Search

Your search keyword '"Irma Gutierrez"' showing total 5 results
Start Over Author "Irma Gutierrez" Topic 0301 basic medicine
5 results on '"Irma Gutierrez"'

1. 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
Full Text
View/download PDF

2. 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
Full Text
View/download PDF

3. 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
Full Text
View/download PDF

4. 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
Full Text
View/download PDF

5. Functional and structural analyses of novel Smith-Kingsmore Syndrome-Associated MTOR variants reveal potential new mechanisms and predictors of pathogenicity

Author

Irma Gutierrez-Mejia, Thorsten Althoff, Anja A. Kattentidt-Mouravieva, Yvette van Ierland, Joshua Sadik, Mark Nellist, Aaron D. Besterman, Julian A. Martinez-Agosto, Jonathan A. Bernstein, Jeff Abramson, Peter Elfferich, Kwiatkowski, David J, and Clinical Genetics

Subjects
0301 basic medicine, Male, Cancer Research, Developmental Disabilities, Disease, Pathogenesis, QH426-470, Pathology and Laboratory Medicine, Biochemistry, Fats, Database and Informatics Methods, 0302 clinical medicine, Neurodevelopmental disorder, Medicine and Health Sciences, Macromolecular Structure Analysis, Missense mutation, 2.1 Biological and endogenous factors, Megalencephaly, Aetiology, Child, Genetics (clinical), TOR Serine-Threonine Kinases, Middle Aged, Phenotype, Lipids, Hypotonia, Oncology, Child, Preschool, Female, medicine.symptom, Research Article, Adult, Protein Structure, Intellectual and Developmental Disabilities (IDD), Immunoblotting, Mutation, Missense, Molecular Probe Techniques, Computational biology, Biology, Transfection, Research and Analysis Methods, 03 medical and health sciences, Rare Diseases, Protein Domains, SDG 3 - Good Health and Well-being, Intellectual Disability, medicine, Genetics, Humans, Molecular Biology Techniques, Preschool, Molecular Biology, Ecology, Evolution, Behavior and Systematics, PI3K/AKT/mTOR pathway, Mechanism (biology), Neurosciences, Biology and Life Sciences, Cancers and Neoplasms, Proteins, medicine.disease, Brain Disorders, 030104 developmental biology, Biological Databases, Neurodevelopmental Disorders, Mutation Databases, Mutation, Missense, 030217 neurology & neurosurgery, Developmental Biology
Abstract

Smith-Kingsmore syndrome (SKS) is a rare neurodevelopmental disorder characterized by macrocephaly/megalencephaly, developmental delay, intellectual disability, hypotonia, and seizures. It is caused by dominant missense mutations in MTOR. The pathogenicity of novel variants in MTOR in patients with neurodevelopmental disorders can be difficult to determine and the mechanism by which variants cause disease remains poorly understood. We report 7 patients with SKS with 4 novel MTOR variants and describe their phenotypes. We perform in vitro functional analyses to confirm MTOR activation and interrogate disease mechanisms. We complete structural analyses to understand the 3D properties of pathogenic variants. We examine the accuracy of relative accessible surface area, a quantitative measure of amino acid side-chain accessibility, as a predictor of MTOR variant pathogenicity. We describe novel clinical features of patients with SKS. We confirm MTOR Complex 1 activation and identify MTOR Complex 2 activation as a new potential mechanism of disease in SKS. We find that pathogenic MTOR variants disproportionately cluster in hotspots in the core of the protein, where they disrupt alpha helix packing due to the insertion of bulky amino acid side chains. We find that relative accessible surface area is significantly lower for SKS-associated variants compared to benign variants. We expand the phenotype of SKS and demonstrate that additional pathways of activation may contribute to disease. Incorporating 3D properties of MTOR variants may help in pathogenicity classification. We hope these findings may contribute to improving the precision of care and therapeutic development for individuals with SKS., Author summary Smith-Kingsmore Syndrome is a rare disease caused by damage in a gene named MTOR that is associated with excessive growth of the head and brain, delays in development and deficits in intellectual functioning. We report 7 patients who have changes in MTOR that have never been reported before. We describe new medical findings in these patients that may be common in Smith-Kingsmore Syndrome more broadly. We then identify how these new gene changes impact the function of the MTOR protein and thus cell function downstream. Lastly, we show that changes in the gene that lie deep inside the 3D structure of the MTOR protein are more likely to cause disease than those changes that lie on the surface of the protein. We may be able to use the 3D properties of MTOR gene changes to predict if future changes we see are likely to cause disease or not.

Published
2021

Catalog

Books, media, physical & digital resources
See catalog results