jacinda B. Sampson, Carsten Bonnenmann, J. Lawrence Merritt, Joan M. Stoler, Richard L. Maas, Paul G. Fisher, Jeanette C. Papp, Kimberly LeBlanc, Lilianna Solnica-Krezel, Mustafa Tekin, Mathias Woidy, Andrew B. Crouse, Katleen Ballon, David Murphy, Matthew T. Wheeler, Joseph Loscalzo, Ellen Macnamara, Cecelia P. Tamburro, Lefkothea P. Karaviti, Chunli Zhao, Ingrid A. Holm, Pankaj B. Agrawal, Alana L. Grajewski, Stephen C. Pak, Ian R. Lanza, Mohammad Doosti, Jennifer E. Posey, Rebecca Signer, Katie Golden-Grant, Christopher A. Walsh, Alica M. Goldman, Jyoti G. Dayal, Queenie K.-G. Tan, Martin G. Martin, Joy D. Cogan, Kevin S. Smith, Deborah A. Nickerson, Elisabeth McGee, Laure Fresard, Rena A. Godfrey, Sharyn A. Lincoln, Kathleen E. Sullivan, Mariska Davids, Melissa A. Walker, Prashant Sharma, Maria Iascone, Neil H. Parker, Carlos Ferreira, Elizabeth L. Fieg, Edwin K. Silverman, Michael L. Cunningham, Pengfei Liu, Edward M. Behrens, Sandra K. Loo, David R. Murdock, F. Sessions Cole, C. Ron Scott, Dan Doherty, Elly Brokamp, John H. Newman, Alden Y. Huang, Laura A. Pace, Avi Nath, Jimmy Bennet, Georg Christoph Korenke, Alyssa A. Tran, Gabriel F. Batzli, Jimann Shin, Matthew A. Deardorff, Naghmeh Dorrani, Diane Beysen, Irma Gutierrez, Stanislav Kmoch, Majid Alfadhel, Fred F. Telischi, Jennifer A. Sullivan, William A. Gahl, María Palomares-Bralo, Gerard T. Berry, Colleen E. McCormack, Lance H. Rodan, Reza Maroofian, Lenka Nosková, Judy Schaechter, Lynne A. Wolfe, Deborah Krakow, Daryl A. Scott, Tara Wenger, Jason Hom, Dustin Baldridge, Lynette Rives, Lee-kai Wang, Dawn L. Earl, Ralph L. Sacco, Fernando Santos-Simarro, Irman Forghani, Fuki M. Hisama, Terra R. Coakley, Hsiao-Tuan Chao, Jeremy D. Woods, Emily G. Kelley, Jean M. Johnston, Neil A. Hanchard, Amy K. Robertson, Matt Velinder, Byron L. Lam, Wendy H. Raskind, William J. Craigen, Stephan Züchner, Guney Bademci, Julian A. Martinez-Agosto, Mary Koziura, Beth A. Martin, Angela Sun, John A. Phillips, Seema R. Lalani, Daniela Buhas, Emily Solem, Gary D. Clark, Gill Bejerano, Ingo Kurth, Deborah Barbouth, Tiina K. Urv, Fanny Kortüm, Ian A. Glass, Ta Chen Peter Chang, Yong Huang, Roy C. Levitt, Paola Francesca Ajmone, Brenna Boyd, René Santer, Tim Schedl, David D. Draper, Ghayda M. Mirzaa, Aroa Rodríguez Alonso, Stephanie Wallace, Colleen E. Wahl, Calum A. MacRae, Gail P. Jarvik, Jacob L. McCauley, Jill A. Rosenfeld, Ronit Marom, Monte Westerfield, Matthew Might, Poupak Javaher-Haghighi, Brendan C. Lanpher, Devon Bonner, Cynthia J. Tifft, Cecilia Esteves, May Christine V. Malicdan, Jim Bale, Fariha Jamal, Nicola Longo, Christina G.S. Palmer, Lisa Emrick, Peter H. Byers, Vandana Shashi, Tiphanie P. Vogel, Richard A. Lewis, Jijun Wan, Barbara N. Pusey, Maria T. Acosta, Jaak Jaeken, Allyn McConkie-Rosell, Shirley Sutton, John Yang, Lorenzo D. Botto, Hilde Peeters, Rong Mao, Catherine Groden, Brendan Lee, Marta M. Majcherska, Rami Abou Jamra, Ashok Balasubramanyam, Joel B. Krier, Majid Mojarrad, Maria Francesca Bedeschi, Mahshid S. Azamian, Shruti Marwaha, Heather A. Colley, Katrina M. Dipple, Sirisak Chanprasert, Alexa T. McCray, Nicholas Stong, Anne V. Hing, Laura A. Mamounas, Edward C. Smith, Lauren C. Briere, John J.E. Mulvihill, Virginia P. Sybert, Maura R.Z. Ruzhnikov, Valerie Maduro, Frances A. High, Manish J. Butte, Willa Thorson, J. Carl Pallais, Jennefer N. Kohler, Dana Kiley, Raphael Bernier, Christina Lam, Michael J. Bamshad, Patricia A. Ward, Michael F. Wangler, Anita E. Beck, Shinya Yamamoto, Beverly Berg-Rood, Robb Rowley, Gabor T. Marth, Cynthia M. Cooper, Jeffrey G. Jarvik, Thomas C. Markello, Saskia Biskup, Devin Oglesbee, Laura Duncan, Elijah Kravets, Daniel J. Wegner, Mercedes E. Alejandro, Sarah K. Nicholas, Jennifer A. Wambach, Marni J. Falk, Brianna M. Tucker, Marie Morimoto, Corina Heller, Donna Novacic, Camilo Toro, Ashley Andrews, James P. Orengo, Shweta U. Dhar, and Pauline E. Schneeberger
Subjects: 0301 basic medicine, MAPK/ERK pathway, Death Domain Receptor Signaling Adaptor Proteins, Programmed cell death, Developmental Disabilities, Biology, 03 medical and health sciences, 0302 clinical medicine, Epidermal growth factor, medicine, Guanine Nucleotide Exchange Factors, Humans, Death domain, Kinase, Original Articles, Phenotype, Hypotonia, Protein Transport, 030104 developmental biology, Mutation, Cancer research, Human medicine, Neurology (clinical), Nervous System Diseases, Signal transduction, medicine.symptom, 030217 neurology & neurosurgery, Signal Transduction
Abstract: In pleiotropic diseases, multiple organ systems are affected causing a variety of clinical manifestations. Here, we report a pleiotropic disorder with a unique constellation of neurological, endocrine, exocrine, and haematological findings that is caused by biallelic MADD variants. MADD, the mitogen-activated protein kinase (MAPK) activating death domain protein, regulates various cellular functions, such as vesicle trafficking, activity of the Rab3 and Rab27 small GTPases, tumour necrosis factor-α (TNF-α)-induced signalling and prevention of cell death. Through national collaboration and GeneMatcher, we collected 23 patients with 21 different pathogenic MADD variants identified by next-generation sequencing. We clinically evaluated the series of patients and categorized the phenotypes in two groups. Group 1 consists of 14 patients with severe developmental delay, endo- and exocrine dysfunction, impairment of the sensory and autonomic nervous system, and haematological anomalies. The clinical course during the first years of life can be potentially fatal. The nine patients in Group 2 have a predominant neurological phenotype comprising mild-to-severe developmental delay, hypotonia, speech impairment, and seizures. Analysis of mRNA revealed multiple aberrant MADD transcripts in two patient-derived fibroblast cell lines. Relative quantification of MADD mRNA and protein in fibroblasts of five affected individuals showed a drastic reduction or loss of MADD. We conducted functional tests to determine the impact of the variants on different pathways. Treatment of patient-derived fibroblasts with TNF-α resulted in reduced phosphorylation of the extracellular signal-regulated kinases 1 and 2, enhanced activation of the pro-apoptotic enzymes caspase-3 and -7 and increased apoptosis compared to control cells. We analysed internalization of epidermal growth factor in patient cells and identified a defect in endocytosis of epidermal growth factor. We conclude that MADD deficiency underlies multiple cellular defects that can be attributed to alterations of TNF-α-dependent signalling pathways and defects in vesicular trafficking. Our data highlight the multifaceted role of MADD as a signalling molecule in different organs and reveal its physiological role in regulating the function of the sensory and autonomic nervous system and endo- and exocrine glands.
Published: 2020
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14. De Novo Variants in the ATPase Module of MORC2 Cause a Neurodevelopmental Disorder with Growth Retardation and Variable Craniofacial Dysmorphism

Author: Rosanna Weksberg, Courtney Kiss, Marta Szybowska, Nina Ekhilevitch, Irina Anselm, David A. Sweetser, Michael Marble, Kristin Lindstrom, Cara Forster, Haley Streff, Renata C. Gallagher, John Pappas, Jessica Nance, Patricia G Wheeler, Melissa A. Walker, Grace Yoon, Carl E. Stafstrom, Weiyi Mu, Mary Kay Koenig, Wei Wang, Jane Juusola, Lauren C. Briere, Eric Muller, Julie S. Cohen, E. Hallie Andrew, Frances A. High, Cheryl Cytrynbaum, Jamie L. Fraser, Joel B. Krier, Hannah Meddaugh, Ali Fatemi, Robert E. Kingston, Kristin W. Barañano, Bridget Ostrem, Maria J. Guillen Sacoto, Ellen Moran, Marvin R. Natowicz, Karin Weiss, Erin Torti, Iva A. Tchasovnikarova, William J. Craigen, Cara Inglese, Andrea Guerin, Matthew J. Elrick, Devon Haynes, Chantal F. Morel, and Adam L. Numis
Subjects: Adult, Male, 0301 basic medicine, Heterozygote, Microcephaly, Adolescent, Biology, Chromatin remodeling, Craniofacial Abnormalities, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual Disability, Report, Intellectual disability, Genetics, medicine, Humans, Child, Growth Disorders, Genetics (clinical), Exome sequencing, Adenosine Triphosphatases, Genetic Diseases, Inborn, Infant, Spinal muscular atrophy, Hyporeflexia, Middle Aged, medicine.disease, Phenotype, 030104 developmental biology, Neurodevelopmental Disorders, Child, Preschool, Mutation, Female, medicine.symptom, 030217 neurology & neurosurgery, Transcription Factors
Abstract: MORC2 encodes an ATPase that plays a role in chromatin remodeling, DNA repair, and transcriptional regulation. Heterozygous variants in MORC2 have been reported in individuals with autosomal-dominant Charcot-Marie-Tooth disease type 2Z and spinal muscular atrophy, and the onset of symptoms ranges from infancy to the second decade of life. Here, we present a cohort of 20 individuals referred for exome sequencing who harbor pathogenic variants in the ATPase module of MORC2. Individuals presented with a similar phenotype consisting of developmental delay, intellectual disability, growth retardation, microcephaly, and variable craniofacial dysmorphism. Weakness, hyporeflexia, and electrophysiologic abnormalities suggestive of neuropathy were frequently observed but were not the predominant feature. Five of 18 individuals for whom brain imaging was available had lesions reminiscent of those observed in Leigh syndrome, and five of six individuals who had dilated eye exams had retinal pigmentary abnormalities. Functional assays revealed that these MORC2 variants result in hyperactivation of epigenetic silencing by the HUSH complex, supporting their pathogenicity. The described set of morphological, growth, developmental, and neurological findings and medical concerns expands the spectrum of genetic disorders resulting from pathogenic variants in MORC2.
Published: 2020
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15. Quantifying Downstream Healthcare Utilization in Studies of Genomic Testing

Author: Zoë P. Mackay, Dmitry Dukhovny, Kathryn A. Phillips, Alan H. Beggs, Robert C. Green, Richard B. Parad, Kurt D. Christensen, Pankaj B. Agrawal, Ozge Ceyhan-Birsoy, Shawn Fayer, Leslie A. Frankel, Casie A. Genetti, Amanda M. Gutierrez, Maegan Harden, Ingrid A. Holm, Joel B. Krier, Matthew S. Lebo, Kalotina Machini, Amy L. McGuire, Medha Naik, Tiffany T. Nguyen, Stacey Pereira, Vivek Ramanathan, Heidi L. Rehm, Amy Roberts, Jill O. Robinson, Sergei Roumiantsev, Talia S. Schwartz, Tina K. Truong, Grace E. VanNoy, Susan E. Waisbren, and Timothy W. Yu
Subjects: Male, Parents, Psychological intervention, Disease, Article, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Surveys and Questionnaires, Humans, Medicine, Genetic Testing, Longitudinal Studies, 030212 general & internal medicine, Medical diagnosis, Genetic testing, Downstream (petroleum industry), medicine.diagnostic_test, business.industry, 030503 health policy & services, Health Policy, Medical record, Public Health, Environmental and Occupational Health, Infant, Genomics, Patient Acceptance of Health Care, medicine.disease, Telephone, Healthcare utilization, Female, Personalized medicine, Medical emergency, 0305 other medical science, business
Abstract: Objectives The challenges of understanding how interventions influence follow-up medical care are magnified during genomic testing because few patients have received it to date and because the scope of information it provides is complex and often unexpected. We tested a novel strategy for quantifying downstream healthcare utilization after genomic testing to more comprehensively and efficiently identify related services. We also evaluated the effectiveness of different methods for collecting these data. Methods We developed a risk-based approach for a trial of newborn genomic sequencing in which we defined primary conditions based on existing diagnoses and family histories of disease and defined secondary conditions based on unexpected findings. We then created patient-specific lists of services associated with managing primary and secondary conditions. Services were quantified based on medical record reviews, surveys, and telephone check-ins with parents. Results By focusing on services that genomic testing would most likely influence in the short-term, we reduced the number of services in our analyses by more than 90% compared with analyses of all observed services. We also identified the same services that were ordered in response to unexpected findings as were identified during expert review and by confirming whether recommendations were completed. Data also showed that quantifying healthcare utilization with surveys and telephone check-ins alone would have missed the majority of attributable services. Conclusions Our risk-based strategy provides an improved approach for assessing the short-term impact of genomic testing and other interventions on healthcare utilization while conforming as much as possible to existing best-practice recommendations.
Published: 2020
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16. De novo EIF2AK1 and EIF2AK2 Variants Are Associated with Developmental Delay, Leukoencephalopathy, and Neurologic Decompensation

Author: Dongxue Mao, Chloe M. Reuter, Maura R.Z. Ruzhnikov, Anita E. Beck, Emily G. Farrow, Lisa T. Emrick, Jill A. Rosenfeld, Katherine M. Mackenzie, Laurie Robak, Matthew T. Wheeler, Lindsay C. Burrage, Mahim Jain, Pengfei Liu, Daniel Calame, Sébastien Küry, Martin Sillesen, Klaus Schmitz-Abe, Davide Tonduti, Luigina Spaccini, Maria Iascone, Casie A. Genetti, Mary K. Koenig, Madeline Graf, Alyssa Tran, Mercedes Alejandro, Brendan H. Lee, Isabelle Thiffault, Pankaj B. Agrawal, Jonathan A. Bernstein, Hugo J. Bellen, Hsiao-Tuan Chao, Maria T. Acosta, Margaret Adam, David R. Adams, Mercedes E. Alejandro, Patrick Allard, Justin Alvey, Laura Amendola, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanyam, Dustin Baldridge, Jim Bale, Michael Bamshad, Deborah Barbouth, Gabriel F. Batzli, Pinar Bayrak-Toydemir, Anita Beck, Alan H. Beggs, Gill Bejerano, Jimmy Bennet, Beverly Berg-Rood, Raphael Bernier, Gerard T. Berry, Anna Bican, Stephanie Bivona, Elizabeth Blue, John Bohnsack, Carsten Bonnenmann, Devon Bonner, Lorenzo Botto, Lauren C. Briere, Elly Brokamp, Elizabeth A. Burke, Manish J. Butte, Peter Byers, John Carey, Olveen Carrasquillo, Ta Chen Peter Chang, Sirisak Chanprasert, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Michael Cunningham, Precilla D’Souza, Hongzheng Dai, Surendra Dasari, Mariska Davids, Jyoti G. Dayal, Esteban C. Dell’Angelica, Shweta U. Dhar, Katrina Dipple, Daniel Doherty, Naghmeh Dorrani, Emilie D. Douine, David D. Draper, Laura Duncan, Dawn Earl, David J. Eckstein, Christine M. Eng, Cecilia Esteves, Tyra Estwick, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Paul G. Fisher, Brent L. Fogel, Irman Forghani, Laure Fresard, William A. Gahl, Ian Glass, Rena A. Godfrey, Katie Golden-Grant, Alica M. Goldman, David B. Goldstein, Alana Grajewski, Catherine A. Groden, Andrea L. Gropman, Sihoun Hahn, Rizwan Hamid, Neil A. Hanchard, Nichole Hayes, Frances High, Anne Hing, Fuki M. Hisama, Ingrid A. Holm, Jason Hom, Martha Horike-Pyne, Alden Huang, Yong Huang, Rosario Isasi, Fariha Jamal, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Yong-hui Jiang, Jean M. Johnston, Lefkothea Karaviti, Emily G. Kelley, Dana Kiley, Isaac S. Kohane, Jennefer N. Kohler, Deborah Krakow, Donna M. Krasnewich, Susan Korrick, Mary Koziura, Joel B. Krier, Seema R. Lalani, Byron Lam, Christina Lam, Brendan C. Lanpher, Ian R. Lanza, C. Christopher Lau, Kimberly LeBlanc, Hane Lee, Roy Levitt, Richard A. Lewis, Sharyn A. Lincoln, Xue Zhong Liu, Nicola Longo, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Marta M. Majcherska, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Kenneth Maravilla, Thomas C. Markello, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Julian A. Martínez-Agosto, Shruti Marwaha, Jacob McCauley, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Heather Mefford, J. Lawrence Merritt, Matthew Might, Ghayda Mirzaa, Eva Morava-Kozicz, Paolo M. Moretti, Marie Morimoto, John J. Mulvihill, David R. Murdock, Avi Nath, Stan F. Nelson, John H. Newman, Sarah K. Nicholas, Deborah Nickerson, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, Stephen Pak, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, John H. Postlethwait, Lorraine Potocki, Barbara N. Pusey, Aaron Quinlan, Wendy Raskind, Archana N. Raja, Genecee Renteria, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Robb K. Rowley, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Susan L. Samson, Mario Saporta, C. Ron Scott, Judy Schaechter, Timothy Schedl, Kelly Schoch, Daryl A. Scott, Lisa Shakachite, Prashant Sharma, Vandana Shashi, Jimann Shin, Rebecca Signer, Catherine H. Sillari, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Kevin S. Smith, Lilianna Solnica-Krezel, Rebecca C. Spillmann, Joan M. Stoler, Nicholas Stong, Jennifer A. Sullivan, Angela Sun, Shirley Sutton, David A. Sweetser, Virginia Sybert, Holly K. Tabor, Cecelia P. Tamburro, Queenie K.-G. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Tiina K. Urv, Matt Velinder, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Stephanie Wallace, Nicole M. Walley, Chris A. Walsh, Melissa Walker, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Daniel Wegner, Mark Wener, Monte Westerfield, Anastasia L. Wise, Lynne A. Wolfe, Jeremy D. Woods, Shinya Yamamoto, John Yang, Amanda J. Yoon, Guoyun Yu, Diane B. Zastrow, Chunli Zhao, and Stephan Zuchner
Subjects: Male, 0301 basic medicine, Proband, Ataxia, Adolescent, Developmental Disabilities, Nervous System Malformations, Leukoencephalopathy, eIF-2 Kinase, 03 medical and health sciences, 0302 clinical medicine, Leukoencephalopathies, Report, Genetics, medicine, Humans, Missense mutation, Kinase activity, Child, Genetics (clinical), biology, Leukodystrophy, Genetic Variation, Infant, medicine.disease, White Matter, Hypotonia, Hereditary Central Nervous System Demyelinating Diseases, 030104 developmental biology, Child, Preschool, eIF2B, Immunology, biology.protein, Female, medicine.symptom, 030217 neurology & neurosurgery
Abstract: EIF2AK1 and EIF2AK2 encode members of the eukaryotic translation initiation factor 2 alpha kinase (EIF2AK) family that inhibits protein synthesis in response to physiologic stress conditions. EIF2AK2 is also involved in innate immune response and the regulation of signal transduction, apoptosis, cell proliferation, and differentiation. Despite these findings, human disorders associated with deleterious variants in EIF2AK1 and EIF2AK2 have not been reported. Here, we describe the identification of nine unrelated individuals with heterozygous de novo missense variants in EIF2AK1 (1/9) or EIF2AK2 (8/9). Features seen in these nine individuals include white matter alterations (9/9), developmental delay (9/9), impaired language (9/9), cognitive impairment (8/9), ataxia (6/9), dysarthria in probands with verbal ability (6/9), hypotonia (7/9), hypertonia (6/9), and involuntary movements (3/9). Individuals with EIF2AK2 variants also exhibit neurological regression in the setting of febrile illness or infection. We use mammalian cell lines and proband-derived fibroblasts to further confirm the pathogenicity of variants in these genes and found reduced kinase activity. EIF2AKs phosphorylate eukaryotic translation initiation factor 2 subunit 1 (EIF2S1, also known as EIF2α), which then inhibits EIF2B activity. Deleterious variants in genes encoding EIF2B proteins cause childhood ataxia with central nervous system hypomyelination/vanishing white matter (CACH/VWM), a leukodystrophy characterized by neurologic regression in the setting of febrile illness and other stressors. Our findings indicate that EIF2AK2 missense variants cause a neurodevelopmental syndrome that may share phenotypic and pathogenic mechanisms with CACH/VWM.
Published: 2020
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17. Clinical Reasoning: A 42-year-old woman with progressive cognitive difficulties and gait imbalance

Author: Dorlan J. Kimbrough, Michaël C.C. Slama, Joel B. Krier, Umberto De Girolami, Matthew Torre, Joome Suh, Stephanie M. Shatzman, and Tracey A. Milligan
Subjects: Adult, medicine.medical_specialty, Etanercept, 03 medical and health sciences, Psoriatic arthritis, 0302 clinical medicine, Physical medicine and rehabilitation, Leukoencephalopathies, medicine, Humans, 030212 general & internal medicine, Family history, Gait Disorders, Neurologic, business.industry, Cognition, Pronator drift, medicine.disease, Gait, Reflex, Female, Gait imbalance, Neurology (clinical), Cognition Disorders, business, 030217 neurology & neurosurgery, medicine.drug
Abstract: A 42-year-old woman presented with 6 months of generalized fatigue, disequilibrium, subjective leg weakness, and difficulty concentrating and completing complex tasks. She had a history of psoriatic arthritis, previously treated with the tumor necrosis factor–α (TNF-α) inhibitor etanercept, which was discontinued about 2 months prior to onset of neurologic symptoms. There was no family history of a similar clinical syndrome. Initial neurologic examination was normal, including normal attention with serial 7s, normal immediate and delayed recall of 3 words, normal muscle tone, full strength with no pronator drift, normal and symmetric reflexes with negative Hoffman signs and flexor plantar responses, intact coordination to finger and foot tapping, unremarkable gait with intact ability to tandem, and negative Romberg sign.
Published: 2020
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18. Psychosocial Effect of Newborn Genomic Sequencing on Families in the BabySeq Project: A Randomized Clinical Trial

Author: Heidi L. Rehm, Bethany Zettler, Amy L. McGuire, Sergei Roumiantsev, Dmitry Dukhovny, Kalotina Machini, Talia S. Schwartz, Ozge Ceyhan-Birsoy, Hadley Stevens Smith, Timothy W. Yu, Jill O. Robinson, Devan Petersen, Pankaj B. Agrawal, Chet Graham, Amy E. Roberts, Tiffany T. Nguyen Dolphyn, Tina K. Truong, Maegan Harden, Carrie L. Blout Zawatsky, Casie A. Genetti, Ingrid A. Holm, Shawn Fayer, Xingquan Lu, Harvey L. Levy, Vivek Ramanathan, Richard B. Parad, Leslie A. Frankel, Jaclyn B. Murry, Amanda M. Gutierrez, Wendi N. Betting, Kaitlyn B. Lee, Grace E. VanNoy, Susan E. Waisbren, Robert C. Green, Stacey Pereira, Alan H. Beggs, Matthew S. Lebo, Kurt D. Christensen, Medha Naik, Hayley A. Peoples, Rubaiya Islam, Uma Ramamurthy, and Joel B. Krier
Subjects: Adult, Male, Parents, Pediatrics, medicine.medical_specialty, law.invention, Neonatal Screening, Randomized controlled trial, law, Intensive care, Exome Sequencing, Medicine, Humans, Genetic Predisposition to Disease, Parent-Child Relations, Family history, Child, Generalized estimating equation, Original Investigation, Newborn screening, business.industry, Infant, Newborn, Genomics, Edinburgh Postnatal Depression Scale, Pediatrics, Perinatology and Child Health, Anxiety, Female, medicine.symptom, business, Psychosocial
Abstract: Importance Newborn genomic sequencing (nGS) may provide health benefits throughout the life span, but there are concerns that it could also have an unfavorable (ie, negative) psychosocial effect on families. Objective To assess the psychosocial effect of nGS on families from the BabySeq Project, a randomized clinical trial evaluating the effect of nGS on the clinical care of newborns from well-baby nurseries and intensive care units. Design, Setting, and Participants In this randomized clinical trial conducted from May 14, 2015, to May 21, 2019, at well-baby nurseries and intensive care units at 3 Boston, Massachusetts, area hospitals, 519 parents of 325 infants completed surveys at enrollment, immediately after disclosure of nGS results, and 3 and 10 months after results disclosure. Statistical analysis was performed on a per-protocol basis from January 16, 2019, to December 1, 2019. Intervention Newborns were randomized to receive either standard newborn screening and a family history report (control group) or the same plus an nGS report of childhood-onset conditions and highly actionable adult-onset conditions (nGS group). Main Outcomes and Measures Mean responses were compared between groups and, within the nGS group, between parents of children who received a monogenic disease risk finding and those who did not in 3 domains of psychosocial impact: parent-child relationship (Mother-to-Infant Bonding Scale), parents’ relationship (Kansas Marital Satisfaction Scale), and parents’ psychological distress (Edinburgh Postnatal Depression Scale anxiety subscale). Results A total of 519 parents (275 women [53.0%]; mean [SD] age, 35.1 [4.5] years) were included in this study. Although mean scores differed for some outcomes at singular time points, generalized estimating equations models did not show meaningful differences in parent-child relationship (between-group difference in adjusted mean [SE] Mother-to-Infant Bonding Scale scores: postdisclosure, 0.04 [0.15]; 3 months, –0.18 [0.18]; 10 months, –0.07 [0.20]; jointP = .57) or parents’ psychological distress (between-group ratio of adjusted mean [SE] Edinburgh Postnatal Depression Scale anxiety subscale scores: postdisclosure, 1.04 [0.08]; 3 months, 1.07 [0.11]; jointP = .80) response patterns between study groups over time for any measures analyzed in these 2 domains. Response patterns on one parents’ relationship measure differed between groups over time (between-group difference in adjusted mean [SE] Kansas Marital Satisfaction Scale scores: postdisclosure, –0.19 [0.07]; 3 months, –0.04 [0.07]; and 10 months, –0.01 [0.08]; jointP = .02), but the effect decreased over time and no difference was observed on the conflict measure responses over time. We found no evidence of persistent negative psychosocial effect in any domain. Conclusions and Relevance In this randomized clinical trial of nGS, there was no persistent negative psychosocial effect on families among those who received nGS nor among those who received a monogenic disease risk finding for their infant. Trial Registration ClinicalTrials.gov Identifier:NCT02422511
Published: 2021

19. Returning actionable genomic results in a research biobank: Analytic validity, clinical implementation, and resource utilization

Author: Scott T. Weiss, Marcie A. Steeves, Kurt D. Christensen, Jordan W. Smoller, Kalotina Machini, Lisa Mahanta, Christopher Koch, Nidhi Shah, Nina B. Gold, Robert C. Green, Carrie L. Blout Zawatsky, Hana Zouk, Matthew S. Lebo, Heidi L. Rehm, Janelle Shea, Emma Perez, Natalie T. Boutin, Joel B. Krier, Melissa K Uveges, and Elizabeth W. Karlson
Subjects: Adult, Male, Genetic Research, Staff support, Computational biology, Disclosure, Biology, DNA sequencing, Article, Cohort Studies, genomic, Genetics, medicine, Humans, Disease, Genetic Testing, Genotyping, Genetics (clinical), Likely pathogenic, Genetic testing, Biological Specimen Banks, Duty to Recontact, Informed Consent, research, medicine.diagnostic_test, Genome, Human, Genetic Variation, Reproducibility of Results, DNA, Genomics, Middle Aged, Biobank, biobank, Cohort, Female, genetic, Resource utilization
Abstract: Summary Over 100 million research participants around the world have had research array-based genotyping (GT) or genome sequencing (GS), but only a small fraction of these have been offered return of actionable genomic findings (gRoR). Between 2017 and 2021, we analyzed genomic results from 36,417 participants in the Mass General Brigham Biobank and offered to confirm and return pathogenic and likely pathogenic variants (PLPVs) in 59 genes. Variant verification prior to participant recontact revealed that GT falsely identified PLPVs in 44.9% of samples, and GT failed to identify 72.0% of PLPVs detected in a subset of samples that were also sequenced. GT and GS detected verified PLPVs in 1% and 2.5% of the cohort, respectively. Of 256 participants who were alerted that they carried actionable PLPVs, 37.5% actively or passively declined further disclosure. 76.3% of those carrying PLPVs were unaware that they were carrying the variant, and over half of those met published professional criteria for genetic testing but had never been tested. This gRoR protocol cost approximately $129,000 USD per year in laboratory testing and research staff support, representing $14 per participant whose DNA was analyzed or $3,224 per participant in whom a PLPV was confirmed and disclosed. These data provide logistical details around gRoR that could help other investigators planning to return genomic results.
Published: 2021

20. Magnetic Resonance Imaging characteristics in case of TOR1AIP1 muscular dystrophy

Author: Aashim Bhatia, Bret C. Mobley, Joy Cogan, Mary E. Koziura, Elly Brokamp, John Phillips, John Newman, Steven A. Moore, Rizwan Hamid, Maria T. Acosta, David R. Adams, Pankaj Agrawal, Mercedes E. Alejandro, Patrick Allard, Justin Alvey, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanyam, Dustin Baldridge, Jim Bale, Deborah Barbouth, Gabriel F. Batzli, Pinar Bayrak-Toydemir, Alan H. Beggs, Gill Bejerano, Hugo J. Bellen, Jonathan A. Bernstein, Gerard T. Berry, Anna Bican, David P. Bick, Camille L. Birch, Stephanie Bivona, John Bohnsack, Carsten Bonnenmann, Devon Bonner, Braden E. Boone, Bret L. Bostwick, Lorenzo Botto, Lauren C. Briere, Donna M. Brown, Matthew Brush, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, John Carey, Olveen Carrasquillo, Ta Chen Peter Chang, Hsiao-Tuan Chao, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Precilla D'Souza, Surendra Dasari, Mariska Davids, Jyoti G. Dayal, Esteban C. Dell'Angelica, Shweta U. Dhar, Naghmeh Dorrani, Daniel C. Dorset, Emilie D. Douine, David D. Draper, Laura Duncan, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Cecilia Esteves, Tyra Estwick, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Paul G. Fisher, Brent L. Fogel, Irman Forghani, Laure Fresard, William A. Gahl, Rena A. Godfrey, Alica M. Goldman, David B. Goldstein, Jean-Philippe F. Gourdine, Alana Grajewski, Catherine A. Groden, Andrea L. Gropman, Melissa Haendel, Neil A. Hanchard, Nichole Hayes, Frances High, Ingrid A. Holm, Jason Hom, Alden Huang, Yong Huang, Rosario Isasi, Fariha Jamal, Yong-hui Jiang, Jean M. Johnston, Angela L. Jones, Lefkothea Karaviti, Emily G. Kelley, Dana Kiley, David M. Koeller, Isaac S. Kohane, Jennefer N. Kohler, Deborah Krakow, Susan Korrick, Mary Koziura, Joel B. Krier, Jennifer E. Kyle, Seema R. Lalani, Byron Lam, Brendan C. Lanpher, Ian R. Lanza, C. Christopher Lau, Jozef Lazar, Kimberly LeBlanc, Brendan H. Lee, Hane Lee, Roy Levitt, Shawn E. Levy, Richard A. Lewis, Sharyn A. Lincoln, Pengfei Liu, Xue Zhong Liu, Sandra K. Loo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Marta M. Majcherska, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Thomas C. Markello, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Julian A. Martínez-Agosto, Shruti Marwaha, Thomas May, Jacob McCauley, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Thomas O. Metz, Matthew Might, Eva Morava-Kozicz, Paolo M. Moretti, Marie Morimoto, John J. Mulvihill, David R. Murdock, Avi Nath, Stan F. Nelson, J. Scott Newberry, John H. Newman, Sarah K. Nicholas, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, John H. Postlethwait, Lorraine Potocki, Barbara N. Pusey, Aaron Quinlan, Archana N. Raja, Genecee Renteria, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Jill A. Rosenfeld, Robb K. Rowley, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Susan L. Samson, Mario Saporta, Judy Schaechter, Timothy Schedl, Kelly Schoch, Daryl A. Scott, Lisa Shakachite, Prashant Sharma, Vandana Shashi, Kathleen Shields, Jimann Shin, Rebecca Signer, Catherine H. Sillari, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Kevin S. Smith, Lilianna Solnica-Krezel, Rebecca C. Spillmann, Joan M. Stoler, Nicholas Stong, Jennifer A. Sullivan, Shirley Sutton, David A. Sweetser, Holly K. Tabor, Cecelia P. Tamburro, Queenie K.-G. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Tiina K. Urv, Matt Velinder, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Nicole M. Walley, Chris A. Walsh, Melissa Walker, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Katrina M. Waters, Bobbie-Jo M. Webb-Robertson, Daniel Wegner, Monte Westerfield, Matthew T. Wheeler, Anastasia L. Wise, Lynne A. Wolfe, Jeremy D. Woods, Elizabeth A. Worthey, Shinya Yamamoto, John Yang, Amanda J. Yoon, Guoyun Yu, Diane B. Zastrow, Chunli Zhao, and Stephan Zuchner
Subjects: medicine.medical_specialty, Adolescent, Gene mutation, Article, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Atrophy, Humans, Medicine, Radiology, Nuclear Medicine and imaging, Muscular dystrophy, Muscle, Skeletal, Gluteal muscles, Muscle Weakness, Muscle biopsy, medicine.diagnostic_test, business.industry, Muscle weakness, Magnetic resonance imaging, medicine.disease, Magnetic Resonance Imaging, Muscular Atrophy, medicine.anatomical_structure, Lower Extremity, Muscular Dystrophies, Limb-Girdle, 030220 oncology & carcinogenesis, Female, Radiology, Iliopsoas, medicine.symptom, business, Molecular Chaperones
Abstract: Mutations in the torsinA-interacting protein 1 (TOR1AIP1) gene result in a severe muscular dystrophy with minimal literature in the pediatric population. We review a case of TOR1AIP1 gene mutation in a 16-year-old Caucasian female with a long history of muscle weakness. Extensive clinical workup was performed and MRI at time of initial presentation demonstrated no significant muscular atrophy with heterogenous STIR hyperintensity of the lower extremity muscles. MRI findings seven years later included extensive atrophy of the lower extremities, with severe progression, including the gluteal muscles, iliopsoas, rectus femoris, and obturator internus. There was also significant atrophy of the rectus abdominis and internal and external oblique muscles, and iliacus muscles. The MRI findings showed more proximal involvement of lower extremities and no atrophy of the tibialis anterior, making TOR1AIP1 the more likely genetic cause. Muscle biopsy findings supported TOR1AIP1 limb-girdle muscular dystrophy. Though rare, TOR1AIP1 gene mutation occurs in pediatric patients and MRI can aid in diagnosis and help differentiate from other types of muscular dystrophy. Genetic and pathology workup is also crucial to accurate diagnosis and possible treatment of these patients.
Published: 2019
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21. Lysosomal Storage and Albinism Due to Effects of a De Novo CLCN7 Variant on Lysosomal Acidification

Author: Elena-Raluca Nicoli, Mary R. Weston, Mary Hackbarth, Alissa Becerril, Austin Larson, Wadih M. Zein, Peter R. Baker, John Douglas Burke, Heidi Dorward, Mariska Davids, Yan Huang, David R. Adams, Patricia M. Zerfas, Dong Chen, Thomas C. Markello, Camilo Toro, Tim Wood, Gene Elliott, Mylinh Vu, Wei Zheng, Lisa J. Garrett, Cynthia J. Tifft, William A. Gahl, Debra L. Day-Salvatore, Joseph A. Mindell, May Christine V. Malicdan, Maria T. Acosta, Pankaj Agrawal, Mercedes E. Alejandro, Patrick Allard, Justin Alvey, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanyam, Dustin Baldridge, Jim Bale, Deborah Barbouth, Gabriel F. Batzli, Pinar Bayrak-Toydemir, Alan H. Beggs, Gill Bejerano, Hugo J. Bellen, Jonathan A. Bernstein, Gerard T. Berry, Anna Bican, David P. Bick, Camille L. Birch, Stephanie Bivona, John Bohnsack, Carsten Bonnenmann, Devon Bonner, Braden E. Boone, Bret L. Bostwick, Lorenzo Botto, Lauren C. Briere, Elly Brokamp, Donna M. Brown, Matthew Brush, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, John Carey, Olveen Carrasquillo, Ta Chen Peter Chang, Hsiao-Tuan Chao, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Precilla D'Souza, Surendra Dasari, Jyoti G. Dayal, Esteban C. Dell'Angelica, Shweta U. Dhar, Naghmeh Dorrani, Daniel C. Dorset, Emilie D. Douine, David D. Draper, Laura Duncan, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Cecilia Esteves, Tyra Estwick, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Paul G. Fisher, Brent L. Fogel, Irman Forghani, Laure Fresard, Rena A. Godfrey, Alica M. Goldman, David B. Goldstein, Jean-Philippe F. Gourdine, Alana Grajewski, Catherine A. Groden, Andrea L. Gropman, Melissa Haendel, Rizwan Hamid, Neil A. Hanchard, Nichole Hayes, Frances High, Ingrid A. Holm, Jason Hom, Alden Huang, Yong Huang, Rosario Isasi, Fariha Jamal, Yong-hui Jiang, Jean M. Johnston, Angela L. Jones, Lefkothea Karaviti, Emily G. Kelley, Dana Kiley, David M. Koeller, Isaac S. Kohane, Jennefer N. Kohler, Deborah Krakow, Donna M. Krasnewich, Susan Korrick, Mary Koziura, Joel B. Krier, Jennifer E. Kyle, Seema R. Lalani, Byron Lam, Brendan C. Lanpher, Ian R. Lanza, C. Christopher Lau, Jozef Lazar, Kimberly LeBlanc, Brendan H. Lee, Hane Lee, Roy Levitt, Shawn E. Levy, Richard A. Lewis, Sharyn A. Lincoln, Pengfei Liu, Xue Zhong Liu, Nicola Longo, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Marta M. Majcherska, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Julian A. Martínez-Agosto, Shruti Marwaha, Thomas May, Jacob McCauley, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Thomas O. Metz, Matthew Might, Eva Morava-Kozicz, Paolo M. Moretti, Marie Morimoto, John J. Mulvihill, David R. Murdock, Avi Nath, Stan F. Nelson, J. Scott Newberry, John H. Newman, Sarah K. Nicholas, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, Stephen Pak, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, John H. Postlethwait, Lorraine Potocki, Barbara N. Pusey, Aaron Quinlan, Archana N. Raja, Genecee Renteria, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Jill A. Rosenfeld, Robb K. Rowley, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Susan L. Samson, Mario Saporta, Judy Schaechter, Timothy Schedl, Kelly Schoch, Daryl A. Scott, Lisa Shakachite, Prashant Sharma, Vandana Shashi, Kathleen Shields, Jimann Shin, Rebecca Signer, Catherine H. Sillari, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Kevin S. Smith, Lilianna Solnica-Krezel, Rebecca C. Spillmann, Joan M. Stoler, Nicholas Stong, Jennifer A. Sullivan, Shirley Sutton, David A. Sweetser, Holly K. Tabor, Cecelia P. Tamburro, Queenie K.-G. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Alyssa A. Tran, Tiina K. Urv, Matt Velinder, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Nicole M. Walley, Chris A. Walsh, Melissa Walker, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Katrina M. Waters, Bobbie-Jo M. Webb-Robertson, Daniel Wegner, Monte Westerfield, Matthew T. Wheeler, Anastasia L. Wise, Lynne A. Wolfe, Jeremy D. Woods, Elizabeth A. Worthey, Shinya Yamamoto, John Yang, Amanda J. Yoon, Guoyun Yu, Diane B. Zastrow, Chunli Zhao, and Stephan Zuchner
Subjects: Male, 0301 basic medicine, Albinism, Antiporter, Vacuole, Article, Organomegaly, Mice, Xenopus laevis, 03 medical and health sciences, 0302 clinical medicine, Chloride Channels, Lysosome, Genetics, medicine, Lysosomal storage disease, Animals, Humans, Genetics (clinical), Hypopigmentation, biology, Chemistry, Genetic Variation, Infant, Fibroblasts, Hydrogen-Ion Concentration, medicine.disease, Molecular biology, Lysosomal Storage Diseases, 030104 developmental biology, medicine.anatomical_structure, Oocytes, biology.protein, Female, CLCN7, medicine.symptom, Lysosomes, Acids, 030217 neurology & neurosurgery, Intracellular
Abstract: Optimal lysosome function requires maintenance of an acidic pH maintained by proton pumps in combination with a counterion transporter such as the Cl(−)/H(+) exchanger, CLCN7 (ClC-7), encoded by CLCN7. The role of ClC-7 in maintaining lysosomal pH has been controversial. In this paper, we performed clinical and genetic evaluations of two children of different ethnicities. Both children had delayed myelination and development, organomegaly, and hypopigmentation, but neither had osteopetrosis. Whole-exome and -genome sequencing revealed a de novo c.2144A>G variant in CLCN7 in both affected children. This p.Tyr715Cys variant, located in the C-terminal domain of ClC-7, resulted in increased outward currents when it was heterologously expressed in Xenopus oocytes. Fibroblasts from probands displayed a lysosomal pH approximately 0.2 units lower than that of control cells, and treatment with chloroquine normalized the pH. Primary fibroblasts from both probands also exhibited markedly enlarged intracellular vacuoles; this finding was recapitulated by the overexpression of human p.Tyr715Cys CLCN7 in control fibroblasts, reflecting the dominant, gain-of-function nature of the variant. A mouse harboring the knock-in Clcn7 variant exhibited hypopigmentation, hepatomegaly resulting from abnormal storage, and enlarged vacuoles in cultured fibroblasts. Our results show that p.Tyr715Cys is a gain-of-function CLCN7 variant associated with developmental delay, organomegaly, and hypopigmentation resulting from lysosomal hyperacidity, abnormal storage, and enlarged intracellular vacuoles. Our data supports the hypothesis that the ClC-7 antiporter plays a critical role in maintaining lysosomal pH.
Published: 2019
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22. Interpretation of Genomic Sequencing Results in Healthy and Ill Newborns: Results from the BabySeq Project

Author: Ozge Ceyhan-Birsoy, Jaclyn B. Murry, Kalotina Machini, Matthew S. Lebo, Timothy W. Yu, Shawn Fayer, Casie A. Genetti, Talia S. Schwartz, Pankaj B. Agrawal, Richard B. Parad, Ingrid A. Holm, Amy L. McGuire, Robert C. Green, Heidi L. Rehm, Alan H. Beggs, Wendi N. Betting, Kurt D. Christensen, Dmitry Dukhovny, Leslie A. Frankel, Chet Graham, Amanda M. Guiterrez, Maegan Harden, Joel B. Krier, Harvey L. Levy, Xingquan Lu, Medha Naik, Tiffany T. Nguyen, Hayley A. Peoples, Stacey Pereira, Devan Petersen, Uma Ramamurthy, Vivek Ramanathan, Amy Roberts, Jill O. Robinson, Serguei Roumiantsev, Tina K. Truong, Grace E. VanNoy, and Susan E. Waisbren
Subjects: Male, 0301 basic medicine, Heterozygote, Pediatrics, medicine.medical_specialty, Neonatal intensive care unit, Disease, 030105 genetics & heredity, 03 medical and health sciences, Exome Sequencing, Genetics, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, Age of Onset, Family history, Genetics (clinical), Exome sequencing, Genetic testing, Newborn screening, medicine.diagnostic_test, Genome, Human, business.industry, Racial Groups, Infant, Newborn, Genetic Variation, Genomics, Sequence Analysis, DNA, 030104 developmental biology, Health, Pharmacogenetics, Pharmacogenomics, Female, Age of onset, business
Abstract: Genomic sequencing provides many opportunities in newborn clinical care, but the challenges of interpreting and reporting newborn genomic sequencing (nGS) results need to be addressed for its broader and effective application. The BabySeq Project is a pilot randomized clinical trial that explores the medical, behavioral, and economic impacts of nGS in well newborns and those admitted to a neonatal intensive care unit (NICU). Here we present childhood-onset and actionable adult-onset disease risk, carrier status, and pharmacogenomics findings from nGS of 159 newborns in the BabySeq Project. nGS revealed a risk of childhood-onset disease in 15/159 (9.4%) newborns; none of the disease risks were anticipated based on the infants' known clinical or family histories. nGS also revealed actionable adult-onset disease risk in 3/85 (3.5%) newborns whose parents consented to receive this information. Carrier status for recessive diseases and pharmacogenomics variants were reported in 88% and 5% of newborns, respectively. Additional indication-based analyses were performed in 29/32 (91%) NICU newborns and 6/127 (5%) healthy newborns who later had presentations that prompted a diagnostic analysis. No variants that sufficiently explained the reason for the indications were identified; however, suspicious but uncertain results were reported in five newborns. Testing parental samples contributed to the interpretation and reporting of results in 13/159 (8%) newborns. Our results suggest that nGS can effectively detect risk and carrier status for a wide range of disorders that are not detectable by current newborn screening assays or predicted based on the infant's known clinical or family history, and the interpretation of results can substantially benefit from parental testing.
Published: 2019
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23. Expanding the Spectrum of BAF-Related Disorders: De Novo Variants in SMARCC2 Cause a Syndrome with Intellectual Disability and Developmental Delay

Author: Keren Machol, Justine Rousseau, Sophie Ehresmann, Thomas Garcia, Thi Tuyet Mai Nguyen, Rebecca C. Spillmann, Jennifer A. Sullivan, Vandana Shashi, Yong-hui Jiang, Nicholas Stong, Elise Fiala, Marcia Willing, Rolph Pfundt, Tjitske Kleefstra, Megan T. Cho, Heather McLaughlin, Monica Rosello Piera, Carmen Orellana, Francisco Martínez, Alfonso Caro-Llopis, Sandra Monfort, Tony Roscioli, Cheng Yee Nixon, Michael F. Buckley, Anne Turner, Wendy D. Jones, Peter M. van Hasselt, Floris C. Hofstede, Koen L.I. van Gassen, Alice S. Brooks, Marjon A. van Slegtenhorst, Katherine Lachlan, Jessica Sebastian, Suneeta Madan-Khetarpal, Desai Sonal, Naidu Sakkubai, Julien Thevenon, Laurence Faivre, Alice Maurel, Slavé Petrovski, Ian D. Krantz, Jennifer M. Tarpinian, Jill A. Rosenfeld, Brendan H. Lee, Philippe M. Campeau, David R. Adams, Mercedes E. Alejandro, Patrick Allard, Mahshid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Hayk Barseghyan, Gabriel F. Batzli, Alan H. Beggs, Babak Behnam, Anna Bican, David P. Bick, Camille L. Birch, Devon Bonner, Braden E. Boone, Bret L. Bostwick, Lauren C. Briere, Donna M. Brown, Matthew Brush, Elizabeth A. Burke, Lindsay C. Burrage, Shan Chen, Gary D. Clark, Terra R. Coakley, Joy D. Cogan, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Precilla D’Souza, Mariska Davids, Jyoti G. Dayal, Esteban C. Dell’Angelica, Shweta U. Dhar, Ani Dillon, Katrina M. Dipple, Laurel A. Donnell-Fink, Naghmeh Dorrani, Daniel C. Dorset, Emilie D. Douine, David D. Draper, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Ascia Eskin, Cecilia Esteves, Tyra Estwick, Carlos Ferreira, Brent L. Fogel, Noah D. Friedman, William A. Gahl, Emily Glanton, Rena A. Godfrey, David B. Goldstein, Sarah E. Gould, Jean-Philippe F. Gourdine, Catherine A. Groden, Andrea L. Gropman, Melissa Haendel, Rizwan Hamid, Neil A. Hanchard, Lori H. Handley, Matthew R. Herzog, Ingrid A. Holm, Jason Hom, Ellen M. Howerton, Yong Huang, Howard J. Jacob, Mahim Jain, Jean M. Johnston, Angela L. Jones, Isaac S. Kohane, Donna M. Krasnewich, Elizabeth L. Krieg, Joel B. Krier, Seema R. Lalani, C. Christopher Lau, Jozef Lazar, Hane Lee, Shawn E. Levy, Richard A. Lewis, Sharyn A. Lincoln, Allen Lipson, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Marta M. Majcherska, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Thomas C. Markello, Ronit Marom, Julian A. Martínez-Agosto, Shruti Marwaha, Thomas May, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Matthew Might, Paolo M. Moretti, Marie Morimoto, John J. Mulvihill, Jennifer L. Murphy, Donna M. Muzny, Michele E. Nehrebecky, Stan F. Nelson, J. Scott Newberry, John H. Newman, Sarah K. Nicholas, Donna Novacic, Jordan S. Orange, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, Loren D.M. Pena, John A. Phillips, Jennifer E. Posey, John H. Postlethwait, Lorraine Potocki, Barbara N. Pusey, Chloe M. Reuter, Amy K. Robertson, Lance H. Rodan, Jacinda B. Sampson, Susan L. Samson, Kelly Schoch, Molly C. Schroeder, Daryl A. Scott, Prashant Sharma, Rebecca Signer, Edwin K. Silverman, Janet S. Sinsheimer, Kevin S. Smith, Kimberly Splinter, Joan M. Stoler, David A. Sweetser, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Tiina K. Urv, Zaheer M. Valivullah, Eric Vilain, Tiphanie P. Vogel, Colleen E. Wahl, Nicole M. Walley, Chris A. Walsh, Patricia A. Ward, Katrina M. Waters, Monte Westerfield, Anastasia L. Wise, Lynne A. Wolfe, Elizabeth A. Worthey, Shinya Yamamoto, Yaping Yang, Guoyun Yu, Diane B. Zastrow, Allison Zheng, and Clinical Genetics
Subjects: Male, 0301 basic medicine, Hypertrichosis, speech delay, Bafopathy, Developmental Disabilities, CACNB4, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual disability, Bafopathy, developmental delay, dysmorphisms, genotype-phenotype correlation, intellectual disability, neurodevelopmental disorder, speech delay, transcriptome, Genetics(clinical), Child, Genetics (clinical), Genetics, Syndrome, Hypotonia, DNA-Binding Proteins, developmental delay, Corticogenesis, intellectual disability, Child, Preschool, Speech delay, Female, medicine.symptom, Hand Deformities, Congenital, dysmorphisms, Adolescent, Micrognathism, genotype-phenotype correlation, Biology, Chromatin remodeling, 03 medical and health sciences, Journal Article, medicine, Humans, Abnormalities, Multiple, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], medicine.disease, neurodevelopmental disorder, Reelin Protein, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], 030104 developmental biology, Face, Mutation, biology.protein, transcriptome, Neck, 030217 neurology & neurosurgery, Transcription Factors
Abstract: Contains fulltext : 202800.pdf (Publisher’s version ) (Open Access) SMARCC2 (BAF170) is one of the invariable core subunits of the ATP-dependent chromatin remodeling BAF (BRG1-associated factor) complex and plays a crucial role in embryogenesis and corticogenesis. Pathogenic variants in genes encoding other components of the BAF complex have been associated with intellectual disability syndromes. Despite its significant biological role, variants in SMARCC2 have not been directly associated with human disease previously. Using whole-exome sequencing and a web-based gene-matching program, we identified 15 individuals with variable degrees of neurodevelopmental delay and growth retardation harboring one of 13 heterozygous variants in SMARCC2, most of them novel and proven de novo. The clinical presentation overlaps with intellectual disability syndromes associated with other BAF subunits, such as Coffin-Siris and Nicolaides-Baraitser syndromes and includes prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features such as hypertrichosis, thick eyebrows, thin upper lip vermilion, and upturned nose. Nine out of the fifteen individuals harbor variants in the highly conserved SMARCC2 DNA-interacting domains (SANT and SWIRM) and present with a more severe phenotype. Two of these individuals present cardiac abnormalities. Transcriptomic analysis of fibroblasts from affected individuals highlights a group of differentially expressed genes with possible roles in regulation of neuronal development and function, namely H19, SCRG1, RELN, and CACNB4. Our findings suggest a novel SMARCC2-related syndrome that overlaps with neurodevelopmental disorders associated with variants in BAF-complex subunits.
Published: 2019
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24. An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids

Author: Sacha Ferdinandusse, Kirsty McWalter, Heleen te Brinke, Lodewijk IJlst, Petra M. Mooijer, Jos P.N. Ruiter, Alida E.M. van Lint, Mia Pras-Raves, Eric Wever, Francisca Millan, Maria J. Guillen Sacoto, Amber Begtrup, Mark Tarnopolsky, Lauren Brady, Roger L. Ladda, Susan L. Sell, Catherine B. Nowak, Jessica Douglas, Cuixia Tian, Elizabeth Ulm, Seth Perlman, Arlene V. Drack, Karen Chong, Nicole Martin, Jennifer Brault, Elly Brokamp, Camilo Toro, William A. Gahl, Ellen F. Macnamara, Lynne Wolfe, Mercedes E. Alejandro, Mahshid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Lindsay C. Burrage, Hsiao-Tuan Chao, Gary D. Clark, William J. Craigen, Hongzheng Dai, Shweta U. Dhar, Lisa T. Emrick, Alica M. Goldman, Neil A. Hanchard, Fariha Jamal, Lefkothea Karaviti, Seema R. Lalani, Brendan H. Lee, Richard A. Lewis, Ronit Marom, Paolo M. Moretti, David R. Murdock, Sarah K. Nicholas, James P. Orengo, Jennifer E. Posey, Lorraine Potocki, Jill A. Rosenfeld, Susan L. Samson, Daryl A. Scott, Alyssa A. Tran, Tiphanie P. Vogel, Michael F. Wangler, Shinya Yamamoto, Christine M. Eng, Pengfei Liu, Patricia A. Ward, Edward Behrens, Matthew Deardorff, Marni Falk, Kelly Hassey, Kathleen Sullivan, Adeline Vanderver, David B. Goldstein, Heidi Cope, Allyn McConkie-Rosell, Kelly Schoch, Vandana Shashi, Edward C. Smith, Rebecca C. Spillmann, Jennifer A. Sullivan, Queenie K.-G. Tan, Nicole M. Walley, Pankaj B. Agrawal, Alan H. Beggs, Gerard T. Berry, Lauren C. Briere, Laurel A. Cobban, Matthew Coggins, Cynthia M. Cooper, Elizabeth L. Fieg, Frances High, Ingrid A. Holm, Susan Korrick, Joel B. Krier, Sharyn A. Lincoln, Joseph Loscalzo, Richard L. Maas, Calum A. MacRae, J. Carl Pallais, Deepak A. Rao, Lance H. Rodan, Edwin K. Silverman, Joan M. Stoler, David A. Sweetser, Melissa Walker, Chris A. Walsh, Cecilia Esteves, Emily G. Kelley, Isaac S. Kohane, Kimberly LeBlanc, Alexa T. McCray, Anna Nagy, Surendra Dasari, Brendan C. Lanpher, Ian R. Lanza, Eva Morava, Devin Oglesbee, Guney Bademci, Deborah Barbouth, Stephanie Bivona, Olveen Carrasquillo, Ta Chen Peter Chang, Irman Forghani, Alana Grajewski, Rosario Isasi, Byron Lam, Roy Levitt, Xue Zhong Liu, Jacob McCauley, Ralph Sacco, Mario Saporta, Judy Schaechter, Mustafa Tekin, Fred Telischi, Willa Thorson, Stephan Zuchner, Heather A. Colley, Jyoti G. Dayal, David J. Eckstein, Laurie C. Findley, Donna M. Krasnewich, Laura A. Mamounas, Teri A. Manolio, John J. Mulvihill, Grace L. LaMoure, Madison P. Goldrich, Tiina K. Urv, Argenia L. Doss, Maria T. Acosta, Carsten Bonnenmann, Precilla D’Souza, David D. Draper, Carlos Ferreira, Rena A. Godfrey, Catherine A. Groden, Valerie V. Maduro, Thomas C. Markello, Avi Nath, Donna Novacic, Barbara N. Pusey, Colleen E. Wahl, Eva Baker, Elizabeth A. Burke, David R. Adams, May Christine V. Malicdan, Cynthia J. Tifft, Lynne A. Wolfe, John Yang, Bradley Power, Bernadette Gochuico, Laryssa Huryn, Lea Latham, Joie Davis, Deborah Mosbrook-Davis, Francis Rossignol, Ben Solomon, John MacDowall, Audrey Thurm, Wadih Zein, Muhammad Yousef, Margaret Adam, Laura Amendola, Michael Bamshad, Anita Beck, Jimmy Bennett, Beverly Berg-Rood, Elizabeth Blue, Brenna Boyd, Peter Byers, Sirisak Chanprasert, Michael Cunningham, Katrina Dipple, Daniel Doherty, Dawn Earl, Ian Glass, Katie Golden-Grant, Sihoun Hahn, Anne Hing, Fuki M. Hisama, Martha Horike-Pyne, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Christina Lam, Kenneth Maravilla, Heather Mefford, J. Lawrence Merritt, Ghayda Mirzaa, Deborah Nickerson, Wendy Raskind, Natalie Rosenwasser, C. Ron Scott, Angela Sun, Virginia Sybert, Stephanie Wallace, Mark Wener, Tara Wenger, Euan A. Ashley, Gill Bejerano, Jonathan A. Bernstein, Devon Bonner, Terra R. Coakley, Liliana Fernandez, Paul G. Fisher, Laure Fresard, Jason Hom, Yong Huang, Jennefer N. Kohler, Elijah Kravets, Marta M. Majcherska, Beth A. Martin, Shruti Marwaha, Colleen E. McCormack, Archana N. Raja, Chloe M. Reuter, Maura Ruzhnikov, Jacinda B. Sampson, Kevin S. Smith, Shirley Sutton, Holly K. Tabor, Brianna M. Tucker, Matthew T. Wheeler, Diane B. Zastrow, Chunli Zhao, William E. Byrd, Andrew B. Crouse, Matthew Might, Mariko Nakano-Okuno, Jordan Whitlock, Gabrielle Brown, Manish J. Butte, Esteban C. Dell’Angelica, Naghmeh Dorrani, Emilie D. Douine, Brent L. Fogel, Irma Gutierrez, Alden Huang, Deborah Krakow, Hane Lee, Sandra K. Loo, Bryan C. Mak, Martin G. Martin, Julian A. Martínez-Agosto, Elisabeth McGee, Stanley F. Nelson, Shirley Nieves-Rodriguez, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, Genecee Renteria, Rebecca H. Signer, Janet S. Sinsheimer, Jijun Wan, Lee-kai Wang, Katherine Wesseling Perry, Jeremy D. Woods, Justin Alvey, Ashley Andrews, Jim Bale, John Bohnsack, Lorenzo Botto, John Carey, Laura Pace, Nicola Longo, Gabor Marth, Paolo Moretti, Aaron Quinlan, Matt Velinder, Dave Viskochil, Pinar Bayrak-Toydemir, Rong Mao, Monte Westerfield, Anna Bican, Laura Duncan, Rizwan Hamid, Jennifer Kennedy, Mary Kozuira, John H. Newman, John A. Phillips, Lynette Rives, Amy K. Robertson, Emily Solem, Joy D. Cogan, F. Sessions Cole, Nichole Hayes, Dana Kiley, Kathy Sisco, Jennifer Wambach, Daniel Wegner, Dustin Baldridge, Stephen Pak, Timothy Schedl, Jimann Shin, Lilianna Solnica-Krezel, Quinten Waisfisz, Petra J.G. Zwijnenburg, Alban Ziegler, Magalie Barth, Rosemarie Smith, Sara Ellingwood, Deborah Gaebler-Spira, Somayeh Bakhtiari, Michael C. Kruer, Antoine H.C. van Kampen, Ronald J.A. Wanders, Hans R. Waterham, David Cassiman, Frédéric M. Vaz, Laboratory Genetic Metabolic Diseases, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, APH - Methodology, Epidemiology and Data Science, APH - Personalized Medicine, Laboratory for General Clinical Chemistry, ARD - Amsterdam Reproduction and Development, Human genetics, ACS - Atherosclerosis & ischemic syndromes, and Amsterdam Reproduction & Development (AR&D)
Subjects: Candidate gene, Hereditary spastic paraplegia, Undiagnosed Diseases Network, Neurological disorder, Biology, medicine.disease, Molecular biology, Article, Biochemical phenotype, Bilateral Cataracts, Gene panel, medicine, Ether lipid synthesis, In patient, Genetics (clinical)
Abstract: Author(s): Ferdinandusse, Sacha; McWalter, Kirsty; Te Brinke, Heleen; IJlst, Lodewijk; Mooijer, Petra M; Ruiter, Jos PN; van Lint, Alida EM; Pras-Raves, Mia; Wever, Eric; Millan, Francisca; Guillen Sacoto, Maria J; Begtrup, Amber; Tarnopolsky, Mark; Brady, Lauren; Ladda, Roger L; Sell, Susan L; Nowak, Catherine B; Douglas, Jessica; Tian, Cuixia; Ulm, Elizabeth; Perlman, Seth; Drack, Arlene V; Chong, Karen; Martin, Nicole; Brault, Jennifer; Brokamp, Elly; Toro, Camilo; Gahl, William A; Macnamara, Ellen F; Wolfe, Lynne; Undiagnosed Diseases Network; Waisfisz, Quinten; Zwijnenburg, Petra JG; Ziegler, Alban; Barth, Magalie; Smith, Rosemarie; Ellingwood, Sara; Gaebler-Spira, Deborah; Bakhtiari, Somayeh; Kruer, Michael C; van Kampen, Antoine HC; Wanders, Ronald JA; Waterham, Hans R; Cassiman, David; Vaz, Frederic M | Abstract: PurposeIn this study we investigate the disease etiology in 12 patients with de novo variants in FAR1 all resulting in an amino acid change at position 480 (p.Arg480Cys/His/Leu).MethodsFollowing next-generation sequencing and clinical phenotyping, functional characterization was performed in patients' fibroblasts using FAR1 enzyme analysis, FAR1 immunoblotting/immunofluorescence, and lipidomics.ResultsAll patients had spastic paraparesis and bilateral congenital/juvenile cataracts, in most combined with speech and gross motor developmental delay and truncal hypotonia. FAR1 deficiency caused by biallelic variants results in defective ether lipid synthesis and plasmalogen deficiency. In contrast, patients' fibroblasts with the de novo FAR1 variants showed elevated plasmalogen levels. Further functional studies in fibroblasts showed that these variants cause a disruption of the plasmalogen-dependent feedback regulation of FAR1 protein levels leading to uncontrolled ether lipid production.ConclusionHeterozygous de novo variants affecting the Arg480 residue of FAR1 lead to an autosomal dominant disorder with a different disease mechanism than that of recessive FAR1 deficiency and a diametrically opposed biochemical phenotype. Our findings show that for patients with spastic paraparesis and bilateral cataracts, FAR1 should be considered as a candidate gene and added to gene panels for hereditary spastic paraplegia, cerebral palsy, and juvenile cataracts.
Published: 2021
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25. Clinical utility of brain MRS imaging of patients with adult-onset non-cirrhotic hyperammonemia

Author: Gerard T. Berry, Joel B. Krier, Andrew B. Stergachis, Sai Merugumala, and Alexander P. Lin
Subjects: Pathology, medicine.medical_specialty, Medicine (General), Urea cycle disorder, QH301-705.5, Gln - Glutamine, 03 medical and health sciences, PCG, Posterior cingulate gyrus, 0302 clinical medicine, Endocrinology, R5-920, Magnetic resonance spectroscopy, mI, Myo-inositol, NAAG, N-acetylaspartylglutamate, Genetics, medicine, PWM, Parietal white matter, Brain magnetic resonance imaging, In patient, Clinical care, Biology (General), Molecular Biology, Cerebral glutamine, Gln, Glutamine, 0303 health sciences, business.industry, 030305 genetics & heredity, Hyperammonemia, medicine.disease, Glutamine, Non-cirrhotic hyperammonemia, NCH, Non-cirrhotic hyperammonemia, Central pontine myelinolysis, Cerebral myo-inositol, business, NAA, N-acetylaspartate, 030217 neurology & neurosurgery, BG, Basal ganglia, Research Paper
Abstract: Adult-onset non-cirrhotic hyperammonemia (NCH) is a rare, but often fatal condition that can result in both reversible and irreversible neurological defects. Here we present five cases of adult-onset non-cirrhotic hyperammonemia wherein brain magnetic resonance spectroscopy (MRS) scans for cerebral glutamine (Gln) and myo-inositol (mI) levels helped guide clinical management. Specifically, we demonstrate that when combined with traditional brain magnetic resonance imaging (MRI) scans, cerebral Gln and mI MRS can help disentangle the reversible from irreversible neurological defects associated with hyperammonemic crisis. Specifically, we demonstrate that whereas an elevated brain MRS Gln level is associated with reversible neurological defects, markedly low mI levels are associated with a risk for irreversible neurological defects such as central pontine myelinolysis. Overall, our findings indicate the utility of brain MRS in guiding clinical care and prognosis in patients with adult-onset non-cirrhotic hyperammonemia.
Published: 2021

26. Clinical Utility of Pharmacogenomic Data Collected by a Health-System Biobank to Predict and Prevent Adverse Drug Events

Author: Sonam N, Shah, Roseann S, Gammal, Mary G, Amato, Maryam, Alobaidly, Dariel Delos, Reyes, Sarah, Hasan, Diane L, Seger, Joel B, Krier, and David W, Bates
Subjects: Drug-Related Side Effects and Adverse Reactions, HLA-A Antigens, HLA-B Antigens, Pharmacogenetics, Vitamin K Epoxide Reductases, Humans, Oxcarbazepine, Warfarin, Biological Specimen Banks
Abstract: Medication-related harm represents a significant issue for patient safety and quality of care. One strategy to avoid preventable adverse drug events is to utilize patient-specific factors such as pharmacogenomics (PGx) to individualize therapy.We measured the number of patients enrolled in a health-system biobank with actionable PGx results who received relevant medications and assessed the incidence of adverse drug events (ADEs) that might have been prevented had the PGx results been used to inform prescribing.Patients with actionable PGx results in the following four genes with Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines were identified: HLA-A*31:01, HLA-B*15:02, TPMT, and VKORC1. The patients who received interacting medications (carbamazepine, oxcarbazepine, thiopurines, or warfarin) were identified, and electronic health records were reviewed to determine the incidence of potentially preventable ADEs.Of 36,424 patients with PGx results, 2327 (6.4%) were HLA-A*31:01 positive; 3543 (9.7%) were HLA-B*15:02 positive; 2893 (7.9%) were TPMT intermediate metabolizers; and 4249 (11.7%) were homozygous for the VKORC1 c.1639 GA variant. Among patients positive for one of the HLA variants who received carbamazepine or oxcarbazepine (n = 92), four (4.3%) experienced a rash that warranted drug discontinuation. Among the TPMT intermediate metabolizers who received a thiopurine (n = 56), 11 (19.6%) experienced severe myelosuppression that warranted drug discontinuation. Among patients homozygous for the VKORC1 c.1639 GA variant who received warfarin (n = 379), 85 (22.4%) experienced active bleeding and/or international normalized ratio (INR) 5 that warranted drug discontinuation or dose reduction.Patients with actionable PGx results from a health-system biobank who received relevant medications experienced predictable ADEs. These ADEs may have been prevented if the patients' PGx results were available in the electronic health record with clinical decision support prior to prescribing.
Published: 2021

27. Discordant results between conventional newborn screening and genomic sequencing in the BabySeq Project

Author: Monica H. Wojcik, Tian Zhang, Ozge Ceyhan-Birsoy, Casie A. Genetti, Matthew S. Lebo, Timothy W. Yu, Richard B. Parad, Ingrid A. Holm, Heidi L. Rehm, Alan H. Beggs, Robert C. Green, Pankaj B. Agrawal, Wendi N. Betting, Kurt D. Christensen, Dmitry Dukhovny, Shawn Fayer, Leslie A. Frankel, Chet Graham, Amanda M. Guiterrez, Maegan Harden, Joel B. Krier, Harvey L. Levy, Xingquan Lu, Kalotina Machini, Amy L. McGuire, Jaclyn B. Murry, Medha Naik, Tiffany T. Nguyen, Hayley A. Peoples, Stacey Pereira, Devan Petersen, Uma Ramamurthy, Vivek Ramanathan, Amy Roberts, Jill O. Robinson, Serguei Roumiantsev, Talia S. Schwartz, Tina K. Truong, Grace E. VanNoy, and Susan E. Waisbren
Subjects: 0301 basic medicine, Pediatrics, medicine.medical_specialty, Population, 030105 genetics & heredity, Monogenic disease, Article, 03 medical and health sciences, Neonatal Screening, Risk Factors, Exome Sequencing, False positive paradox, Medicine, Humans, education, Genetics (clinical), Exome sequencing, Newborn screening, education.field_of_study, business.industry, Genomic sequencing, Infant, Newborn, food and beverages, Chromosome Mapping, Infant, Hearing screen, Genomics, 030104 developmental biology, embryonic structures, business, Genetic diagnosis
Abstract: Purpose Newborn screening (NBS) is performed to identify neonates at risk for actionable, severe, early-onset disorders, many of which are genetic. The BabySeq Project randomized neonates to receive conventional NBS or NBS plus exome sequencing (ES) capable of detecting sequence variants that may also diagnose monogenic disease or indicate genetic disease risk. We therefore evaluated how ES and conventional NBS results differ in this population. Methods We compared results of NBS (including hearing screens) and ES for 159 infants in the BabySeq Project. Infants were considered "NBS positive" if any abnormal result was found indicating disease risk and "ES positive" if ES identified a monogenic disease risk or a genetic diagnosis. Results Most infants (132/159, 84%) were NBS and ES negative. Only one infant was positive for the same disorder by both modalities. Nine infants were NBS positive/ES negative, though seven of these were subsequently determined to be false positives. Fifteen infants were ES positive/NBS negative, all of which represented risk of genetic conditions that are not included in NBS programs. No genetic explanation was identified for eight infants referred on the hearing screen. Conclusion These differences highlight the complementarity of information that may be gleaned from NBS and ES in the newborn period.
Published: 2021

28. AMELIE 3: Fully Automated Mendelian Patient Reanalysis at Under 1 Alert per Patient per Year

Author: Stan F. Nelson, Matthew T. Wheeler, Euan A. Ashley, Christina G.S. Palmer, Rizwan Hamid, David Neil Cooper, Joy D. Cogan, Paolo Moretti, Jonathan A. Bernstein, Karthik A. Jagadeesh, Johannes Birgmeier, Joel B. Krier, Joan M. Stoler, David R. Adams, Gill Bejerano, Elizabeth A. Worthey, Cole A. Deisseroth, Peter D. Stenson, Julian A. Martinez-Agosto, Shruti Marwaha, Ethan Steinberg, Jill A. Rosenfeld, Vandana Shashi, Devon Bonner, Ethan E. Bodle, Christine M. Eng, and Jennefer N. Kohler
Subjects: business.industry, medicine.disease, Digital health, symbols.namesake, Fully automated, Mendelian inheritance, symbols, Medicine, Per patient per year, Medical emergency, Medical diagnosis, business, Mendelian disorders, Exome sequencing
Abstract: BackgroundMany thousands of patients with a suspected Mendelian disease have their exomes/genomes sequenced every year, but only about 30% receive a definitive diagnosis. Since a novel Mendelian gene-disease association is published on average every business day, thousands of undiagnosed patient cases could receive a diagnosis each year if their genomes were regularly compared to the latest literature. With millions of genomes expected to be sequenced for rare disease analysis by 2025, and considering the current publication rate of 1.1 million new articles per annum in PubMed, manually reanalyzing the growing cases of undiagnosed patients is not sustainable.MethodsWe describe a fully automated reanalysis framework for patients with suspected, but undiagnosed, Mendelian disorders. The presented framework was tested by automatically parsing all ∼100,000 newly published peer reviewed papers every month and matching them on genotype and phenotype with all stored undiagnosed patients. If a new article contains a possible diagnosis for an undiagnosed patient, the system provides notification. We test the accuracy of the automatic reanalysis system on 110 patients, including 61 with available trio data.ResultsEven when trained only on older data, our system identifies 80% of reanalysis diagnoses, while sending only 0.5-1 alerts per patient per year, a 100-1,000-fold efficiency gain over manual literature surveillance of equivalent yield.ConclusionWe show that automatic reanalysis of patients with suspected Mendelian disease is feasible and has the potential to greatly streamline diagnosis. Our system is not intended to replace clinical judgment. Rather, clinical diagnostic services could greatly benefit from a modest re-allocation of time from manual literature exploration to review of automated reanalysis alerts. Our system additionally supports a new paradigm for medical IT systems: proactive, continuously learning and consequently able to autonomously identify valuable insights as they emerge in digital health records. We have launched automated patient reanalysis, trained on the latest data, with user accounts and daily literature updates at https://AMELIE.stanford.edu.
Published: 2021
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29. Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations

Author: Lance H. Rodan, Rebecca C. Spillmann, Harley T. Kurata, Shawn M. Lamothe, Jasmine Maghera, Rami Abou Jamra, Anna Alkelai, Stylianos E. Antonarakis, Isis Atallah, Omer Bar-Yosef, Frédéric Bilan, Kathrine Bjorgo, Xavier Blanc, Patrick Van Bogaert, Yoav Bolkier, Lindsay C. Burrage, Björn U. Christ, Jorge L. Granadillo, Patricia Dickson, Kirsten A. Donald, Christèle Dubourg, Aviva Eliyahu, Lisa Emrick, Kendra Engleman, Michaela Veronika Gonfiantini, Jean-Marc Good, Judith Kalser, Chiara Kloeckner, Guus Lachmeijer, Marina Macchiaiolo, Francesco Nicita, Sylvie Odent, Emily O’Heir, Xilma Ortiz-Gonzalez, Marta Pacio-Miguez, María Palomares-Bralo, Loren Pena, Konrad Platzer, Mathieu Quinodoz, Emmanuelle Ranza, Jill A. Rosenfeld, Eliane Roulet-Perez, Avni Santani, Fernando Santos-Simarro, Ben Pode-Shakked, Cara Skraban, Rachel Slaugh, Andrea Superti-Furga, Isabelle Thiffault, Richard H. van Jaabrsveld, Marie Vincent, Hong-Gang Wang, Pia Zacher, Mercedes E. Alejandro, Mahshid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Hsiao-Tuan Chao, Gary D. Clark, William J. Craigen, Hongzheng Dai, Shweta U. Dhar, Lisa T. Emrick, Alica M. Goldman, Neil A. Hanchard, Fariha Jamal, Lefkothea Karaviti, Seema R. Lalani, Brendan H. Lee, Richard A. Lewis, Ronit Marom, Paolo M. Moretti, David R. Murdock, Sarah K. Nicholas, James P. Orengo, Jennifer E. Posey, Lorraine Potocki, Susan L. Samson, Daryl A. Scott, Alyssa A. Tran, Tiphanie P. Vogel, Michael F. Wangler, Shinya Yamamoto, Christine M. Eng, Pengfei Liu, Patricia A. Ward, Edward Behrens, Matthew Deardorff, Marni Falk, Kelly Hassey, Kathleen Sullivan, Adeline Vanderver, David B. Goldstein, Heidi Cope, Allyn McConkie-Rosell, Kelly Schoch, Vandana Shashi, Edward C. Smith, Jennifer A. Sullivan, Queenie K.-G. Tan, Nicole M. Walley, Pankaj B. Agrawal, Alan H. Beggs, Gerard T. Berry, Lauren C. Briere, Laurel A. Cobban, Matthew Coggins, Cynthia M. Cooper, Elizabeth L. Fieg, Frances High, Ingrid A. Holm, Susan Korrick, Joel B. Krier, Sharyn A. Lincoln, Joseph Loscalzo, Richard L. Maas, Calum A. MacRae, J. Carl Pallais, Deepak A. Rao, Edwin K. Silverman, Joan M. Stoler, David A. Sweetser, Melissa Walker, Chris A. Walsh, Cecilia Esteves, Emily G. Kelley, Isaac S. Kohane, Kimberly LeBlanc, Alexa T. McCray, Anna Nagy, Surendra Dasari, Brendan C. Lanpher, Ian R. Lanza, Eva Morava, Devin Oglesbee, Guney Bademci, Deborah Barbouth, Stephanie Bivona, Olveen Carrasquillo, Ta Chen Peter Chang, Irman Forghani, Alana Grajewski, Rosario Isasi, Byron Lam, Roy Levitt, Xue Zhong Liu, Jacob McCauley, Ralph Sacco, Mario Saporta, Judy Schaechter, Mustafa Tekin, Fred Telischi, Willa Thorson, Stephan Zuchner, Heather A. Colley, Jyoti G. Dayal, David J. Eckstein, Laurie C. Findley, Donna M. Krasnewich, Laura A. Mamounas, Teri A. Manolio, John J. Mulvihill, Grace L. LaMoure, Madison P. Goldrich, Tiina K. Urv, Argenia L. Doss, Maria T. Acosta, Carsten Bonnenmann, Precilla D’Souza, David D. Draper, Carlos Ferreira, Rena A. Godfrey, Catherine A. Groden, Ellen F. Macnamara, Valerie V. Maduro, Thomas C. Markello, Avi Nath, Donna Novacic, Barbara N. Pusey, Camilo Toro, Colleen E. Wahl, Eva Baker, Elizabeth A. Burke, David R. Adams, William A. Gahl, May Christine V. Malicdan, Cynthia J. Tifft, Lynne A. Wolfe, John Yang, Bradley Power, Bernadette Gochuico, Laryssa Huryn, Lea Latham, Joie Davis, Deborah Mosbrook-Davis, Francis Rossignol, null Ben Solomon, John MacDowall, Audrey Thurm, Wadih Zein, Muhammad Yousef, Margaret Adam, Laura Amendola, Michael Bamshad, Anita Beck, Jimmy Bennett, Beverly Berg-Rood, Elizabeth Blue, Brenna Boyd, Peter Byers, Sirisak Chanprasert, Michael Cunningham, Katrina Dipple, Daniel Doherty, Dawn Earl, Ian Glass, Katie Golden-Grant, Sihoun Hahn, Anne Hing, Fuki M. Hisama, Martha Horike-Pyne, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Christina Lam, Kenneth Maravilla, Heather Mefford, J. Lawrence Merritt, Ghayda Mirzaa, Deborah Nickerson, Wendy Raskind, Natalie Rosenwasser, C. Ron Scott, Angela Sun, Virginia Sybert, Stephanie Wallace, Mark Wener, Tara Wenger, Euan A. Ashley, Gill Bejerano, Jonathan A. Bernstein, Devon Bonner, Terra R. Coakley, Liliana Fernandez, Paul G. Fisher, Laure Fresard, Jason Hom, Yong Huang, Jennefer N. Kohler, Elijah Kravets, Marta M. Majcherska, Beth A. Martin, Shruti Marwaha, Colleen E. McCormack, Archana N. Raja, Chloe M. Reuter, Maura Ruzhnikov, Jacinda B. Sampson, Kevin S. Smith, Shirley Sutton, Holly K. Tabor, Brianna M. Tucker, Matthew T. Wheeler, Diane B. Zastrow, Chunli Zhao, William E. Byrd, Andrew B. Crouse, Matthew Might, Mariko Nakano-Okuno, Jordan Whitlock, Gabrielle Brown, Manish J. Butte, Esteban C. Dell’Angelica, Naghmeh Dorrani, Emilie D. Douine, Brent L. Fogel, Irma Gutierrez, Alden Huang, Deborah Krakow, Hane Lee, Sandra K. Loo, Bryan C. Mak, Martin G. Martin, Julian A. Martínez-Agosto, Elisabeth McGee, Stanley F. Nelson, Shirley Nieves-Rodriguez, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, Genecee Renteria, Rebecca H. Signer, Janet S. Sinsheimer, Jijun Wan, Lee-kai Wang, Katherine Wesseling Perry, Jeremy D. Woods, Justin Alvey, Ashley Andrews, Jim Bale, John Bohnsack, Lorenzo Botto, John Carey, Laura Pace, Nicola Longo, Gabor Marth, Paolo Moretti, Aaron Quinlan, Matt Velinder, Dave Viskochil, Pinar Bayrak-Toydemir, Rong Mao, Monte Westerfield, Anna Bican, Elly Brokamp, Laura Duncan, Rizwan Hamid, Jennifer Kennedy, Mary Kozuira, John H. Newman, John A. PhillipsIII, Lynette Rives, Amy K. Robertson, Emily Solem, Joy D. Cogan, F. Sessions Cole, Nichole Hayes, Dana Kiley, Kathy Sisco, Jennifer Wambach, Daniel Wegner, Dustin Baldridge, Stephen Pak, Timothy Schedl, Jimann Shin, Lilianna Solnica-Krezel, Eric Rush, Geoffrey S. Pitt, Ping Yee Billie Au, Boston Children's Hospital, University of Alberta, Universität Leipzig [Leipzig], Geneva University Hospital (HUG), Tel Aviv University [Tel Aviv], Service Génétique Médicale [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Cibles moléculaires et thérapeutiques de la maladie d'Alzheimer (CIMoTHeMA), Université de Poitiers, Laboratoire Jacques-Louis Lions (LJLL (UMR_7598)), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Baylor College of Medicine (BCM), Baylor University, Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Lausanne University Hospital, Centre de référence Maladies Rares CLAD-Ouest [Rennes], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Children’s Hospital of Philadelphia (CHOP ), Hospital Universitario La Paz, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre hospitalier universitaire de Nantes (CHU Nantes), Duke University [Durham], University of Kansas Medical Center [Lawrence], University of Missouri System, Children's Mercy Hospital [Kansas City], Weill Cornell Medicine [New York], University of Calgary, Research reported in this paper was supported by the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director under award number(s) (U01HG007709 [Baylor College of Medicine] and U01HG007672 [Duke University to V.S.]). Additional funding for this project was under award number 1RO1HD090132-01A1 (Cornell University to G.P.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional funding was provided by a Canadian Institutes of Health Research Grant (MOP-97988 to H.T.K.), and a Rowland and Muriel Haryett Fellowship (University of Alberta, to S.M.L.) and a fellowship from the Ministry of Education and Research of the Community of Madrid to M.P.M. (B2017/BMD-3721), and microgrant from the Rare Disease Foundation (P.Y.B.A. and H.T.K.). Sequencing and analysis was supported by the National Human Genome Research Institute grants UM1 HG008900 and R01 HG009141. K.A.D., B.C., and E.O. were supported the National Institute of Mental Health U01 MH119689., Universität Leipzig, Columbia University Medical Center (CUMC), Columbia University [New York], Tel Aviv University (TAU), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Unité de recherche de l'institut du thorax (ITX-lab), University of Kansas Medical Center [Kansas City, KS, USA], Weill Cornell Medicine [Cornell University], and Cornell University [New York]
Subjects: Ataxia, Calcium Channels, L-Type, Long QT syndrome, Timothy syndrome, Bioinformatics, Article, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Intellectual disability, medicine, Missense mutation, Humans, Autistic Disorder, Genetics (clinical), 030304 developmental biology, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, medicine.disease, Hypotonia, Long QT Syndrome, Phenotype, Autism, Syndactyly, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: International audience; Purpose:CACNA1C encodes the alpha-1-subunit of a voltage-dependent L-type calcium channel expressed in human heart and brain. Heterozygous variants in CACNA1C have previously been reported in association with Timothy syndrome and long QT syndrome. Several case reports have suggested that CACNA1C variation may also be associated with a primarily neurological phenotype.Methods:We describe 25 individuals from 22 families with heterozygous variants in CACNA1C, who present with predominantly neurological manifestations.Results:Fourteen individuals have de novo, nontruncating variants and present variably with developmental delays, intellectual disability, autism, hypotonia, ataxia, and epilepsy. Functional studies of a subgroup of missense variants via patch clamp experiments demonstrated differential effects on channel function in vitro, including loss of function (p.Leu1408Val), neutral effect (p.Leu614Arg), and gain of function (p.Leu657Phe, p.Leu614Pro). The remaining 11 individuals from eight families have truncating variants in CACNA1C. The majority of these individuals have expressive language deficits, and half have autism.Conclusion:We expand the phenotype associated with CACNA1C variants to include neurodevelopmental abnormalities and epilepsy, in the absence of classic features of Timothy syndrome or long QT syndrome.
Published: 2020
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30. Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor beta Signaling

Author: Brett V. Johnson, Raman Kumar, Sabrina Oishi, Suzy Alexander, Maria Kasherman, Michelle Sanchez Vega, Atma Ivancevic, Alison Gardner, Deepti Domingo, Mark Corbett, Euan Parnell, Sehyoun Yoon, Tracey Oh, Matthew Lines, Henrietta Lefroy, Usha Kini, Margot Van Allen, Sabine Grønborg, Sandra Mercier, Sébastien Küry, Stéphane Bézieau, Laurent Pasquier, Martine Raynaud, Alexandra Afenjar, Thierry Billette de Villemeur, Boris Keren, Julie Désir, Lionel Van Maldergem, Martina Marangoni, Nicola Dikow, David A. Koolen, Peter M. VanHasselt, Marjan Weiss, Petra Zwijnenburg, Joaquim Sa, Claudia Falcao Reis, Carlos López-Otín, Olaya Santiago-Fernández, Alberto Fernández-Jaén, Anita Rauch, Katharina Steindl, Pascal Joset, Amy Goldstein, Suneeta Madan-Khetarpal, Elena Infante, Elaine Zackai, Carey Mcdougall, Vinodh Narayanan, Keri Ramsey, Saadet Mercimek-Andrews, Loren Pena, Vandana Shashi, Kelly Schoch, Jennifer A. Sullivan, Filippo Pinto e Vairo, Pavel N. Pichurin, Sarah A. Ewing, Sarah S. Barnett, Eric W. Klee, M. Scott Perry, Mary Kay Koenig, Catherine E. Keegan, Jane L. Schuette, Stephanie Asher, Yezmin Perilla-Young, Laurie D. Smith, Jill A. Rosenfeld, Elizabeth Bhoj, Paige Kaplan, Dong Li, Renske Oegema, Ellen van Binsbergen, Bert van der Zwaag, Marie Falkenberg Smeland, Ioana Cutcutache, Matthew Page, Martin Armstrong, Angela E. Lin, Marcie A. Steeves, Nicolette den Hollander, Mariëtte J.V. Hoffer, Margot R.F. Reijnders, Serwet Demirdas, Daniel C. Koboldt, Dennis Bartholomew, Theresa Mihalic Mosher, Scott E. Hickey, Christine Shieh, Pedro A. Sanchez-Lara, John M. Graham, Kamer Tezcan, G.B. Schaefer, Noelle R. Danylchuk, Alexander Asamoah, Kelly E. Jackson, Naomi Yachelevich, Margaret Au, Luis A. Pérez-Jurado, Tjitske Kleefstra, Peter Penzes, Stephen A. Wood, Thomas Burne, Tyler Mark Pierson, Michael Piper, Jozef Gécz, Lachlan A. Jolly, Maria T. Acosta, David R. Adams, Aaron Aday, Mercedes E. Alejandro, Patrick Allard, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanyam, Dustin Baldridge, Deborah Barbouth, Gabriel F. Batzli, Alan H. Beggs, Hugo J. Bellen, Jonathan A. Bernstein, Gerard T. Berry, Anna Bican, David P. Bick, Camille L. Birch, Stephanie Bivona, Carsten Bonnenmann, Devon Bonner, Braden E. Boone, Bret L. Bostwick, Lauren C. Briere, Elly Brokamp, Donna M. Brown, Matthew Brush, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, Olveen Carrasquillo, Ta Chen Peter Chang, Hsiao-Tuan Chao, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Precilla D'Souza, Surendra Dasari, Mariska Davids, Jean M. Davidson, Jyoti G. Dayal, Esteban C. Dell'Angelica, Shweta U. Dhar, Naghmeh Dorrani, Daniel C. Dorset, Emilie D. Douine, David D. Draper, Annika M. Dries, Laura Duncan, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Gregory M. Enns, Cecilia Esteves, Tyra Estwick, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Paul G. Fisher, Brent L. Fogel, Irman Forghani, Noah D. Friedman, William A. Gahl, Rena A. Godfrey, Alica M. Goldman, David B. Goldstein, Jean-Philippe F. Gourdine, Alana Grajewski, Catherine A. Groden, Andrea L. Gropman, Melissa Haendel, Rizwan Hamid, Neil A. Hanchard, Frances High, Ingrid A. Holm, Jason Hom, Alden Huang, Yong Huang, Rosario Isasi, Fariha Jamal, Yong-hui Jiang, Jean M. Johnston, Angela L. Jones, Lefkothea Karaviti, Emily G. Kelley, David M. Koeller, Isaac S. Kohane, Jennefer N. Kohler, Deborah Krakow, Donna M. Krasnewich, Susan Korrick, Mary Koziura, Joel B. Krier, Jennifer E. Kyle, Seema R. Lalani, Byron Lam, Brendan C. Lanpher, Ian R. Lanza, C. Christopher Lau, Jozef Lazar, Kimberly LeBlanc, Brendan H. Lee, Hane Lee, Roy Levitt, Shawn E. Levy, Richard A. Lewis, Sharyn A. Lincoln, Pengfei Liu, Xue Zhong Liu, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Marta M. Majcherska, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Thomas C. Markello, Ronit Marom, Martin G. Martin, Julian A. Martínez-Agosto, Shruti Marwaha, Thomas May, Jacob McCauley, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Jason D. Merker, Thomas O. Metz, Matthew Might, Eva Morava-Kozicz, Paolo M. Moretti, Marie Morimoto, John J. Mulvihill, David R. Murdock, Avi Nath, Stan F. Nelson, J. Scott Newberry, John H. Newman, Sarah K. Nicholas, Donna Novacic, Devin Oglesbee, James P. Orengo, Stephen Pak, J. Carl Pallais, Christina GS. Palmer, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, John H. Postlethwait, Lorraine Potocki, Barbara N. Pusey, Genecee Renteri, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Robb K. Rowley, Ralph Sacco, Jacinda B. Sampson, Susan L. Samson, Mario Saporta, Judy Schaechter, Timothy Schedl, Daryl A. Scott, Lisa Shakachite, Prashant Sharma, Kathleen Shields, Jimann Shin, Rebecca Signer, Catherine H. Sillari, Edwin K. Silverman, Janet S. Sinsheimer, Kevin S. Smith, Lilianna Solnica-Krezel, Rebecca C. Spillmann, Joan M. Stoler, Nicholas Stong, David A. Sweetser, Cecelia P. Tamburro, Queenie K.-G. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Tiina K. Urv, Tiphanie P. Vogel, Daryl M. Waggott, Colleen E. Wahl, Nicole M. Walley, Chris A. Walsh, Melissa Walker, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Katrina M. Waters, Bobbie-Jo M. Webb-Robertson, Daniel Wegner, Monte Westerfield, Matthew T. Wheeler, Anastasia L. Wise, Lynne A. Wolfe, Jeremy D. Woods, Elizabeth A. Worthey, Shinya Yamamoto, John Yang, Amanda J. Yoon, Guoyun Yu, Diane B. Zastrow, Chunli Zhao, Stephan Zuchner, William Gahl, Clinical Genetics, Human genetics, Amsterdam Reproduction & Development (AR&D), ACS - Atherosclerosis & ischemic syndromes, MUMC+: DA KG Polikliniek (9), and RS: FHML non-thematic output
Subjects: Male, 0301 basic medicine, Brain malformation, Developmental Disabilities, INTERACTS, USP9X, Haploinsufficiency, in-vitro, CELL-MIGRATION, Deubiquitylating enzyme, Biology, Hippocampus, of-function mutations, Article, liquid facets, TGFβ, Mice, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, TGF beta, Transforming Growth Factor beta, Intellectual Disability, Intellectual disability, medicine, Animals, Humans, Missense mutation, deubiquitinating enzyme, Biological Psychiatry, fam/usp9x, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Male Phenotype, medicine.disease, Phenotype, Hypotonia, 030104 developmental biology, Female, medicine.symptom, Ubiquitin Thiolesterase, Neuroscience, 030217 neurology & neurosurgery, Signal Transduction, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Transforming growth factor
Abstract: Contains fulltext : 218305.pdf (Publisher’s version ) (Closed access) BACKGROUND: The X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative. METHODS: We used clinically recommended guidelines to collect and interrogate the pathogenicity of 44 USP9X variants associated with neurodevelopmental disorders in males. Functional studies in patient-derived cell lines and mice were used to determine mechanisms of pathology. RESULTS: Twelve missense variants showed strong evidence of pathogenicity. We define a characteristic phenotype of the central nervous system (white matter disturbances, thin corpus callosum, and widened ventricles); global delay with significant alteration of speech, language, and behavior; hypotonia; joint hypermobility; visual system defects; and other common congenital and dysmorphic features. Comparison of in silico and phenotypical features align additional variants of unknown significance with likely pathogenicity. In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor beta signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocampal-dependent learning and memory. CONCLUSIONS: Our data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects and identify plausible mechanisms of pathogenesis centered on disrupted transforming growth factor beta signaling and hippocampal function.
Published: 2020
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31. KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation

Author: Nihr BioResource, F. Lucy Raymond, Shekeeb S. Mohammad, TD Graves, Susan J. Hayflick, Bert B.A. de Vries, Katy Barwick, Conor Fearon, Dora Steel, Mark Hallett, Asif Doja, Emilie Chan Seng, Camilo Toro, Fiona Stewart, Diane Demailly, Suh Young Jeong, Claudio M. de Gusmao, Frédérique Pavillard, Nutan Sharma, Fabienne Cyprien, Juan C Pallais, Brent L. Fogel, David R. FitzPatrick, Lucia Abela, Russell C. Dale, Bettina Balint, Natalie Trump, Michel Tchan, Sony Malhotra, Swasti Pal, Maya Topf, Manju A. Kurian, Michelle Sahagian, Julia Rankin, Laila Selim, Jeff L. Waugh, Sidney Krystal, Gustavo Polo, Caleb Rogers, Michel Mondain, Kailash P. Bhatia, Ishwar C. Verma, Marisela Dy-Hollins, Kelly A. Mills, Derek Wong, Laura Cif, William A. Gahl, Meredith W Allain, Sanaz Attaripour Isfahani, Agathe Roubertie, Jenny L. Wilson, Allison Gregory, Victoria Gonzalez, Carolyn D. Applegate, Nathalie Dorison, Jennifer A. Bassetti, Catherine Blanchet, Ada Hamosh, Deciphering Developmental Disorders Study, Hane Lee, Julien Baleine, Emma L. Baple, Gaetan Lesca, Anna Znaczko, Thomas Roujeau, Mario Sa, Laurence Lion François, Neil Mahant, Diane Doummar, Sandra Jansen, Marie Hully, Christine Coubes, Eva B. Forman, Victor S.C. Fung, Gaëtan Poulen, Raghda Zaitoun, Serena Galosi, Timothy Lynch, Xavier Vasques, Elise Schaefer, Richard Selway, Adeline Ngoh, Tuula Rinne, Philippe Coubes, Elizabeth L. Fieg, Rachel Fox, Jennifer Friedman, Andrea K. Petersen, Hugo Morales-Briceño, Rebecca Signer, Luis Rohena, Sandra Chantot Bastaraud, Chloé Laurencin, Kishore R. Kumar, Julian A. Martinez-Agosto, Ellyn Farrelly, Kathleen M. Gorman, Esther Meyer, Joel B. Krier, Ariane Soldatos, Lydie Burglen, Jean-Pierre Lin, Pierre-François Perrigault, Dolly Zhen, Harutomo Hasegawa, Mary D. King, Alba Sanchis-Juan, David A. Stevenson, Gilles Cambonie, Wui K. Chong, Christophe Milési, Vincent d'Hardemare, John R. Østergaard, Laboratoire de Recherche en Neurosciences Cliniques, IBM Systems Group, Service de Neurochirurgie [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Gui de Chauliac [Montpellier], Evelina London Children's Hospital, Institute of Child Health [London], University College of London [London] (UCL), Birkbeck College [University of London], Great Ormond Street Hospital for Children [London] (GOSH), Cambridge University Hospitals - NHS (CUH), University of Cambridge [UK] (CAM), Royal Devon and Exeter NHS Foundation Trust [UK], and Stanford University
Subjects: 0301 basic medicine, Male, Pediatrics, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Deep Brain Stimulation, DYT1 DYSTONIA, GENERALIZED DYSTONIA, VARIANTS, Cohort Studies, 0302 clinical medicine, genetics, [MATH]Mathematics [math], Deep brain stimulation (DBS), Child, Laryngeal dystonia, ComputingMilieux_MISCELLANEOUS, Dystonia, Fetal Growth Retardation, neurodevelopment, Parkinsonism, KMT2B, 3. Good health, INSIGHTS, Phenotype, Treatment Outcome, Dystonic Disorders, Child, Preschool, Cohort, Disease Progression, deep brain stimulation (DBS), dystonia, Female, Chromosome Deletion, Adult, medicine.medical_specialty, Deep brain stimulation, Adolescent, DATABASE, Mutation, Missense, Endocrine System Diseases, Laryngeal Diseases, 03 medical and health sciences, Young Adult, All institutes and research themes of the Radboud University Medical Center, medicine, Genetics, Humans, Computer Simulation, Gait Disorders, Neurologic, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, MUTATIONS, Histone-Lysine N-Methyltransferase, Original Articles, medicine.disease, Status dystonicus, 030104 developmental biology, Disease Presentation, Brain stimulation, Mutation, Quality of Life, Neurology (clinical), business, FOLLOW-UP, GAIT, 030217 neurology & neurosurgery, SYSTEM
Abstract: Heterozygous mutations in KMT2B are associated with an early-onset, progressive and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal and cervical involvement. Although KMT2B-related disease is emerging as one of the most common causes of early-onset genetic dystonia, much remains to be understood about the full spectrum of the disease. We describe a cohort of 53 patients with KMT2B mutations, with detailed delineation of their clinical phenotype and molecular genetic features. We report new disease presentations, including atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype. In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies. Analysis of this study cohort (n = 53) in tandem with published cases (n = 80) revealed that patients with chromosomal deletions and protein truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants. Eighteen individuals had detailed longitudinal data available after insertion of deep brain stimulation for medically refractory dystonia. Median age at deep brain stimulation was 11.5 years (range: 4.5–37.0 years). Follow-up after deep brain stimulation ranged from 0.25 to 22 years. Significant improvement of motor function and disability (as assessed by the Burke Fahn Marsden’s Dystonia Rating Scales, BFMDRS-M and BFMDRS-D) was evident at 6 months, 1 year and last follow-up (motor, P = 0.001, P = 0.004, and P = 0.012; disability, P = 0.009, P = 0.002 and P = 0.012). At 1 year post-deep brain stimulation, >50% of subjects showed BFMDRS-M and BFMDRS-D improvements of >30%. In the long-term deep brain stimulation cohort (deep brain stimulation inserted for >5 years, n = 8), improvement of >30% was maintained in 5/8 and 3/8 subjects for the BFMDRS-M and BFMDRS-D, respectively. The greatest BFMDRS-M improvements were observed for trunk (53.2%) and cervical (50.5%) dystonia, with less clinical impact on laryngeal dystonia. Improvements in gait dystonia decreased from 20.9% at 1 year to 16.2% at last assessment; no patient maintained a fully independent gait. Reduction of BFMDRS-D was maintained for swallowing (52.9%). Five patients developed mild parkinsonism following deep brain stimulation. KMT2B-related disease comprises an expanding continuum from infancy to adulthood, with early evidence of genotype-phenotype correlations. Except for laryngeal dysphonia, deep brain stimulation provides a significant improvement in quality of life and function with sustained clinical benefit depending on symptoms distribution.
Published: 2020
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32. Parental Interest in Genomic Sequencing of Newborns: Enrollment Experience from the BabySeq Project

Author: Casie A. Genetti, Talia S. Schwartz, Jill O. Robinson, Grace E. VanNoy, Devan Petersen, Stacey Pereira, Shawn Fayer, Hayley A. Peoples, Pankaj B. Agrawal, Wendi N. Betting, Ingrid A. Holm, Amy L. McGuire, Susan E. Waisbren, Timothy W. Yu, Robert C. Green, Alan H. Beggs, Richard B. Parad, Ozge Ceyhan-Birsoy, Kurt D. Christensen, Dmitry Dukhovny, Leslie A. Frankel, Chet Graham, Amanda M. Gutierrez, Maegan Harden, Joel B. Krier, Matthew S. Lebo, Harvey L. Levy, Xingquan Lu, Kalotina Machini, Jaclyn B. Murry, Medha Naik, Tiffany T. Nguyen, Uma Ramamurthy, Vivek Ramanathan, Heidi L. Rehm, Amy Roberts, Serguei Roumiantsev, and Tina K. Truong
Subjects: 0301 basic medicine, Adult, Male, Parents, medicine.medical_specialty, Parental Concerns, media_common.quotation_subject, Genetic counseling, Consent for Genomic Testing, 030105 genetics & heredity, Article, law.invention, 03 medical and health sciences, 0302 clinical medicine, Neonatal Screening, Randomized controlled trial, law, Informed consent, 030225 pediatrics, medicine, Humans, Genetic Testing, Predictive testing, Insurability, Genetics (clinical), media_common, Genetic testing, Newborn screening, Genomic Sequencing, Informed Consent, medicine.diagnostic_test, business.industry, Patient Selection, Infant, Newborn, Sequence Analysis, DNA, Newborn, 3. Good health, Feeling, Family medicine, Female, business, Attitude to Health, Newborn Screening
Abstract: Purpose: Newborn genomic sequencing (nGS) has great potential to improve pediatric care. Parental interest and concerns about genomics are relatively unexplored. Understanding why parents decline research consent for nGS may reveal implementation barriers. Methods: We evaluated parental interest in a randomized trial of nGS in well-baby and ICU nursery settings. Interested families attended an informational enrollment session (ES) with a genetic counselor prior to consenting. Reason(s) for declining participation and sociodemographic associations were analyzed. Results: Of 3,860 eligible approached families, 10% attended ES, 67% of whom enrolled. Of 1,760 families queried for decline reasons, 58% were uninterested in research. Among 499 families considering research, principal reasons for decline prior to ES included burdensome study logistics (48%), feeling overwhelmed postpartum (17%), and lack of interest/discomfort with genetic testing (17%). Decliners after ES more often cited concerns about privacy/insurability (41%) and uncertain/unfavorable results (23%). Conclusions: Low interest in research and study logistics were major initial barriers to postpartum enrollment and are likely generic to many postpartum research efforts. Concerns over privacy and result implications were most commonly cited in decliners after ES. Understanding parental concerns around research nGS may inform future integration of nGS into newborn screening, predictive testing, and pediatric diagnostics.
Published: 2018

33. Automated typing of red blood cell and platelet antigens: a whole-genome sequencing study

Author: Kalotina Machini, Nicole Soranzo, Maria Aguad, Christine E. Seidman, Leslie E. Silberstein, Erica F. Schonman, Michael F. Murray, David W. Bates, Denise L. Perry, Heather M. McLaughlin, John Danesh, Sek Won Kong, Klaudia Walter, Tina Hambuch, Isaac S. Kohane, Judy Garber, William J. Lane, Allison L. Cirino, Carrie L. Blout, Connie M. Westhoff, Matthew S. Lebo, Ellen A. Tsai, Pamela M. Diamond, Eleanor Steffens, Lindsay Z. Feuerman, Heidi L. Rehm, Helen Mah, Cynthia C. Morton, Wendi N. Betting, David J. Roberts, Sunitha Vege, Richard M. Kaufman, Lisa Soleymani Lehmann, Jill O. Robinson, Daimon P. Simmons, Amy L. McGuire, Peter Kraft, Nicholas A. Watkins, Kaitlyn B. Lee, Adam S. Butterworth, Emanuele Di Angelantonio, Willem H. Ouwehand, J. Scott Roberts, Shamil R. Sunyaev, Calum A. MacRae, Nicholas Gleadall, Joel B. Krier, Robin Smeland-Wagman, Jason L. Vassy, Ozge Ceyhan-Birsoy, Danielle R. Azzariti, Samuel J. Aronson, Tiffany T. Nguyen, Robert C. Green, Kurt D. Christensen, Carolyn Y. Ho, Kelly Davis, Peter A. Ubel, Melody J. Slashinski, and Jennifer Blumenthal-Barby
Subjects: 0301 basic medicine, Whole genome sequencing, medicine.medical_specialty, Blood transfusion, business.industry, medicine.medical_treatment, Transfusion medicine, Hematology, Computational biology, 030204 cardiovascular system & hematology, Genome, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, ABO blood group system, medicine, SNP, Human genome, Typing, business
Abstract: Summary Background There are more than 300 known red blood cell (RBC) antigens and 33 platelet antigens that differ between individuals. Sensitisation to antigens is a serious complication that can occur in prenatal medicine and after blood transfusion, particularly for patients who require multiple transfusions. Although pre-transfusion compatibility testing largely relies on serological methods, reagents are not available for many antigens. Methods based on single-nucleotide polymorphism (SNP) arrays have been used, but typing for ABO and Rh—the most important blood groups—cannot be done with SNP typing alone. We aimed to develop a novel method based on whole-genome sequencing to identify RBC and platelet antigens. Methods This whole-genome sequencing study is a subanalysis of data from patients in the whole-genome sequencing arm of the MedSeq Project randomised controlled trial (NCT01736566) with no measured patient outcomes. We created a database of molecular changes in RBC and platelet antigens and developed an automated antigen-typing algorithm based on whole-genome sequencing (bloodTyper). This algorithm was iteratively improved to address cis–trans haplotype ambiguities and homologous gene alignments. Whole-genome sequencing data from 110 MedSeq participants (30 × depth) were used to initially validate bloodTyper through comparison with conventional serology and SNP methods for typing of 38 RBC antigens in 12 blood-group systems and 22 human platelet antigens. bloodTyper was further validated with whole-genome sequencing data from 200 INTERVAL trial participants (15 × depth) with serological comparisons. Findings We iteratively improved bloodTyper by comparing its typing results with conventional serological and SNP typing in three rounds of testing. The initial whole-genome sequencing typing algorithm was 99·5% concordant across the first 20 MedSeq genomes. Addressing discordances led to development of an improved algorithm that was 99·8% concordant for the remaining 90 MedSeq genomes. Additional modifications led to the final algorithm, which was 99·2% concordant across 200 INTERVAL genomes (or 99·9% after adjustment for the lower depth of coverage). Interpretation By enabling more precise antigen-matching of patients with blood donors, antigen typing based on whole-genome sequencing provides a novel approach to improve transfusion outcomes with the potential to transform the practice of transfusion medicine. Funding National Human Genome Research Institute, Doris Duke Charitable Foundation, National Health Service Blood and Transplant, National Institute for Health Research, and Wellcome Trust.
Published: 2018
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34. Correction to: An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids

Author: Sacha Ferdinandusse, Kirsty McWalter, Heleen te Brinke, Lodewijk IJlst, Petra M. Mooijer, Jos P.N. Ruiter, Alida E.M. van Lint, Mia Pras-Raves, Eric Wever, Francisca Millan, Maria J. Guillen Sacoto, Amber Begtrup, Mark Tarnopolsky, Lauren Brady, Roger L. Ladda, Susan L. Sell, Catherine B. Nowak, Jessica Douglas, Cuixia Tian, Elizabeth Ulm, Seth Perlman, Arlene V. Drack, Karen Chong, Nicole Martin, Jennifer Brault, Elly Brokamp, Camilo Toro, William A. Gahl, Ellen F. Macnamara, Lynne Wolfe, Mercedes E. Alejandro, Mahshid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Lindsay C. Burrage, Hsiao-Tuan Chao, Gary D. Clark, William J. Craigen, Hongzheng Dai, Shweta U. Dhar, Lisa T. Emrick, Alica M. Goldman, Neil A. Hanchard, Fariha Jamal, Lefkothea Karaviti, Seema R. Lalani, Brendan H. Lee, Richard A. Lewis, Ronit Marom, Paolo M. Moretti, David R. Murdock, Sarah K. Nicholas, James P. Orengo, Jennifer E. Posey, Lorraine Potocki, Jill A. Rosenfeld, Susan L. Samson, Daryl A. Scott, Alyssa A. Tran, Tiphanie P. Vogel, Michael F. Wangler, Shinya Yamamoto, Christine M. Eng, Pengfei Liu, Patricia A. Ward, Edward Behrens, Matthew Deardorff, Marni Falk, Kelly Hassey, Kathleen Sullivan, Adeline Vanderver, David B. Goldstein, Heidi Cope, Allyn McConkie-Rosell, Kelly Schoch, Vandana Shashi, Edward C. Smith, Rebecca C. Spillmann, Jennifer A. Sullivan, Queenie K.-G. Tan, Nicole M. Walley, Pankaj B. Agrawal, Alan H. Beggs, Gerard T. Berry, Lauren C. Briere, Laurel A. Cobban, Matthew Coggins, Cynthia M. Cooper, Elizabeth L. Fieg, Frances High, Ingrid A. Holm, Susan Korrick, Joel B. Krier, Sharyn A. Lincoln, Joseph Loscalzo, Richard L. Maas, Calum A. MacRae, J. Carl Pallais, Deepak A. Rao, Lance H. Rodan, Edwin K. Silverman, Joan M. Stoler, David A. Sweetser, Melissa Walker, Chris A. Walsh, Cecilia Esteves, Emily G. Kelley, Isaac S. Kohane, Kimberly LeBlanc, Alexa T. McCray, Anna Nagy, Surendra Dasari, Brendan C. Lanpher, Ian R. Lanza, Eva Morava, Devin Oglesbee, Guney Bademci, Deborah Barbouth, Stephanie Bivona, Olveen Carrasquillo, Ta Chen Peter Chang, Irman Forghani, Alana Grajewski, Rosario Isasi, Byron Lam, Roy Levitt, Xue Zhong Liu, Jacob McCauley, Ralph Sacco, Mario Saporta, Judy Schaechter, Mustafa Tekin, Fred Telischi, Willa Thorson, Stephan Zuchner, Heather A. Colley, Jyoti G. Dayal, David J. Eckstein, Laurie C. Findley, Donna M. Krasnewich, Laura A. Mamounas, Teri A. Manolio, John J. Mulvihill, Grace L. LaMoure, Madison P. Goldrich, Tiina K. Urv, Argenia L. Doss, Maria T. Acosta, Carsten Bonnenmann, Precilla D’Souza, David D. Draper, Carlos Ferreira, Rena A. Godfrey, Catherine A. Groden, Valerie V. Maduro, Thomas C. Markello, Avi Nath, Donna Novacic, Barbara N. Pusey, Colleen E. Wahl, Eva Baker, Elizabeth A. Burke, David R. Adams, May Christine V. Malicdan, Cynthia J. Tifft, Lynne A. Wolfe, John Yang, Bradley Power, Bernadette Gochuico, Laryssa Huryn, Lea Latham, Joie Davis, Deborah Mosbrook-Davis, Francis Rossignol, Ben Solomon, John MacDowall, Audrey Thurm, Wadih Zein, Muhammad Yousef, Margaret Adam, Laura Amendola, Michael Bamshad, Anita Beck, Jimmy Bennett, Beverly Berg-Rood, Elizabeth Blue, Brenna Boyd, Peter Byers, Sirisak Chanprasert, Michael Cunningham, Katrina Dipple, Daniel Doherty, Dawn Earl, Ian Glass, Katie Golden-Grant, Sihoun Hahn, Anne Hing, Fuki M. Hisama, Martha Horike-Pyne, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Christina Lam, Kenneth Maravilla, Heather Mefford, J. Lawrence Merritt, Ghayda Mirzaa, Deborah Nickerson, Wendy Raskind, Natalie Rosenwasser, C. Ron Scott, Angela Sun, Virginia Sybert, Stephanie Wallace, Mark Wener, Tara Wenger, Euan A. Ashley, Gill Bejerano, Jonathan A. Bernstein, Devon Bonner, Terra R. Coakley, Liliana Fernandez, Paul G. Fisher, Laure Fresard, Jason Hom, Yong Huang, Jennefer N. Kohler, Elijah Kravets, Marta M. Majcherska, Beth A. Martin, Shruti Marwaha, Colleen E. McCormack, Archana N. Raja, Chloe M. Reuter, Maura Ruzhnikov, Jacinda B. Sampson, Kevin S. Smith, Shirley Sutton, Holly K. Tabor, Brianna M. Tucker, Matthew T. Wheeler, Diane B. Zastrow, Chunli Zhao, William E. Byrd, Andrew B. Crouse, Matthew Might, Mariko Nakano-Okuno, Jordan Whitlock, Gabrielle Brown, Manish J. Butte, Esteban C. Dell’Angelica, Naghmeh Dorrani, Emilie D. Douine, Brent L. Fogel, Irma Gutierrez, Alden Huang, Deborah Krakow, Hane Lee, Sandra K. Loo, Bryan C. Mak, Martin G. Martin, Julian A. Martínez-Agosto, Elisabeth McGee, Stanley F. Nelson, Shirley Nieves-Rodriguez, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, Genecee Renteria, Rebecca H. Signer, Janet S. Sinsheimer, Jijun Wan, Lee-kai Wang, Katherine Wesseling Perry, Jeremy D. Woods, Justin Alvey, Ashley Andrews, Jim Bale, John Bohnsack, Lorenzo Botto, John Carey, Laura Pace, Nicola Longo, Gabor Marth, Paolo Moretti, Aaron Quinlan, Matt Velinder, Dave Viskochil, Pinar Bayrak-Toydemir, Rong Mao, Monte Westerfield, Anna Bican, Laura Duncan, Rizwan Hamid, Jennifer Kennedy, Mary Kozuira, John H. Newman, John A. Phillips, Lynette Rives, Amy K. Robertson, Emily Solem, Joy D. Cogan, F. Sessions Cole, Nichole Hayes, Dana Kiley, Kathy Sisco, Jennifer Wambach, Daniel Wegner, Dustin Baldridge, Stephen Pak, Timothy Schedl, Jimann Shin, Lilianna Solnica-Krezel, Quinten Waisfisz, Petra J.G. Zwijnenburg, Alban Ziegler, Magalie Barth, Rosemarie Smith, Sara Ellingwood, Deborah Gaebler-Spira, Somayeh Bakhtiari, Michael C. Kruer, Antoine H.C. van Kampen, Ronald J.A. Wanders, Hans R. Waterham, David Cassiman, and Frédéric M. Vaz
Subjects: Phenotype, Spastic Paraplegia, Hereditary, Correction, Humans, Aldehyde Oxidoreductases, Lipids, Genetics (clinical), Ethers
Abstract: In this study we investigate the disease etiology in 12 patients with de novo variants in FAR1 all resulting in an amino acid change at position 480 (p.Arg480Cys/His/Leu).Following next-generation sequencing and clinical phenotyping, functional characterization was performed in patients' fibroblasts using FAR1 enzyme analysis, FAR1 immunoblotting/immunofluorescence, and lipidomics.All patients had spastic paraparesis and bilateral congenital/juvenile cataracts, in most combined with speech and gross motor developmental delay and truncal hypotonia. FAR1 deficiency caused by biallelic variants results in defective ether lipid synthesis and plasmalogen deficiency. In contrast, patients' fibroblasts with the de novo FAR1 variants showed elevated plasmalogen levels. Further functional studies in fibroblasts showed that these variants cause a disruption of the plasmalogen-dependent feedback regulation of FAR1 protein levels leading to uncontrolled ether lipid production.Heterozygous de novo variants affecting the Arg480 residue of FAR1 lead to an autosomal dominant disorder with a different disease mechanism than that of recessive FAR1 deficiency and a diametrically opposed biochemical phenotype. Our findings show that for patients with spastic paraparesis and bilateral cataracts, FAR1 should be considered as a candidate gene and added to gene panels for hereditary spastic paraplegia, cerebral palsy, and juvenile cataracts.
Published: 2021

35. Correction: Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations

Author: Lance H. Rodan, Rebecca C. Spillmann, Harley T. Kurata, Shawn M. Lamothe, Jasmine Maghera, Rami Abou Jamra, Anna Alkelai, Stylianos E. Antonarakis, Isis Atallah, Omer Bar-Yosef, Frédéric Bilan, Kathrine Bjorgo, Xavier Blanc, Patrick Van Bogaert, Yoav Bolkier, Lindsay C. Burrage, Björn U. Christ, Jorge L. Granadillo, Patricia Dickson, Kirsten A. Donald, Christèle Dubourg, Aviva Eliyahu, Lisa Emrick, Kendra Engleman, Michaela Veronika Gonfiantini, Jean-Marc Good, Judith Kalser, Chiara Kloeckner, Guus Lachmeijer, Marina Macchiaiolo, Francesco Nicita, Sylvie Odent, Emily O’Heir, Xilma Ortiz-Gonzalez, Marta Pacio-Miguez, María Palomares-Bralo, Loren Pena, Konrad Platzer, Mathieu Quinodoz, Emmanuelle Ranza, Jill A. Rosenfeld, Eliane Roulet-Perez, Avni Santani, Fernando Santos-Simarro, Ben Pode-Shakked, Cara Skraban, Rachel Slaugh, Andrea Superti-Furga, Isabelle Thiffault, Richard H. van Jaabrsveld, Marie Vincent, Hong-Gang Wang, Pia Zacher, Mercedes E. Alejandro, Mahshid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Hsiao-Tuan Chao, Gary D. Clark, William J. Craigen, Hongzheng Dai, Shweta U. Dhar, Lisa T. Emrick, Alica M. Goldman, Neil A. Hanchard, Fariha Jamal, Lefkothea Karaviti, Seema R. Lalani, Brendan H. Lee, Richard A. Lewis, Ronit Marom, Paolo M. Moretti, David R. Murdock, Sarah K. Nicholas, James P. Orengo, Jennifer E. Posey, Lorraine Potocki, Susan L. Samson, Daryl A. Scott, Alyssa A. Tran, Tiphanie P. Vogel, Michael F. Wangler, Shinya Yamamoto, Christine M. Eng, Pengfei Liu, Patricia A. Ward, Edward Behrens, Matthew Deardorff, Marni Falk, Kelly Hassey, Kathleen Sullivan, Adeline Vanderver, David B. Goldstein, Heidi Cope, Allyn McConkie-Rosell, Kelly Schoch, Vandana Shashi, Edward C. Smith, Jennifer A. Sullivan, Queenie K.-G. Tan, Nicole M. Walley, Pankaj B. Agrawal, Alan H. Beggs, Gerard T. Berry, Lauren C. Briere, Laurel A. Cobban, Matthew Coggins, Cynthia M. Cooper, Elizabeth L. Fieg, Frances High, Ingrid A. Holm, Susan Korrick, Joel B. Krier, Sharyn A. Lincoln, Joseph Loscalzo, Richard L. Maas, Calum A. MacRae, J. Carl Pallais, Deepak A. Rao, Edwin K. Silverman, Joan M. Stoler, David A. Sweetser, Melissa Walker, Chris A. Walsh, Cecilia Esteves, Emily G. Kelley, Isaac S. Kohane, Kimberly LeBlanc, Alexa T. McCray, Anna Nagy, Surendra Dasari, Brendan C. Lanpher, Ian R. Lanza, Eva Morava, Devin Oglesbee, Guney Bademci, Deborah Barbouth, Stephanie Bivona, Olveen Carrasquillo, Ta Chen Peter Chang, Irman Forghani, Alana Grajewski, Rosario Isasi, Byron Lam, Roy Levitt, Xue Zhong Liu, Jacob McCauley, Ralph Sacco, Mario Saporta, Judy Schaechter, Mustafa Tekin, Fred Telischi, Willa Thorson, Stephan Zuchner, Heather A. Colley, Jyoti G. Dayal, David J. Eckstein, Laurie C. Findley, Donna M. Krasnewich, Laura A. Mamounas, Teri A. Manolio, John J. Mulvihill, Grace L. LaMoure, Madison P. Goldrich, Tiina K. Urv, Argenia L. Doss, Maria T. Acosta, Carsten Bonnenmann, Precilla D’Souza, David D. Draper, Carlos Ferreira, Rena A. Godfrey, Catherine A. Groden, Ellen F. Macnamara, Valerie V. Maduro, Thomas C. Markello, Avi Nath, Donna Novacic, Barbara N. Pusey, Camilo Toro, Colleen E. Wahl, Eva Baker, Elizabeth A. Burke, David R. Adams, William A. Gahl, May Christine V. Malicdan, Cynthia J. Tifft, Lynne A. Wolfe, John Yang, Bradley Power, Bernadette Gochuico, Laryssa Huryn, Lea Latham, Joie Davis, Deborah Mosbrook-Davis, Francis Rossignol, null Ben Solomon, John MacDowall, Audrey Thurm, Wadih Zein, Muhammad Yousef, Margaret Adam, Laura Amendola, Michael Bamshad, Anita Beck, Jimmy Bennett, Beverly Berg-Rood, Elizabeth Blue, Brenna Boyd, Peter Byers, Sirisak Chanprasert, Michael Cunningham, Katrina Dipple, Daniel Doherty, Dawn Earl, Ian Glass, Katie Golden-Grant, Sihoun Hahn, Anne Hing, Fuki M. Hisama, Martha Horike-Pyne, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Christina Lam, Kenneth Maravilla, Heather Mefford, J. Lawrence Merritt, Ghayda Mirzaa, Deborah Nickerson, Wendy Raskind, Natalie Rosenwasser, C. Ron Scott, Angela Sun, Virginia Sybert, Stephanie Wallace, Mark Wener, Tara Wenger, Euan A. Ashley, Gill Bejerano, Jonathan A. Bernstein, Devon Bonner, Terra R. Coakley, Liliana Fernandez, Paul G. Fisher, Laure Fresard, Jason Hom, Yong Huang, Jennefer N. Kohler, Elijah Kravets, Marta M. Majcherska, Beth A. Martin, Shruti Marwaha, Colleen E. McCormack, Archana N. Raja, Chloe M. Reuter, Maura Ruzhnikov, Jacinda B. Sampson, Kevin S. Smith, Shirley Sutton, Holly K. Tabor, Brianna M. Tucker, Matthew T. Wheeler, Diane B. Zastrow, Chunli Zhao, William E. Byrd, Andrew B. Crouse, Matthew Might, Mariko Nakano-Okuno, Jordan Whitlock, Gabrielle Brown, Manish J. Butte, Esteban C. Dell’Angelica, Naghmeh Dorrani, Emilie D. Douine, Brent L. Fogel, Irma Gutierrez, Alden Huang, Deborah Krakow, Hane Lee, Sandra K. Loo, Bryan C. Mak, Martin G. Martin, Julian A. Martínez-Agosto, Elisabeth McGee, Stanley F. Nelson, Shirley Nieves-Rodriguez, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, Genecee Renteria, Rebecca H. Signer, Janet S. Sinsheimer, Jijun Wan, Lee-kai Wang, Katherine Wesseling Perry, Jeremy D. Woods, Justin Alvey, Ashley Andrews, Jim Bale, John Bohnsack, Lorenzo Botto, John Carey, Laura Pace, Nicola Longo, Gabor Marth, Paolo Moretti, Aaron Quinlan, Matt Velinder, Dave Viskochil, Pinar Bayrak-Toydemir, Rong Mao, Monte Westerfield, Anna Bican, Elly Brokamp, Laura Duncan, Rizwan Hamid, Jennifer Kennedy, Mary Kozuira, John H. Newman, John A. PhillipsIII, Lynette Rives, Amy K. Robertson, Emily Solem, Joy D. Cogan, F. Sessions Cole, Nichole Hayes, Dana Kiley, Kathy Sisco, Jennifer Wambach, Daniel Wegner, Dustin Baldridge, Stephen Pak, Timothy Schedl, Jimann Shin, Lilianna Solnica-Krezel, Eric Rush, Geoffrey S. Pitt, and Ping Yee Billie Au
Subjects: Genetics (clinical)
Published: 2021
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36. The Undiagnosed Diseases Network: Accelerating Discovery about Health and Disease

Author: Rachel B. Ramoni, John J. Mulvihill, David R. Adams, Patrick Allard, Euan A. Ashley, Jonathan A. Bernstein, William A. Gahl, Rizwan Hamid, Joseph Loscalzo, Alexa T. McCray, Vandana Shashi, Cynthia J. Tifft, Anastasia L. Wise, Christopher J. Adams, Mercedes E. Alejandro, Mashid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Hayk Barseghyan, Alan H. Beggs, Hugo J. Bellen, David Bernick, Anna Bican, David P. Bick, Camille L. Birch, Braden E. Boone, Lauren C. Briere, Donna M. Brown, Catherine A. Brownstein, Matthew Brush, Elizabeth A. Burke, Lindsay C. Burrage, Katherine R. Chao, Gary D. Clark, Joy D. Cogan, Cynthia M. Cooper, William J. Craigen, Mariska Davids, Jyoti G. Dayal, Esteban C. Dell’Angelica, Shweta U. Dhar, Katrina M. Dipple, Laurel A. Donnell-Fink, Naghmeh Dorrani, Daniel C. Dorset, David D. Draper, Annika M. Dries, Rachel Eastwood, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Cecilia Esteves, Tyra Estwick, Paul G. Fisher, Trevor S. Frisby, Kate Frost, Valerie Gartner, Rena A. Godfrey, Mitchell Goheen, Gretchen A. Golas, David B. Goldstein, Mary 'Gracie' G. Gordon, Sarah E. Gould, Jean-Philippe F. Gourdine, Brett H. Graham, Catherine A. Groden, Andrea L. Gropman, Mary E. Hackbarth, Melissa Haendel, Neil A. Hanchard, Lori H. Handley, Isabel Hardee, Matthew R. Herzog, Ingrid A. Holm, Ellen M. Howerton, Brenda Iglesias, Howard J. Jacob, Mahim Jain, Yong-hui Jiang, Jean M. Johnston, Angela L. Jones, Alanna E. Koehler, David M. Koeller, Isaac S. Kohane, Jennefer N. Kohler, Donna M. Krasnewich, Elizabeth L. Krieg, Joel B. Krier, Jennifer E. Kyle, Seema R. Lalani, Lea Latham, Yvonne L. Latour, C. Christopher Lau, Jozef Lazar, Brendan H. Lee, Hane Lee, Paul R. Lee, Shawn E. Levy, Denise J. Levy, Richard A. Lewis, Adam P. Liebendorder, Sharyn A. Lincoln, Carson R. Loomis, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Thomas C. Markello, Casey Martin, Paul Mazur, Alexandra J. McCarty, Allyn McConkie-Rosell, Thomas O. Metz, Matthew Might, Paolo M. Moretti, Jennifer L. Murphy, Donna M. Muzny, Michele E. Nehrebecky, Stan F. Nelson, J. Scott Newberry, John H. Newman, Sarah K. Nicholas, Donna Novacic, Jordan S. Orange, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Loren D.M. Pena, John A. Phillips, Jennifer E. Posey, John H. Postlethwait, Lorraine Potocki, Barbara N. Pusey, Amy K. Robertson, Lance H. Rodan, Jill A. Rosenfeld, Sarah Sadozai, Katherine E. Schaffer, Kelly Schoch, Molly C. Schroeder, Daryl A. Scott, Prashant Sharma, Edwin K. Silverman, Janet S. Sinsheimer, Ariane G. Soldatos, Rebecca C. Spillmann, Kimberly Splinter, Joan M. Stoler, Nicholas Stong, Kimberly A. Strong, Jennifer A. Sullivan, David A. Sweetser, Sara P. Thomas, Nathanial J. Tolman, Camilo Toro, Alyssa A. Tran, Zaheer M. Valivullah, Eric Vilain, Daryl M. Waggott, Colleen E. Wahl, Nicole M. Walley, Chris A. Walsh, Michael F. Wangler, Mike Warburton, Patricia A. Ward, Katrina M. Waters, Bobbie-Jo M. Webb-Robertson, Alec A. Weech, Monte Westerfield, Matthew T. Wheeler, Lynne A. Wolfe, Elizabeth A. Worthey, Shinya Yamamoto, Yaping Yang, Guoyun Yu, and Patricia A. Zornio
Subjects: 0301 basic medicine, Knowledge management, Genotype, Genotyping Techniques, Best practice, Disease, 030105 genetics & heredity, Bioinformatics, 03 medical and health sciences, Rare Diseases, Diagnostic model, Common fund, Genetics, Humans, Metabolomics, Functional studies, Genetics (clinical), Information Dissemination, business.industry, Disease mechanisms, Sequence Analysis, DNA, United States, Research objectives, Data sharing, Phenotype, 030104 developmental biology, National Institutes of Health (U.S.), Commentary, business
Abstract: Diagnosis at the edges of our knowledge calls upon clinicians to be data driven, cross-disciplinary, and collaborative in unprecedented ways. Exact disease recognition, an element of the concept of precision in medicine, requires new infrastructure that spans geography, institutional boundaries, and the divide between clinical care and research. The National Institutes of Health (NIH) Common Fund supports the Undiagnosed Diseases Network (UDN) as an exemplar of this model of precise diagnosis. Its goals are to forge a strategy to accelerate the diagnosis of rare or previously unrecognized diseases, to improve recommendations for clinical management, and to advance research, especially into disease mechanisms. The network will achieve these objectives by evaluating patients with undiagnosed diseases, fostering a breadth of expert collaborations, determining best practices for translating the strategy into medical centers nationwide, and sharing findings, data, specimens, and approaches with the scientific and medical communities. Building the UDN has already brought insights to human and medical geneticists. The initial focus has been on data sharing, establishing common protocols for institutional review boards and data sharing, creating protocols for referring and evaluating patients, and providing DNA sequencing, metabolomic analysis, and functional studies in model organisms. By extending this precision diagnostic model nationally, we strive to meld clinical and research objectives, improve patient outcomes, and contribute to medical science.
Published: 2017
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37. A Recurrent De Novo Variant in NACC1 Causes a Syndrome Characterized by Infantile Epilepsy, Cataracts, and Profound Developmental Delay

Author: Kelly Schoch, Linyan Meng, Szabolcs Szelinger, David R. Bearden, Asbjorg Stray-Pedersen, Oyvind L. Busk, Nicholas Stong, Eriskay Liston, Ronald D. Cohn, Fernando Scaglia, Jill A. Rosenfeld, Jennifer Tarpinian, Cara M. Skraban, Matthew A. Deardorff, Jeremy N. Friedman, Zeynep Coban Akdemir, Nicole Walley, Mohamad A. Mikati, Peter G. Kranz, Joan Jasien, Allyn McConkie-Rosell, Marie McDonald, Stephanie Burns Wechsler, Michael Freemark, Sujay Kansagra, Sharon Freedman, Deeksha Bali, Francisca Millan, Sherri Bale, Stanley F. Nelson, Hane Lee, Naghmeh Dorrani, David B. Goldstein, Rui Xiao, Yaping Yang, Jennifer E. Posey, Julian A. Martinez-Agosto, James R. Lupski, Michael F. Wangler, Vandana Shashi, Wayne W. Grody, Samuel P. Strom, Eric Vilain, Joshua Deignan, Fabiola Quintero-Rivera, Sibel Kantarci, Sureni Mullegama, Sung-Hae Kang, Mercedes E. Alejandro, Carlos A. Bacino, Ashok Balasubramanyam, Lindsay C. Burrage, Gary D. Clark, William J. Craigen, Shweta U. Dhar, Lisa T. Emrick, Brett H. Graham, Neil A. Hanchard, Mahim Jain, Seema R. Lalani, Brendan H. Lee, Richard A. Lewis, Azamian S. Mashid, Paolo M. Moretti, Sarah K. Nicholas, Jordan S. Orange, Lorraine Potocki, Daryl A. Scott, Alyssa A. Tran, Hugo J. Bellen, Shinya Yamamoto, Christine M. Eng, Donna M. Muzny, Patricia A. Ward, Andrea L. Gropman, Yong-hui Jiang, Loren D.M. Pena, Rebecca C. Spillmann, Jennifer A. Sullivan, Nicole M. Walley, Alan H. Beggs, Lauren C. Briere, Cynthia M. Cooper, Laurel A. Donnell-Fink, Elizabeth L. Krieg, Joel B. Krier, Sharyn A. Lincoln, Joseph Loscalzo, Richard L. Maas, Calum A. MacRae, J. Carl Pallais, Lance H. Rodan, Edwin K. Silverman, Joan M. Stoler, David A. Sweetser, Chris A. Walsh, Cecilia Esteves, Ingrid A. Holm, Isaac S. Kohane, Paul Mazur, Alexa T. McCray, Matthew Might, Rachel B. Ramoni, Kimberly Splinter, David P. Bick, Camille L. Birch, Braden E. Boone, Donna M. Brown, Dan C. Dorset, Lori H. Handley, Howard J. Jacob, Angela L. Jones, Jozef Lazar, Shawn E. Levy, J. Scott Newberry, Molly C. Schroeder, Kimberly A. Strong, Elizabeth A. Worthey, Jyoti G. Dayal, David J. Eckstein, Sarah E. Gould, Ellen M. Howerton, Donna M. Krasnewich, Carson R. Loomis, Laura A. Mamounas, Teri A. Manolio, John J. Mulvihill, Anastasia L. Wise, Ariane G. Soldatos, Matthew Brush, Jean-Philippe F. Gourdine, Melissa Haendel, David M. Koeller, Jennifer E. Kyle, Thomas O. Metz, Katrina M. Waters, Bobbie-Jo M. Webb-Robertson, Euan A. Ashley, Jonathan A. Bernstein, Annika M. Dries, Paul G. Fisher, Jennefer N. Kohler, Daryl M. Waggott, Matt T. Wheeler, Patricia A. Zornio, Patrick Allard, Hayk Barseghyan, Esteban C. Dell’Angelica, Katrina M. Dipple, Matthew R. Herzog, Stan F. Nelson, Christina G.S. Palmer, Jeanette C. Papp, Janet S. Sinsheimer, Christopher J. Adams, Elizabeth A. Burke, Katherine R. Chao, Mariska Davids, David D. Draper, Tyra Estwick, Trevor S. Frisby, Kate Frost, Valerie Gartner, Rena A. Godfrey, Mitchell Goheen, Gretchen A. Golas, Mary 'Gracie' G. Gordon, Catherine A. Groden, Mary E. Hackbarth, Isabel Hardee, Jean M. Johnston, Alanna E. Koehler, Lea Latham, Yvonne L. Latour, C. Christopher Lau, Denise J. Levy, Adam P. Liebendorder, Ellen F. Macnamara, Valerie V. Maduro, Thomas C. Markello, Alexandra J. McCarty, Jennifer L. Murphy, Michele E. Nehrebecky, Donna Novacic, Barbara N. Pusey, Sarah Sadozai, Katherine E. Schaffer, Prashant Sharma, Sara P. Thomas, Nathanial J. Tolman, Camilo Toro, Zaheer M. Valivullah, Colleen E. Wahl, Mike Warburton, Alec A. Weech, Guoyun Yu, David R. Adams, William A. Gahl, May Christine V. Malicdan, Cynthia J. Tifft, Lynne A. Wolfe, Paul R. Lee, John H. Postlethwait, Monte Westerfield, Anna Bican, Rizwan Hamid, John H. Newman, John A. Phillips, Amy K. Robertson, and Joy D. Cogan
Subjects: Male, 0301 basic medicine, Microcephaly, Mutation, Missense, Biology, Cataract, Germline, 03 medical and health sciences, Neurodevelopmental disorder, Cataracts, Report, Intellectual Disability, Intellectual disability, Genetics, medicine, Humans, Missense mutation, Amino Acid Sequence, Child, Alleles, Genetics (clinical), Cerebral atrophy, Brain, Genetic Variation, Infant, medicine.disease, Magnetic Resonance Imaging, Neoplasm Proteins, Pedigree, 3. Good health, Repressor Proteins, Phenotype, 030104 developmental biology, Child, Preschool, Failure to thrive, Female, medicine.symptom, Spasms, Infantile, Genome-Wide Association Study
Abstract: Whole-exome sequencing (WES) has increasingly enabled new pathogenic gene variant identification for undiagnosed neurodevelopmental disorders and provided insights into both gene function and disease biology. Here, we describe seven children with a neurodevelopmental disorder characterized by microcephaly, profound developmental delays and/or intellectual disability, cataracts, severe epilepsy including infantile spasms, irritability, failure to thrive, and stereotypic hand movements. Brain imaging in these individuals reveals delay in myelination and cerebral atrophy. We observe an identical recurrent de novo heterozygous c.892C>T (p.Arg298Trp) variant in the nucleus accumbens associated 1 ( NACC1 ) gene in seven affected individuals. One of the seven individuals is mosaic for this variant. NACC1 encodes a transcriptional repressor implicated in gene expression and has not previously been associated with germline disorders. The probability of finding the same missense NACC1 variant by chance in 7 out of 17,228 individuals who underwent WES for diagnoses of neurodevelopmental phenotypes is extremely small and achieves genome-wide significance (p = 1.25 × 10 −14 ). Selective constraint against missense variants in NACC1 makes this excess of an identical missense variant in all seven individuals more remarkable. Our findings are consistent with a germline recurrent mutational hotspot associated with an allele-specific neurodevelopmental phenotype in NACC1 .
Published: 2017
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38. A Syndromic Neurodevelopmental Disorder Caused by De Novo Variants in EBF3

Author: Hsiao-Tuan Chao, Mariska Davids, Elizabeth Burke, John G. Pappas, Jill A. Rosenfeld, Alexandra J. McCarty, Taylor Davis, Lynne Wolfe, Camilo Toro, Cynthia Tifft, Fan Xia, Nicholas Stong, Travis K. Johnson, Coral G. Warr, Shinya Yamamoto, David R. Adams, Thomas C. Markello, William A. Gahl, Hugo J. Bellen, Michael F. Wangler, May Christine V. Malicdan, Christopher J. Adams, Mercedes E. Alejandro, Patrick Allard, Euan A. Ashley, Carlos A. Bacino, Ashok Balasubramanyam, Hayk Barseghyan, Alan H. Beggs, Jonathan A. Bernstein, David P. Bick, Camille L. Birch, Braden E. Boone, Lauren C. Briere, Donna M. Brown, Matthew Brush, Lindsay C. Burrage, Katherine R. Chao, Gary D. Clark, Joy D. Cogan, Cynthia M. Cooper, William J. Craigen, Jyoti G. Dayal, Esteban C. Dell'Angelica, Shweta U. Dhar, Katrina M. Dipple, Laurel A. Donnell-Fink, Naghmeh Dorrani, Dan C. Dorset, David D. Draper, Annika M. Dries, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Cecilia Esteves, Tyra Estwick, Paul G. Fisher, Trevor S. Frisby, Kate Frost, Valerie Gartner, Rena A. Godfrey, Mitchell Goheen, Gretchen A. Golas, David B. Goldstein, Mary 'Gracie' G. Gordon, Sarah E. Gould, Jean-Philippe F. Gourdine, Brett H. Graham, Catherine A. Groden, Andrea L. Gropman, Mary E. Hackbarth, Melissa Haendel, Rizwan Hamid, Neil A. Hanchard, Lori H. Handley, Isabel Hardee, Matthew R. Herzog, Ingrid A. Holm, Ellen M. Howerton, Howard J. Jacob, Mahim Jain, Yong-hui Jiang, Jean M. Johnston, Angela L. Jones, Alanna E. Koehler, David M. Koeller, Isaac S. Kohane, Jennefer N. Kohler, Donna M. Krasnewich, Elizabeth L. Krieg, Joel B. Krier, Jennifer E. Kyle, Seema R. Lalani, Lea Latham, Yvonne L. Latour, C. Christopher Lau, Jozef Lazar, Brendan H. Lee, Hane Lee, Paul R. Lee, Shawn E. Levy, Denise J. Levy, Richard A. Lewis, Adam P. Liebendorder, Sharyn A. Lincoln, Carson R. Loomis, Joseph Loscalzo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Laura A. Mamounas, Teri A. Manolio, Azamian S. Mashid, Paul Mazur, Allyn McConkie-Rosell, Alexa T. McCray, Thomas O. Metz, Matthew Might, Paolo M. Moretti, John J. Mulvihill, Jennifer L. Murphy, Donna M. Muzny, Michele E. Nehrebecky, Stan F. Nelson, J. Scott Newberry, John H. Newman, Sarah K. Nicholas, Donna Novacic, Jordan S. Orange, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Loren D.M. Pena, John A. Phillips, Jennifer E. Posey, John H. Postlethwait, Lorraine Potocki, Barbara N. Pusey, Rachel B. Ramoni, Lance H. Rodan, Sarah Sadozai, Katherine E. Schaffer, Kelly Schoch, Molly C. Schroeder, Daryl A. Scott, Prashant Sharma, Vandana Shashi, Edwin K. Silverman, Janet S. Sinsheimer, Ariane G. Soldatos, Rebecca C. Spillmann, Kimberly Splinter, Joan M. Stoler, Kimberly A. Strong, Jennifer A. Sullivan, David A. Sweetser, Sara P. Thomas, Cynthia J. Tift, Nathanial J. Tolman, Alyssa A. Tran, Zaheer M. Valivullah, Eric Vilain, Daryl M. Waggott, Colleen E. Wahl, Nicole M. Walley, Chris A. Walsh, Mike Warburton, Patricia A. Ward, Katrina M. Waters, Bobbie-Jo M. Webb-Robertson, Alec A. Weech, Monte Westerfield, Matt T. Wheeler, Anastasia L. Wise, Lynne A. Worthe, Elizabeth A. Worthey, Yaping Yang, Guoyun Yu, and Patricia A. Zornio
Subjects: Central Nervous System, Male, 0301 basic medicine, Ataxia, Developmental Disabilities, Biology, Speech Disorders, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual Disability, Report, Intellectual disability, Genetics, medicine, Humans, Abnormalities, Multiple, Genitalia, Global developmental delay, Child, Transcription factor, Genetics (clinical), Zinc finger, Infant, Newborn, Infant, Zinc Fingers, Syndrome, medicine.disease, Hypotonia, 030104 developmental biology, Neurodevelopmental Disorders, Child, Preschool, Mutation, Muscle Hypotonia, Homeobox, Female, medicine.symptom, 030217 neurology & neurosurgery, Transcription Factors
Abstract: Early B cell factor 3 (EBF3) is a member of the highly evolutionarily conserved Collier/Olf/EBF (COE) family of transcription factors. Prior studies on invertebrate and vertebrate animals have shown that EBF3 homologs are essential for survival and that loss-of-function mutations are associated with a range of nervous system developmental defects, including perturbation of neuronal development and migration. Interestingly, aristaless-related homeobox (ARX), a homeobox-containing transcription factor critical for the regulation of nervous system development, transcriptionally represses EBF3 expression. However, human neurodevelopmental disorders related to EBF3 have not been reported. Here, we describe three individuals who are affected by global developmental delay, intellectual disability, and expressive speech disorder and carry de novo variants in EBF3. Associated features seen in these individuals include congenital hypotonia, structural CNS malformations, ataxia, and genitourinary abnormalities. The de novo variants affect a single conserved residue in a zinc finger motif crucial for DNA binding and are deleterious in a fly model. Our findings indicate that mutations in EBF3 cause a genetic neurodevelopmental syndrome and suggest that loss of EBF3 function might mediate a subset of neurologic phenotypes shared by ARX-related disorders, including intellectual disability, abnormal genitalia, and structural CNS malformations.
Published: 2017
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39. Rare Inherited Defects of the Complement System in Purpura Fulminans

Author: Walter H. Dzik, Betty Rouaisnel, Agnes Toth-Petroczy, Michael Bouzinier, Justine H. Ryu, Olga Pozdnyakova, Bryce E. Pasko, Richard L. Maas, Valentina Nardi, Joel B. Krier, Julie-Aurore Losman, Pavan K. Bendapudi, Lindsay Tomczak, James Hudspeth, Elizabeth L. Fieg, Onuralp Soylemez, Alissa Robbins, Sanjay Ram, and Meaghan Colling
Subjects: medicine.medical_specialty, business.industry, Immunology, Cell Biology, Hematology, Complement receptor, medicine.disease, Biochemistry, Thrombosis, Sepsis, Internal medicine, Cohort, Coagulopathy, medicine, Complication, business, Exome sequencing, Purpura fulminans
Abstract: Background: Purpura fulminans (PF) is a rare but devastating complication of sepsis in which patients experience overwhelming systemic thrombosis leading to end organ damage, distal limb ischemia, and death. Survivors are often left with lifelong disfigurement and/or disability due to severe acral tissue injury and the need for amputation of necrotic extremities. Given that most patients who develop PF have no known underlying medical conditions and are much younger than those typically afflicted with sepsis, we sought to investigate whether genetic determinants predispose individuals to developing PF. Methods: We performed whole exome sequencing on the Boston PF Cohort (N=40). We used pathway-based collapsing analysis (PBCA) combined with mutational burden testing to evaluate for enrichment of rare coding variants in the complement system using as a comparator unselected patients with sepsis from the NHLBI ARDSnet iSPAAR cohort (N=87). Several novel variants in integrin complement receptors were identified and subsequently cloned and functionally characterized. Results: Patients in the Boston PF Cohort were relatively young at the time of presentation, with a median (IQR) age of 37.5 (20.3-58.8) years. Patients were afflicted with gram negative organisms 45% of the time, while 27.5% were infected with gram positive organisms. In another 27.5%, no pathogen was identified. PF patients had strikingly abnormal markers of severe sepsis and coagulopathy, including the following median (IQR) values: lactate 7.1 (5.3-11.8) mmol/L, platelet count 28,000 (15,000-48,500) per μl, aPTT 68.0 (48.3-142.5) seconds, INR 2.8 (1.9-4.0), and protein C activity 26.0% (13.5-38.5). No patient had a known congenital immune defect. Whole exome sequencing (mean read depth 80X) identified 30 unique heterozygous complement system variants in 26/40 (65%) patients with PF (Figure 1A-B). Variants in this pathway were highly enriched in PF patients compared to the control cohort (P Conclusions: Our data suggest that rare inherited defects in the complement system predispose individuals to the maladaptive thrombo-inflammatory response to infection that characterizes PF. By advancing our understanding of the molecular pathogenesis of PF, this work could provide important insights into the broader problem of coagulopathy in sepsis. Furthermore, targeted gene discovery approaches based on PBCA may serve as a model for future genomic studies of rare hemostatic diseases. Disclosures No relevant conflicts of interest to declare.
Published: 2020
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40. De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Callosum, Axon, Cardiac, Ocular, and Genital Defects

Author: Andrea Accogli, Sara Calabretta, Judith St-Onge, Nassima Boudrahem-Addour, Alexandre Dionne-Laporte, Pascal Joset, Silvia Azzarello-Burri, Anita Rauch, Joel Krier, Elizabeth Fieg, Juan C. Pallais, Allyn McConkie-Rosell, Marie McDonald, Sharon F. Freedman, Jean-Baptiste Rivière, Joël Lafond-Lapalme, Brittany N. Simpson, Robert J. Hopkin, Aurélien Trimouille, Julien Van-Gils, Amber Begtrup, Kirsty McWalter, Heron Delphine, Boris Keren, David Genevieve, Emanuela Argilli, Elliott H. Sherr, Mariasavina Severino, Guy A. Rouleau, Patricia T. Yam, Frédéric Charron, Myriam Srour, Maria T. Acosta, David R. Adams, Pankaj Agrawal, Mercedes E. Alejandro, Patrick Allard, Justin Alvey, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanyam, Dustin Baldridge, Jim Bale, Deborah Barbouth, Gabriel F. Batzli, Pinar Bayrak-Toydemir, Alan H. Beggs, Gill Bejerano, Hugo J. Bellen, Jonathan A. Bernstein, Gerard T. Berry, Anna Bican, David P. Bick, Camille L. Birch, Stephanie Bivona, John Bohnsack, Carsten Bonnenmann, Devon Bonner, Braden E. Boone, Bret L. Bostwick, Lorenzo Botto, Lauren C. Briere, Elly Brokamp, Donna M. Brown, Matthew Brush, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, John Carey, Olveen Carrasquillo, Ta Chen Peter Chang, Hsiao-Tuan Chao, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Precilla D’Souza, Surendra Dasari, Mariska Davids, Jyoti G. Dayal, Esteban C. Dell’Angelica, Shweta U. Dhar, Naghmeh Dorrani, Daniel C. Dorset, Emilie D. Douine, David D. Draper, Laura Duncan, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Cecilia Esteves, Tyra Estwick, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Paul G. Fisher, Brent L. Fogel, Irman Forghani, Laure Fresard, William A. Gahl, Rena A. Godfrey, Alica M. Goldman, David B. Goldstein, Jean-Philippe F. Gourdine, Alana Grajewski, Catherine A. Groden, Andrea L. Gropman, Melissa Haendel, Rizwan Hamid, Neil A. Hanchard, Nichole Hayes, Frances High, Ingrid A. Holm, Jason Hom, Alden Huang, Yong Huang, Rosario Isasi, Fariha Jamal, Yong-hui Jiang, Jean M. Johnston, Angela L. Jones, Lefkothea Karaviti, Emily G. Kelley, Dana Kiley, David M. Koeller, Isaac S. Kohane, Jennefer N. Kohler, Deborah Krakow, Donna M. Krasnewich, Susan Korrick, Mary Koziura, Joel B. Krier, Jennifer E. Kyle, Seema R. Lalani, Byron Lam, Brendan C. Lanpher, Ian R. Lanza, C. Christopher Lau, Jozef Lazar, Kimberly LeBlanc, Brendan H. Lee, Hane Lee, Roy Levitt, Shawn E. Levy, Richard A. Lewis, Sharyn A. Lincoln, Pengfei Liu, Xue Zhong Liu, Nicola Longo, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Marta M. Majcherska, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Thomas C. Markello, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Julian A. Martínez-Agosto, Shruti Marwaha, Thomas May, Jacob McCauley, Colleen E. McCormack, Alexa T. McCray, Thomas O. Metz, Matthew Might, Eva Morava-Kozicz, Paolo M. Moretti, Marie Morimoto, John J. Mulvihill, David R. Murdock, Avi Nath, Stan F. Nelson, J. Scott Newberry, John H. Newman, Sarah K. Nicholas, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, Stephen Pak, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, John H. Postlethwait, Lorraine Potocki, Barbara N. Pusey, Aaron Quinlan, Archana N. Raja, Genecee Renteria, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Jill A. Rosenfeld, Robb K. Rowley, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Susan L. Samson, Mario Saporta, Judy Schaechter, Timothy Schedl, Kelly Schoch, Daryl A. Scott, Lisa Shakachite, Prashant Sharma, Vandana Shashi, Kathleen Shields, Jimann Shin, Rebecca Signer, Catherine H. Sillari, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Kevin S. Smith, Lilianna Solnica-Krezel, Rebecca C. Spillmann, Joan M. Stoler, Nicholas Stong, Jennifer A. Sullivan, Shirley Sutton, David A. Sweetser, Holly K. Tabor, Cecelia P. Tamburro, Queenie K.-G. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Tiina K. Urv, Matt Velinder, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Nicole M. Walley, Chris A. Walsh, Melissa Walker, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Katrina M. Waters, Bobbie-Jo M. Webb-Robertson, Daniel Wegner, Monte Westerfield, Matthew T. Wheeler, Anastasia L. Wise, Lynne A. Wolfe, Jeremy D. Woods, Elizabeth A. Worthey, Shinya Yamamoto, John Yang, Amanda J. Yoon, Guoyun Yu, Diane B. Zastrow, Chunli Zhao, Stephan Zuchner, McGill University Health Center [Montreal] (MUHC), Istituto di ricovero e cura a carattere scientifico Azienda Ospedaliera Universitaria 'San Martino' (IRCCS AOU San Martino), Institut de Recherches Cliniques de Montréal (IRCM), Université de Montréal (UdeM), Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], University hospital of Zurich [Zurich], Universität Zürich [Zürich] = University of Zurich (UZH), Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Duke University [Durham], Duke University Medical Center, Génétique des Anomalies du Développement (GAD), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB), University of Cincinnati (UC), Cincinnati Children's Hospital Medical Center, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux (UB), GeneDx [Gaithersburg, MD, USA], Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), University of California [San Francisco] (UCSF), University of California, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione 'Istituto Neurologico Nazionale C. Mondino', Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Institute of Physics, Saink School Post, Institut de Physique du Globe de Paris (IPGP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut national des sciences de l'Univers (INSU - CNRS)-IPG PARIS-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Centre National de la Recherche Scientifique (CNRS), Genomics Program and Division of Genetics, Harvard Medical School [Boston] (HMS)-Boston Children's Hospital-The Manton Center for Orphan Disease Research, Représentations musicales (Repmus), Sciences et Technologies de la Musique et du Son (STMS), Institut de Recherche et Coordination Acoustique/Musique (IRCAM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche et Coordination Acoustique/Musique (IRCAM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Drapper, HudsonAlpha Institute for Biotechnology [Huntsville, AL], Queen Mary University of London (QMUL), Institute of Child Health, Department of Molecular and Human Genetics (Baylor College of Medicine), Baylor College of Medecine, Division of Biomedical Statistics and Informatics, Mayo Clinic, Facultat de Fisica, Departament Universitari d'Optica, Universitat de València (UV), Department of Pathology, University of Alabama at Birmingham [ Birmingham] (UAB), Center for Neuroscience Research (CNMC), Center for Neuroscience Research, Oregon Health and Science University [Portland] (OHSU), Baylor College of Medicine (BCM), Baylor University, Stanford University School of Medicine [CA, USA], Department of Molecular Cellular and Developmental Biology, University of California [Los Angeles] (UCLA), University of California-University of California-Howard Hughes Medical Institute (HHMI), Human Genetics, Department of Mathematics [Sussex], University of Sussex, Genomics Program and Division of Genetics [Boston, USA], Laboratoire Bordelais de Recherche en Informatique (LaBRI), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB), Bioinformatics Research Center, North Carolina State University [Raleigh] (NC State), University of North Carolina System (UNC)-University of North Carolina System (UNC), Biological Sciences Division, Pacific Northwest National Laboratory (PNNL), Departament de Fisica i Enginyeria Nuclear (DEPARTAMENT DI FISICA), Universitat Politècnica de Catalunya [Barcelona] (UPC), Institute of Human Genetics, Rheinische Friedrich-Wilhelms-Universität Bonn, National University of Singapore (NUS), Institute of Neuroscience [Eugene, OR, États-Unis], University of Oregon [Eugene], Boston Children's Hospital, Department of Molecular and Human Genetics [Houston, USA], Metacohorts Consortium, Department of Biological Sciences [Nashville], Vanderbilt University [Nashville], Columbia University Medical Center (CUMC), Columbia University [New York], School of Irish, Celtic Studies, Irish Folklore and Linguistics, University College Dublin [Dublin] (UCD), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Institute for Human Genomics, University of Miami [Coral Gables], ZFIN, Graduate School of Information Systems, University of Electro-Communications [Tokyo] (UEC), John P. Hussman Institute for Human Genomics, University of Miami Leonard M. Miller School of Medicine (UMMSM), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Université de Bordeaux (UB)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Heart Defects, Congenital, Heterozygote, [SDV]Life Sciences [q-bio], [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, CDH2, Eye, Frameshift mutation, genital defects, corpus callosum, 03 medical and health sciences, 0302 clinical medicine, Report, Genetics, medicine, Missense mutation, Humans, Genitalia, Axon, Frameshift Mutation, Genetics (clinical), N-cadherin, Corpus Callosum Agenesis, Cadherin, eye defects, Cadherins, Molecular biology, Axons, cardiac defects, 030104 developmental biology, medicine.anatomical_structure, ACOG, Neurodevelopmental Disorders, cell-cell adhesion, intellectual disability, Axon guidance, Neural development, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Cadherins constitute a family of transmembrane proteins that mediate calcium-dependent cell-cell adhesion. The extracellular domain of cadherins consists of extracellular cadherin (EC) domains, separated by calcium binding sites. The EC interacts with other cadherin molecules in cis and in trans to mechanically hold apposing cell surfaces together. CDH2 encodes N-cadherin, whose essential roles in neural development include neuronal migration and axon pathfinding. However, CDH2 has not yet been linked to a Mendelian neurodevelopmental disorder. Here, we report de novo heterozygous pathogenic variants (seven missense, two frameshift) in CDH2 in nine individuals with a syndromic neurodevelopmental disorder characterized by global developmental delay and/or intellectual disability, variable axon pathfinding defects (corpus callosum agenesis or hypoplasia, mirror movements, Duane anomaly), and ocular, cardiac, and genital anomalies. All seven missense variants (c.1057G>A [p.Asp353Asn]; c.1789G>A [p.Asp597Asn]; c.1789G>T [p.Asp597Tyr]; c.1802A>C [p.Asn601Thr]; c.1839C>G [p.Cys613Trp]; c.1880A>G [p.Asp627Gly]; c.2027A>G [p.Tyr676Cys]) result in substitution of highly conserved residues, and six of seven cluster within EC domains 4 and 5. Four of the substitutions affect the calcium-binding site in the EC4-EC5 interdomain. We show that cells expressing these variants in the EC4-EC5 domains have a defect in cell-cell adhesion; this defect includes impaired binding in trans with N-cadherin-WT expressed on apposing cells. The two frameshift variants (c.2563_2564delCT [p.Leu855Valfs∗4]; c.2564_2567dupTGTT [p.Leu856Phefs∗5]) are predicted to lead to a truncated cytoplasmic domain. Our study demonstrates that de novo heterozygous variants in CDH2 impair the adhesive activity of N-cadherin, resulting in a multisystemic developmental disorder, that could be named ACOG syndrome (agenesis of corpus callosum, axon pathfinding, cardiac, ocular, and genital defects).
Published: 2019
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41. Non-cirrhotic hyperammonemia after deceased donor kidney transplantation: A case report

Author: Andrew B. Stergachis, George Z. Li, Stefan G. Tullius, Joel B. Krier, Sayeed K. Malek, Leonardo V. Riella, Maria C. Tio, Linda M. Pak, and Julian L. Seifter
Subjects: medicine.medical_specialty, medicine.drug_class, Urinary system, Antibiotics, Encephalopathy, 030230 surgery, Article, 03 medical and health sciences, 0302 clinical medicine, medicine, Immunology and Allergy, Humans, Hyperammonemia, Transplantation, Homologous, Pharmacology (medical), Obstructive uropathy, Aged, Deceased donor kidney, Transplantation, business.industry, medicine.disease, Prognosis, Kidney Transplantation, Tissue Donors, Surgery, Death, Kidney Failure, Chronic, Female, business, Kidney disease
Abstract: A 72 year-old woman with end stage kidney disease due to recurrent urinary tract infections and obstructive uropathy of a solitary kidney presented to our hospital for renal transplantation. She underwent successful transplantation of a deceased donor allograft, but developed acute mental status deterioration on the fifth postoperative day. Her serum ammonia was found to be markedly elevated to 447 μmol/L in the setting of normal hepatic function. She was treated with emergent dialysis and empiric antibiotics targeting urea-splitting organisms, and ultimately made a full neurologic recovery with stable renal allograft function. Non-cirrhotic hyperammonemia (NCH) is an exceedingly rare clinical entity but seems to have a predilection for patients who have undergone solid organ transplantation. This report emphasizes the importance of rapid diagnosis and initiation of treatment for NCH, which is associated with a high rate of mortality and irreversible neurological morbidity. We outline the successful workup and management approach for this patient.
Published: 2019

42. De Novo Variants in WDR37 Are Associated with Epilepsy, Colobomas, Dysmorphism, Developmental Delay, Intellectual Disability, and Cerebellar Hypoplasia

Author: Oguz Kanca, Jonathan C. Andrews, Pei-Tseng Lee, Chirag Patel, Stephen R. Braddock, Anne M. Slavotinek, Julie S. Cohen, Cynthia S. Gubbels, Kimberly A. Aldinger, Judy Williams, Maanasa Indaram, Ali Fatemi, Timothy W. Yu, Pankaj B. Agrawal, Gilbert Vezina, Cas Simons, Joanna Crawford, C. Christopher Lau, Wendy K. Chung, Thomas C. Markello, William B. Dobyns, David R. Adams, William A. Gahl, Michael F. Wangler, Shinya Yamamoto, Hugo J. Bellen, May Christine V. Malicdan, Maria T. Acosta, Pankaj Agrawal, Mercedes E. Alejandro, Patrick Allard, Justin Alvey, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanyam, Dustin Baldridge, Jim Bale, Deborah Barbouth, Gabriel F. Batzli, Pinar Bayrak-Toydemir, Alan H. Beggs, Gill Bejerano, Jonathan A. Bernstein, Gerard T. Berry, Anna Bican, David P. Bick, Camille L. Birch, Stephanie Bivona, John Bohnsack, Carsten Bonnenmann, Devon Bonner, Braden E. Boone, Bret L. Bostwick, Lorenzo Botto, Lauren C. Briere, Elly Brokamp, Donna M. Brown, Matthew Brush, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, John Carey, Olveen Carrasquillo, Ta Chen Peter Chang, Hsiao-Tuan Chao, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Precilla D'Souza, Surendra Dasari, Mariska Davids, Jyoti G. Dayal, Esteban C. Dell'Angelica, Shweta U. Dhar, Naghmeh Dorrani, Daniel C. Dorset, Emilie D. Douine, David D. Draper, Laura Duncan, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Cecilia Esteves, Tyra Estwick, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Paul G. Fisher, Brent L. Fogel, Irman Forghani, Laure Fresard, Rena A. Godfrey, Alica M. Goldman, David B. Goldstein, Jean-Philippe F. Gourdine, Alana Grajewski, Catherine A. Groden, Andrea L. Gropman, Melissa Haendel, Rizwan Hamid, Neil A. Hanchard, Nichole Hayes, Frances High, Ingrid A. Holm, Jason Hom, Alden Huang, Yong Huang, Rosario Isasi, Fariha Jamal, Yong-hui Jiang, Jean M. Johnston, Angela L. Jones, Lefkothea Karaviti, Emily G. Kelley, Dana Kiley, David M. Koeller, Isaac S. Kohane, Jennefer N. Kohler, Deborah Krakow, Donna M. Krasnewich, Susan Korrick, Mary Koziura, Joel B. Krier, Jennifer E. Kyle, Seema R. Lalani, Byron Lam, Brendan C. Lanpher, Ian R. Lanza, Jozef Lazar, Kimberly LeBlanc, Brendan H. Lee, Hane Lee, Roy Levitt, Shawn E. Levy, Richard A. Lewis, Sharyn A. Lincoln, Pengfei Liu, Xue Zhong Liu, Nicola Longo, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Marta M. Majcherska, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Julian A. Martínez-Agosto, Shruti Marwaha, Thomas May, Jacob McCauley, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Thomas O. Metz, Matthew Might, Eva Morava-Kozicz, Paolo M. Moretti, Marie Morimoto, John J. Mulvihill, David R. Murdock, Avi Nath, Stan F. Nelson, J. Scott Newberry, John H. Newman, Sarah K. Nicholas, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, Stephen Pak, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, John H. Postlethwait, Lorraine Potocki, Barbara N. Pusey, Aaron Quinlan, Archana N. Raja, Genecee Renteria, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Jill A. Rosenfeld, Robb K. Rowley, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Susan L. Samson, Mario Saporta, Judy Schaechter, Timothy Schedl, Kelly Schoch, Daryl A. Scott, Lisa Shakachite, Prashant Sharma, Vandana Shashi, Kathleen Shields, Jimann Shin, Rebecca Signer, Catherine H. Sillari, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Kevin S. Smith, Lilianna Solnica-Krezel, Rebecca C. Spillmann, Joan M. Stoler, Nicholas Stong, Jennifer A. Sullivan, Shirley Sutton, David A. Sweetser, Holly K. Tabor, Cecelia P. Tamburro, Queenie K.-G. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Tiina K. Urv, Matt Velinder, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Nicole M. Walley, Chris A. Walsh, Melissa Walker, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Patricia A. Ward, Katrina M. Waters, Bobbie-Jo M. Webb-Robertson, Daniel Wegner, Monte Westerfield, Matthew T. Wheeler, Anastasia L. Wise, Lynne A. Wolfe, Jeremy D. Woods, Elizabeth A. Worthey, John Yang, Amanda J. Yoon, Guoyun Yu, Diane B. Zastrow, Chunli Zhao, and Stephan Zuchner
Subjects: Male, 0301 basic medicine, Pediatrics, WD40 Repeats, Developmental Disabilities, Sequence Homology, 030105 genetics & heredity, Epilepsy, CHARGE syndrome, 0302 clinical medicine, Cerebellum, Intellectual disability, Child, Cerebellar hypoplasia, Genetics (clinical), Genetics, Microfilament Proteins, Body Dysmorphic Disorders, Null allele, Phenotype, Coloboma, Drosophila melanogaster, Female, Adult, medicine.medical_specialty, Protein family, Allele name, Locus (genetics), Biology, Nervous System Malformations, Young Adult, 03 medical and health sciences, WD40 repeat, Intellectual Disability, Report, medicine, Animals, Humans, Amino Acid Sequence, Allele, Gene, business.industry, Infant, Newborn, Correction, Infant, Regret, medicine.disease, Human genetics, 030104 developmental biology, Mutation, business, 030217 neurology & neurosurgery
Abstract: WD40 repeat-containing proteins form a large family of proteins present in all eukaryotes. Here, we identified five pediatric probands with de novo variants in WDR37, which encodes a member of the WD40 repeat protein family. Two probands shared one variant and the others have variants in nearby amino acids outside the WD40 repeats. The probands exhibited shared phenotypes of epilepsy, colobomas, facial dysmorphology reminiscent of CHARGE syndrome, developmental delay and intellectual disability, and cerebellar hypoplasia. The WDR37 protein is highly conserved in vertebrate and invertebrate model organisms and is currently not associated with a human disease. We generated a null allele of the single Drosophila ortholog to gain functional insights and replaced the coding region of the fly gene CG12333/wdr37 with GAL4. These flies are homozygous viable but display severe bang sensitivity, a phenotype associated with seizures in flies. Additionally, the mutant flies fall when climbing the walls of the vials, suggesting a defect in grip strength, and repeat the cycle of climbing and falling. Similar to wall clinging defect, mutant males often lose grip of the female abdomen during copulation. These phenotypes are rescued by using the GAL4 in the CG12333/wdr37 locus to drive the UAS-human reference WDR37 cDNA. The two variants found in three human subjects failed to rescue these phenotypes, suggesting that these alleles severely affect the function of this protein. Taken together, our data suggest that variants in WDR37 underlie a novel syndromic neurological disorder.
Published: 2019

43. The Undiagnosed Diseases Network as a tool for graduate medical education

Author: J. Carl Pallais, Aaron W. Aday, Calum A. MacRae, Joseph Loscalzo, Joel B. Krier, and Elizabeth L. Fieg
Subjects: Medical education, Extramural, business.industry, MEDLINE, Graduate medical education, Medicine, General Medicine, business, Article
Published: 2019

44. Yield of whole exome sequencing in undiagnosed patients facing insurance coverage barriers to genetic testing

Author: Jean M. Davidson, John A. Phillips, David A. Sweetser, Joseph Loscalzo, Joel B. Krier, Matthew R. Herzog, Jonathan A. Bernstein, Matthew T. Wheeler, Joan M. Stoler, Elly Brokamp, Annika M. Dries, Liliana Fernandez, Shruti Marwaha, Ellen Macnamara, Joyce Hong, Jennefer N. Kohler, Kelly Schoch, Paul G. Fisher, Euan A. Ashley, Chloe M. Reuter, Jill A. Rosenfeld, John J. Mulvihill, David A. Adams, Vandana Shashi, Devon Bonner, Diane B. Zastrow, Rebecca C. Spillmann, Christina G.S. Palmer, and Yaping Yang
Subjects: Male, medicine.medical_specialty, Genetic counseling, media_common.quotation_subject, Undiagnosed Diseases, Insurance Coverage, Article, 03 medical and health sciences, 0302 clinical medicine, Denial, Exome Sequencing, Health insurance, Medicine, Humans, Genetic Testing, Intensive care medicine, Child, Genetics (clinical), Reimbursement, Exome sequencing, Genetic testing, media_common, Retrospective Studies, 0303 health sciences, medicine.diagnostic_test, business.industry, Public health, 030305 genetics & heredity, United States, 030220 oncology & carcinogenesis, Child, Preschool, Female, business, Insurance coverage
Abstract: Background Despite growing evidence of diagnostic yield and clinical utility of whole exome sequencing (WES) in patients with undiagnosed diseases, there remain significant cost and reimbursement barriers limiting access to such testing. The diagnostic yield and resulting clinical actions of WES for patients who previously faced insurance coverage barriers have not yet been explored. Methods We performed a retrospective descriptive analysis of clinical WES outcomes for patients facing insurance coverage barriers prior to clinical WES and who subsequently enrolled in the Undiagnosed Diseases Network (UDN). Clinical WES was completed as a result of participation in the UDN. Payer type, molecular diagnostic yield, and resulting clinical actions were evaluated. Results Sixty-six patients in the UDN faced insurance coverage barriers to WES at the time of enrollment (67% public payer, 26% private payer). Forty-two of 66 (64%) received insurance denial for clinician-ordered WES, 19/66 (29%) had health insurance through a payer known not to cover WES, and 5/66 (8%) had previous payer denial of other genetic tests. Clinical WES results yielded a molecular diagnosis in 23 of 66 patients (35% [78% pediatric, 65% neurologic indication]). Molecular diagnosis resulted in clinical actions in 14 of 23 patients (61%). Conclusions These data demonstrate that a substantial proportion of patients who encountered insurance coverage barriers to WES had a clinically actionable molecular diagnosis, supporting the notion that WES has value as a covered benefit for patients who remain undiagnosed despite objective clinical findings.
Published: 2019

45. Genomic sequencing in clinical practice: applications, challenges, and opportunities

Author: Joel B. Krier, Sarah S. Kalia, and Robert C. Green
Subjects: 0301 basic medicine, Genomics, Computational biology, Bioinformatics, DNA sequencing, 03 medical and health sciences, Clinical Research, medicine, Humans, medical genomics, Genetic Testing, Exome sequencing, Genetic testing, Massive parallel sequencing, medicine.diagnostic_test, Health management system, business.industry, Genomic sequencing, clinical genomics, High-Throughput Nucleotide Sequencing, 3. Good health, genome sequencing, Clinical Practice, 030104 developmental biology, genomic sequencing, business, exome sequencing
Abstract: The development of massively parallel sequencing (or next-generation sequencing) has facilitated a rapid implementation of genomic sequencing in clinical medicine. Genomic sequencing (GS) is now an essential tool for evaluating rare disorders, identifying therapeutic targets in neoplasms, and screening for prenatal aneuploidy. Emerging applications, such as GS for preconception carrier screening and predisposition screening in healthy individuals, are being explored in research settings and utilized by members of the public eager to incorporate genomic information into their health management. The rapid pace of adoption has created challenges for all stakeholders in clinical GS, from standardizing variant interpretation approaches in clinical molecular laboratories to ensuring that nongeneticist clinicians are prepared for new types of clinical information. Clinical GS faces a pivotal moment, as the vast potential of new quantities and types of data enable further clinical innovation and complicated implementation questions continue to be resolved.El desarrollo masivo de la secuenciación paralela o de nueva generación ha facilitado una rápida implementación de la secuenciación genómica en la medicina clínica. Hoy en día la secuenciación genómica (SG) es una herramienta esencial para evaluar trastornos raros, identificar blancos terapéuticos en neoplasias y evaluar la aneuploidía prenatal. Las aplicaciones emergentes, como la SG para el tamizaje antes de la concepción de portadores y la evaluación de predisposiciones en sujetos sanos están siendo exploradas en ambientes de investigación y empleadas por miembros de un público ávido de la incorporación de la información genómica para su atención de salud. El rápido ritmo de adopción ha creado desafíos para todos los interesados en la SG clínica, desde los enfoques centrados en la interpretación de variantes estandarizadas en laboratorios moleculares clínicos hasta asegurar que los clínicos no genetistas estén preparados para nuevos tipos de información clínica. La SG clínica se enfrenta a un momento crucial, ya que el gran potencial de nuevas cantidades y tipos de datos posibilitan una mayor innovación clínica mientras continúa la resolución de las preguntas acerca de la complicada implementación.La mise en place rapide du séquençage génomique en médecine clinique a été facilitée par le développement d'un séquençage massivement parallèle (ou séquençage de deuxième génération). Le séquençage génomique (SG) est maintenant un outil essentiel pour l'évaluation des maladies rares, l'identification des cibles thérapeutiques dans les cancers et le dépistage de l'aneuploïdie prénatale. Les applications naissantes comme le SG pour le test de dépistage du statut de porteur sain d'une anomalie avant la conception d'un enfant et le test de prédisposition génétique pour les sujets sains, font l'objet de recherches et sont utilisées par des usagers soucieux d'inclure l'information génomique dans la prise en charge de leur santé. De par cette adoption rapide, tous les acteurs du SG clinique ont été confrontés à des difficultés allant de la standardisation de différentes approches dans l'interprétation des résultats dans les laboratoires de diagnostic moléculaire à l'assurance de la préparation des médecins non généticiens pour recevoir ces nouvelles formes d'information. Le séquençage génomique est à une phase cruciale compte tenu de l'énorme potentiel des nouveautés dans la quantité et le type de données pouvant déboucher sur de futures innovations cliniques ; des problèmes de mise en ?uvre complexe sont encore à résoudre.
Published: 2016
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46. Gain-of-function mutations inSMAD4cause a distinctive repertoire of cardiovascular phenotypes in patients with Myhre syndrome

Author: Caroline Michot, Julie D. Kaplan, G. Paul Matherne, Makram R. Ebeid, Barrett H. Barnes, Elaine H. Zackai, Mark E. Lindsay, Matthew J. O'Connor, Thomas J. L'Ecuyer, Angela E. Lin, Elizabeth Krieg, Andrew C. Edmondson, Joel B. Krier, Brian B. Ghoshhajra, Valérie Cormier-Daire, and Jennifer B. Humberson
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, Adolescent, Hearing loss, medicine.medical_treatment, Cardiovascular Abnormalities, Cardiomyopathy, 030105 genetics & heredity, Short stature, Pericardial effusion, Young Adult, 03 medical and health sciences, Pericarditis, Intellectual Disability, Internal medicine, Cryptorchidism, Genetics, medicine, Humans, Myhre syndrome, Child, Pericardiectomy, Genetic Association Studies, Growth Disorders, In Situ Hybridization, Fluorescence, Genetics (clinical), Smad4 Protein, Ultrasonography, business.industry, Restrictive cardiomyopathy, Facies, High-Throughput Nucleotide Sequencing, Exons, medicine.disease, Magnetic Resonance Imaging, Phenotype, Treatment Outcome, 030104 developmental biology, Echocardiography, Mutation, Cardiology, Female, medicine.symptom, Tomography, X-Ray Computed, business, Hand Deformities, Congenital
Abstract: Myhre syndrome is a rare, distinctive syndrome due to specific gain-of-function mutations in SMAD4. The characteristic phenotype includes short stature, dysmorphic facial features, hearing loss, laryngotracheal anomalies, arthropathy, radiographic defects, intellectual disability, and a more recently appreciated spectrum of cardiovascular defects with a striking fibroproliferative response to surgical intervention. We report four newly described patients with typical features of Myhre syndrome who had (i) a mildly narrow descending aorta and restrictive cardiomyopathy; (ii) recurrent pericardial and pleural effusions; (iii) a large persistent ductus arteriosus with juxtaductal aortic coarctation; and (iv) restrictive pericardial disease requiring pericardiectomy. Additional information is provided about a fifth previously reported patient with fatal pericardial disease. A literature review of the cardiovascular features of Myhre syndrome was performed on 54 total patients, all with a SMAD4 mutation. Seventy percent had a cardiovascular abnormality including congenital heart defects (63%), pericardial disease (17%), restrictive cardiomyopathy (9%), and systemic hypertension (15%). Pericarditis and restrictive cardiomyopathy are associated with high mortality (three patients each among 10 deaths); one patient with restrictive cardiomyopathy also had epicarditis. Cardiomyopathy and pericardial abnormalities distinguish Myhre syndrome from other disorders caused by mutations in the TGF-β signaling cascade (Marfan, Loeys-Dietz, or Shprintzen-Goldberg syndromes). We hypothesize that the expanded spectrum of cardiovascular abnormalities relates to the ability of the SMAD4 protein to integrate diverse signaling pathways, including canonical TGF-β, BMP, and Activin signaling. The co-occurrence of congenital and acquired phenotypes demonstrates that the gene product of SMAD4 is required for both developmental and postnatal cardiovascular homeostasis. © 2016 Wiley Periodicals, Inc.
Published: 2016
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47. IRF2BPL Is Associated with Neurological Phenotypes

Author: Paul C. Marcogliese, Vandana Shashi, Rebecca C. Spillmann, Nicholas Stong, Jill A. Rosenfeld, Mary Kay Koenig, Julián A. Martínez-Agosto, Matthew Herzog, Agnes H. Chen, Patricia I. Dickson, Henry J. Lin, Moin U. Vera, Noriko Salamon, John M. Graham, Damara Ortiz, Elena Infante, Wouter Steyaert, Bart Dermaut, Bruce Poppe, Hyung-Lok Chung, Zhongyuan Zuo, Pei-Tseng Lee, Oguz Kanca, Fan Xia, Yaping Yang, Edward C. Smith, Joan Jasien, Sujay Kansagra, Gail Spiridigliozzi, Mays El-Dairi, Robert Lark, Kacie Riley, Dwight D. Koeberl, Katie Golden-Grant, Shinya Yamamoto, Michael F. Wangler, Ghayda Mirzaa, Dimitri Hemelsoet, Brendan Lee, Stanley F. Nelson, David B. Goldstein, Hugo J. Bellen, Loren D.M. Pena, Steven Callens, Paul Coucke, Wim Terryn, Rudy Van Coster, David R. Adams, Mercedes E. Alejandro, Patrick Allard, Mahshid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Hayk Barseghyan, Gabriel F. Batzli, Alan H. Beggs, Babak Behnam, Anna Bican, David P. Bick, Camille L. Birch, Devon Bonner, Braden E. Boone, Bret L. Bostwick, Lauren C. Briere, Donna M. Brown, Matthew Brush, Elizabeth A. Burke, Lindsay C. Burrage, Shan Chen, Gary D. Clark, Terra R. Coakley, Joy D. Cogan, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Precilla D’Souza, Mariska Davids, Jyoti G. Dayal, Esteban C. Dell’Angelica, Shweta U. Dhar, Ani Dillon, Katrina M. Dipple, Laurel A. Donnell-Fink, Naghmeh Dorrani, Daniel C. Dorset, Emilie D. Douine, David D. Draper, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Ascia Eskin, Cecilia Esteves, Tyra Estwick, Carlos Ferreira, Brent L. Fogel, Noah D. Friedman, William A. Gahl, Emily Glanton, Rena A. Godfrey, Sarah E. Gould, Jean-Philippe F. Gourdine, Catherine A. Groden, Andrea L. Gropman, Melissa Haendel, Rizwan Hamid, Neil A. Hanchard, Lori H. Handley, Matthew R. Herzog, Ingrid A. Holm, Jason Hom, Ellen M. Howerton, Yong Huang, Howard J. Jacob, Mahim Jain, Yong-hui Jiang, Jean M. Johnston, Angela L. Jones, Isaac S. Kohane, Donna M. Krasnewich, Elizabeth L. Krieg, Joel B. Krier, Seema R. Lalani, C. Christopher Lau, Jozef Lazar, Brendan H. Lee, Hane Lee, Shawn E. Levy, Richard A. Lewis, Sharyn A. Lincoln, Allen Lipson, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Marta M. Majcherska, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Thomas C. Markello, Ronit Marom, Julian A. Martínez-Agosto, Shruti Marwaha, Thomas May, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Matthew Might, Paolo M. Moretti, Marie Morimoto, John J. Mulvihill, Jennifer L. Murphy, Donna M. Muzny, Michele E. Nehrebecky, Stan F. Nelson, J. Scott Newberry, John H. Newman, Sarah K. Nicholas, Donna Novacic, Jordan S. Orange, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, John H. Postlethwait, Lorraine Potocki, Barbara N. Pusey, Chloe M. Reuter, Amy K. Robertson, Lance H. Rodan, Jacinda B. Sampson, Susan L. Samson, Kelly Schoch, Molly C. Schroeder, Daryl A. Scott, Prashant Sharma, Rebecca Signer, Edwin K. Silverman, Janet S. Sinsheimer, Kevin S. Smith, Kimberly Splinter, Joan M. Stoler, Jennifer A. Sullivan, David A. Sweetser, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Tiina K. Urv, Zaheer M. Valivullah, Eric Vilain, Tiphanie P. Vogel, Colleen E. Wahl, Nicole M. Walley, Chris A. Walsh, Patricia A. Ward, Katrina M. Waters, Monte Westerfield, Anastasia L. Wise, Lynne A. Wolfe, Elizabeth A. Worthey, Guoyun Yu, Diane B. Zastrow, and Allison Zheng
Subjects: 0301 basic medicine, Genetics, Ataxia, Correction, Biology, medicine.disease, Phenotype, Hypotonia, Article, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine, Missense mutation, Neuronal ceroid lipofuscinosis, Ectopic expression, medicine.symptom, Allele, Gene, 030217 neurology & neurosurgery, Genetics (clinical)
Abstract: Interferon regulatory factor 2 binding protein-like (IRF2BPL) encodes a member of the IRF2BP family of transcriptional regulators. Currently the biological function of this gene is obscure, and the gene has not been associated with a Mendelian disease. Here we describe seven individuals who carry damaging heterozygous variants in IRF2BPL and are affected with neurological symptoms. Five individuals who carry IRF2BPL nonsense variants resulting in a premature stop codon display severe neurodevelopmental regression, hypotonia, progressive ataxia, seizures, and a lack of coordination. Two additional individuals, both with missense variants, display global developmental delay and seizures and a relatively milder phenotype than those with nonsense alleles. The IRF2BPL bioinformatics signature based on population genomics is consistent with a gene that is intolerant to variation. We show that the fruit-fly IRF2BPL ortholog, called pits (protein interacting with Ttk69 and Sin3A), is broadly detected, including in the nervous system. Complete loss of pits is lethal early in development, whereas partial knockdown with RNA interference in neurons leads to neurodegeneration, revealing a requirement for this gene in proper neuronal function and maintenance. The identified IRF2BPL nonsense variants behave as severe loss-of-function alleles in this model organism, and ectopic expression of the missense variants leads to a range of phenotypes. Taken together, our results show that IRF2BPL and pits are required in the nervous system in humans and flies, and their loss leads to a range of neurological phenotypes in both species.
Published: 2018

48. Homozygous TRPV4 mutation causes congenital distal spinal muscular atrophy and arthrogryposis

Author: Natasha Y. Frank, Jose Velilla, Elicia Estrella, Rachelle Gaudet, Vandana Gupta, Alexis H. Bennett, Joel B. Krier, Claire A Grosgogeat, Basil T. Darras, Nikkola Carmichael, Michael M Marchetti, and Agnes Toth-Petroczy
Subjects: TRPV4, Proband, Pathology, medicine.medical_specialty, In silico, Biology, medicine.disease_cause, Article, 03 medical and health sciences, 0302 clinical medicine, medicine, Genetics (clinical), Exome sequencing, 030304 developmental biology, Genetics, Arthrogryposis, 0303 health sciences, Mutation, Arthrogryposis multiplex congenita, Congenital distal spinal muscular atrophy, Spinal muscular atrophy, medicine.disease, Neurology (clinical), medicine.symptom, 030217 neurology & neurosurgery
Abstract: ObjectiveThe objective of this study is to identify the genetic cause of disease in a congenital form of congenital spinal muscular atrophy and arthrogryposis (CSMAA).MethodsA 2-year-old boy was diagnosed with arthrogryposis multiplex congenita, severe skeletal abnormalities, torticollis, vocal cord paralysis and diminished lower limb movement. Whole exome sequencing was performed on the proband and family members. In silico modeling of protein structure and heterologous protein expression and cytotoxicity assays were performed to validate pathogenicity of the identified variant.ResultsWhole exome sequencing revealed a homozygous mutation in the TRPV4 gene (c.281C>T; p.S94L). The identification of a recessive mutation in TRPV4 extends the spectrum of mutations in recessive forms of the TRPV4-associated disease. p.S94L and other previously identified TRPV4 variants in different protein domains were compared in structural modeling and functional studies. In silico structural modeling suggests that the p.S94L mutation is in the disordered N-terminal region proximal to important regulatory binding sites for phosphoinositides and for PACSIN3, which could lead to alterations in trafficking and/or channel sensitivity. Functional studies by western blot and immunohistochemical analysis show that p.S94L reduces TRPV4 protein stability because of increased cytotoxicity and therefore involves a gain-of-function mechanism.ConclusionThis study identifies a novel homozygous mutation in TRPV4 as a cause of the recessive form of congenital spinal muscular atrophy and arthrogryposis.
Published: 2018
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49. The BabySeq project: implementing genomic sequencing in newborns

Author: Talia S. Schwartz, Peter J. Park, Kurt D. Christensen, Harvey L. Levy, Ozge Ceyhan-Birsoy, Timothy W. Yu, Richard B. Parad, Stacey Pereira, Alan H. Beggs, Leslie A. Frankel, Ingrid A. Holm, Amy L. McGuire, Pankaj B. Agrawal, Joel B. Krier, Rebecca C. LaMay, Robert C. Green, Shawn Fayer, Susan E. Waisbren, Casie A. Genetti, and Heidi L. Rehm
Subjects: 0301 basic medicine, Newborn screening, medicine.medical_specialty, Ethical, legal, social implications, Genetic Counseling, 030105 genetics & heredity, Risk Assessment, Pharmacogenomic Variants, law.invention, 03 medical and health sciences, Study Protocol, Neonatal Screening, Randomized controlled trial, law, Health care, Exome Sequencing, Methods, Medicine, Humans, Family, Genetic Predisposition to Disease, Exome sequencing, Newborn sequencing, business.industry, Genomic sequencing, Medical record, lcsh:RJ1-570, Whole exome sequencing, Infant, Newborn, lcsh:Pediatrics, Health Care Costs, 3. Good health, 030104 developmental biology, Family medicine, Pediatrics, Perinatology and Child Health, Randomized trial, business, Return of results
Abstract: The greatest opportunity for lifelong impact of genomic sequencing is during the newborn period. The “BabySeq Project” is a randomized trial that explores the medical, behavioral, and economic impacts of integrating genomic sequencing into the care of healthy and sick newborns. Families of newborns are enrolled from Boston Children’s Hospital and Brigham and Women’s Hospital nurseries, and half are randomized to receive genomic sequencing and a report that includes monogenic disease variants, recessive carrier variants for childhood onset or actionable disorders, and pharmacogenomic variants. All families participate in a disclosure session, which includes the return of results for those in the sequencing arm. Outcomes are collected through review of medical records and surveys of parents and health care providers and include the rationale for choice of genes and variants to report; what genomic data adds to the medical management of sick and healthy babies; and the medical, behavioral, and economic impacts of integrating genomic sequencing into the care of healthy and sick newborns. The BabySeq Project will provide empirical data about the risks, benefits and costs of newborn genomic sequencing and will inform policy decisions related to universal genomic screening of newborns. The study is registered in ClinicalTrials.gov Identifier: NCT02422511 . Registration date: 10 April 2015.
Published: 2018

50. A Comprehensive Iterative Approach is Highly Effective in Diagnosing Individuals who are Exome Negative

Author: Vandana Shashi, Kelly Schoch, Rebecca Spillmann, Heidi Cope, Queenie K.-G. Tan, Nicole Walley, Loren Pena, Allyn McConkie-Rosell, Yong-Hui Jiang, Nicholas Stong, Anna C. Need, David B. Goldstein, David R. Adams, Mercedes E. Alejandro, Patrick Allard, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Hayk Barseghyan, Gabriel F. Batzli, Alan H. Beggs, Babak Behnam, Hugo J. Bellen, Jonathan A. Bernstein, Anna Bican, David P. Bick, Camille L. Birch, Devon Bonner, Braden E. Boone, Bret L. Bostwick, Lauren C. Briere, Donna M. Brown, Matthew Brush, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, Shan Chen, Gary D. Clark, Terra R. Coakley, Joy D. Cogan, Cynthia M. Cooper, William J. Craigen, Precilla D’Souza, Mariska Davids, Jean M. Davidson, Jyoti G. Dayal, Esteban C. Dell’Angelica, Shweta U. Dhar, Katrina M. Dipple, Laurel A. Donnell-Fink, Naghmeh Dorrani, Daniel C. Dorset, Emilie D. Douine, David D. Draper, Annika M. Dries, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Gregory M. Enns, Ascia Eskin, Cecilia Esteves, Tyra Estwick, Liliana Fernandez, Carlos Ferreira, Paul G. Fisher, Brent L. Fogel, Noah D. Friedman, William A. Gahl, Emily Glanton, Rena A. Godfrey, Sarah E. Gould, Jean-Philippe F. Gourdine, Catherine A. Groden, Andrea L. Gropman, Melissa Haendel, Rizwan Hamid, Neil A. Hanchard, Lori H. Handley, Matthew R. Herzog, Ingrid A. Holm, Jason Hom, Ellen M. Howerton, Yong Huang, Howard J. Jacob, Mahim Jain, Yong-hui Jiang, Jean M. Johnston, Angela L. Jones, David M. Koeller, Isaac S. Kohane, Jennefer N. Kohler, Donna M. Krasnewich, Elizabeth L. Krieg, Joel B. Krier, Jennifer E. Kyle, Seema R. Lalani, C. Christopher Lau, Jozef Lazar, Kimberly LeBlanc, Brendan H. Lee, Hane Lee, Shawn E. Levy, Richard A. Lewis, Sharyn A. Lincoln, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Marta M. Majcherska, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Thomas C. Markello, Ronit Marom, Martin G. Martin, Julian A. Martínez-Agosto, Shruti Marwaha, Thomas May, Colleen E. McCormack, Alexa T. McCray, Jason D. Merker, Thomas O. Metz, Matthew Might, Paolo M. Moretti, Marie Morimoto, John J. Mulvihill, Jennifer L. Murphy, Donna M. Muzny, Michele E. Nehrebecky, Stan F. Nelson, J. Scott Newberry, John H. Newman, Sarah K. Nicholas, Donna Novacic, Jordan S. Orange, J. Carl Pallais, Christina GS. Palmer, Jeanette C. Papp, Neil H. Parker, Loren DM. Pena, John A. Phillips, Jennifer E. Posey, John H. Postlethwait, Lorraine Potocki, Barbara N. Pusey, Chloe M. Reuter, Amy K. Robertson, Lance H. Rodan, Jill A. Rosenfeld, Jacinda B. Sampson, Susan L. Samson, Molly C. Schroeder, Daryl A. Scott, Prashant Sharma, Edwin K. Silverman, Janet S. Sinsheimer, Kevin S. Smith, Rebecca C. Spillmann, Joan M. Stoler, Jennifer A. Sullivan, David A. Sweetser, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Tiina K. Urv, Zaheer M. Valivullah, Eric Vilain, Tiphanie P. Vogel, Daryl M. Waggott, Colleen E. Wahl, Nicole M. Walley, Chris A. Walsh, Jijun Wan, Michael F. Wangler, Patricia A. Ward, Katrina M. Waters, Bobbie-Jo M. Webb-Robertson, Monte Westerfield, Matthew T. Wheeler, Anastasia L. Wise, Lynne A. Wolfe, Elizabeth A. Worthey, Shinya Yamamoto, Yaping Yang, Amanda J. Yoon, Guoyun Yu, Diane B. Zastrow, Chunli Zhao, and Allison Zheng
Subjects: 0301 basic medicine, FASTQ format, Male, Candidate gene, phenotyping, Developmental Disabilities, Computational biology, 030105 genetics & heredity, Candidate Gene Identification, DNA sequencing, Article, 03 medical and health sciences, Pathognomonic, Exome Sequencing, Medicine, Humans, Exome, Genetic Predisposition to Disease, Child, Genetics (clinical), Exome sequencing, whole genome sequencing, business.industry, Whole exome sequencing, rare diseases, Genomics, Sequence Analysis, DNA, undiagnosed diseases, 3. Good health, 030104 developmental biology, Phenotype, Female, business
Abstract: Purpose Sixty-75% of individuals with rare and undiagnosed phenotypes remain undiagnosed after whole exome sequencing (ES). With standard ES reanalysis resolving 10–15% of the ES negatives, further approaches are necessary to maximize diagnoses in these individuals. Methods In 38 ES negative patients an individualized genomic-phenotypic approach was employed utilizing: A) Phenotyping; B) Reanalyses of FASTQ files, with innovative bioinformatics; C) Targeted molecular testing; D) Whole genome sequencing (WGS) and E) Conferring of clinical diagnoses when pathognomonic clinical findings occurred. Results Certain and Highly Likely diagnoses were made in 18/38 (47%) individuals, including identifying two new developmental disorders. The majority of diagnoses (>70%) were due to our bioinformatics, phenotyping and targeted testing identifying variants that were undetected or not prioritized on prior ES. WGS diagnosed 3/18 individuals, with structural variants not amenable to ES. Additionally, Tentative diagnoses were made in three (8%) and in five individuals (13%) candidate genes were identified. Overall, diagnoses/potential leads were identified in 26/38 (68%). Conclusions Our comprehensive approach to ES negatives maximizes the ES and clinical data for both diagnoses and candidate gene identification, without WGS in the majority. This iterative approach is cost-effective and is pertinent to the current conundrum of ES negatives.
Published: 2018

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