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1. P214: SeqFirst DDi: Early whole genome sequencing improves access to early precise genetic diagnosis for children with developmental differences

Author: Katrina Dipple, Daniel Doherty, Kailyn Anderson, Olivia Sommers, Tara Wenger, Kate MacDuffie, Alexandra Keefe, Abbey Scott, Lukas Kruidenier, Jamie Love-Nichols, Heidi Gildersleeve, Chayna Davis, Kati Buckingham, Jessica Chong, David Veenstra, Danny Miller, Deborah Copenheaver, Jane Juusola, Kyle Retterer, Kirsty McWalter, Paul Kruszka, Joon-Ho Yu, and Michael Bamshad
Subjects: Genetics, QH426-470, Medicine
Published: 2024
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2. P248: A genotype-first approach to identifying treatable genomic conditions in a large healthcare-based population

Author: Karyn Meltz Murphy, Rebecca Torene, Melissa Kelly, Christa Martin, and Kyle Retterer
Subjects: Genetics, QH426-470, Medicine
Published: 2024
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3. O35: Feasibility of expanded newborn screening using genome sequencing for early actionable conditions in a diverse city

Author: Wendy Chung, Alban Ziegler, Carrie Koval-Burt, Denise Kay, Sharon Suchy, Amber Bergtrup, Katherine Langley, Laura Amendola, Brenna Boyd, Jennifer Bradley, Tracy Brandt, Lilian Cohen, Alison Coffey, Joseph Devaney, Beata Dygulska, Bethany Friedman, Ramsey Fuleihan, Awura Gyimah, Rebecca Hernan, Sean Hofherr, Kathleen Hruska, Zhanzhi Hu, Mederic Jeanne, Guanjun Jin, Aaron Johnson, Haluk Kavus, Rudolph Leibel, Kirsty McWalter, Kristin Monaghan, Nicole Pimentel Soler, Yeyson Quevedo, Samantha Ratner, Kyle Retterer, Natasha Shapiro, Robert Sicko, Samuel Storm, Rebecca Torene, Olatundun Williams, Julia Wynn, Ryan Taft, Paul Kruszka, and Michele Caggana
Subjects: Genetics, QH426-470, Medicine
Published: 2024
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4. P208: SeqFirst: Impact of a precise genetic diagnosis on end-of-life decision making in the NICU

Author: Alexandra Keefe, Tara Wenger, Joon-Ho Yu, Megan Sikes, Luke Kruidenier, Abbey Scott, Kate McDuffie, Olivia Sommers, Heidi Gildersleeve, Chayna Davis, Paul Kruszka, Kati Buckingham, Jessica Chong, David Veenstra, Kyle Retterer, Kirsty McWalter, Amy Snook, Jane Juusola, Deborah Copenheaver, Danny Miller, Katrina Dipple, Kyle Brothers, and Michael Bamshad
Subjects: Genetics, QH426-470, Medicine
Published: 2023
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5. P414: SeqFirst: Parental perspectives on receiving results from neonatal rapid whole genome sequencing

Author: Tara Wenger, Alexandra Keefe, Megan Sikes, Luke Kruidenier, Joon-Ho Yu, Kate McDuffie, Olivia Sommers, Heidi Gildersleeve, Abbey Scott, Chayna Davis, Paul Kruszka, Kati Buckingham, Jessica Chong, Kyle Retterer, Kirsty McWalter, Amy Snook, Jane Juusola, Deborah Copenheaver, David Veenstra, Danny Miller, Katrina Dipple, and Michael Bamshad
Subjects: Genetics, QH426-470, Medicine
Published: 2023
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6. Age-adjusted association of homologous recombination genes with ovarian cancer using clinical exomes as controls

Author: Kevin J. Arvai, Maegan E. Roberts, Rebecca I. Torene, Lisa R. Susswein, Megan L. Marshall, Zhancheng Zhang, Natalie J. Carter, Lauren Yackowski, Erica S. Rinella, Rachel T. Klein, Kathleen S. Hruska, and Kyle Retterer
Subjects: Ovarian Cancer, BRIP1, Exome sequencing, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282, Genetics, QH426-470
Abstract: Abstract Background Genes in the homologous recombination pathway have shown varying results in the literature regarding ovarian cancer (OC) association. Recent case-control studies have used allele counts alone to quantify genetic associations with cancer. Methods A retrospective case-control study was performed on 6,182 women with OC referred for hereditary cancer multi-gene panel testing (cases) and 4,690 mothers from trios who were referred for whole-exome sequencing (controls). We present age-adjusted odds ratios (ORAdj) to determine association of OC with pathogenic variants (PVs) in homologous recombination genes. Results Significant associations with OC were observed in BRCA1, BRCA2, RAD51C and RAD51D. Other homologous recombination genes, BARD1, NBN, and PALB2, were not significantly associated with OC. ATM and CHEK2 were only significantly associated with OC by crude odds ratio (ORCrude) or by ORAdj, respectively. However, there was no significant difference between ORCrude and ORAdj for these two genes. The significant association of PVs in BRIP1 by ORCrude (2.05, CI = 1.11 to 3.94, P = 0.03) was not observed by ORAdj (0.87, CI = 0.41 to 1.93, P = 0.73). Interestingly, the confidence intervals of the two effect sizes were significantly different (P = 0.04). Conclusion The lack of association of PVs in BRIP1 with OC by ORAdj is inconsistent with some previous literature and current management recommendations, highlighted by the significantly older age of OC onset for BRIP1 PV carriers compared to non-carriers. By reporting ORAdj, this study presents associations that reflect more informed genetic contributions to OC when compared to traditional count-based methods.
Published: 2019
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7. Rare pathogenic variants in WNK3 cause X-linked intellectual disability

Author: Sébastien Küry, Jinwei Zhang, Thomas Besnard, Alfonso Caro-Llopis, Xue Zeng, Stephanie M. Robert, Sunday S. Josiah, Emre Kiziltug, Anne-Sophie Denommé-Pichon, Benjamin Cogné, Adam J. Kundishora, Le T. Hao, Hong Li, Roger E. Stevenson, Raymond J. Louie, Wallid Deb, Erin Torti, Virginie Vignard, Kirsty McWalter, F. Lucy Raymond, Farrah Rajabi, Emmanuelle Ranza, Detelina Grozeva, Stephanie A. Coury, Xavier Blanc, Elise Brischoux-Boucher, Boris Keren, Katrin Õunap, Karit Reinson, Pilvi Ilves, Ingrid M. Wentzensen, Eileen E. Barr, Solveig Heide Guihard, Perrine Charles, Eleanor G. Seaby, Kristin G. Monaghan, Marlène Rio, Yolande van Bever, Marjon van Slegtenhorst, Wendy K. Chung, Ashley Wilson, Delphine Quinquis, Flora Bréhéret, Kyle Retterer, Pierre Lindenbaum, Emmanuel Scalais, Lindsay Rhodes, Katrien Stouffs, Elaine M. Pereira, Sara M. Berger, Sarah S. Milla, Ankita B. Jaykumar, Melanie H. Cobb, Shreyas Panchagnula, Phan Q. Duy, Marie Vincent, Sandra Mercier, Brigitte Gilbert-Dussardier, Xavier Le Guillou, Séverine Audebert-Bellanger, Sylvie Odent, Sébastien Schmitt, Pierre Boisseau, Dominique Bonneau, Annick Toutain, Estelle Colin, Laurent Pasquier, Richard Redon, Arjan Bouman, Jill. A. Rosenfeld, Michael J. Friez, Helena Pérez-Peña, Syed Raza Akhtar Rizvi, Shozeb Haider, Stylianos E. Antonarakis, Charles E. Schwartz, Francisco Martínez, Stéphane Bézieau, Kristopher T. Kahle, Bertrand Isidor, Clinical Genetics, Clinical sciences, Medical Genetics, Reproduction and Genetics, Centre hospitalier universitaire de Nantes (CHU Nantes), 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)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), University of Exeter, MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), The Greenwood Genetic Center, GeneDx [Gaithersburg, MD, USA], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), 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 ), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Genève = University of Geneva (UNIGE), Yale School of Medicine [New Haven, Connecticut] (YSM), This work was granted by the French network of University Hospitals HUGO ('Hôpitaux Universitaires du Grand Ouest'), the French Ministry of Health, and and the Health Regional Agencies from Poitou-Charentes (represented by Frédérique Allaire), Bretagne, Pays de la Loire, and Centre-Val de Loire (HUGODIMS, 2013, RC14_0107). W.K.C. was supported by grants from Simons Foundation Autism Research Initiative, United
Subjects: MESH: Symporters, Exome sequencing, Male, KCC2, Mutation, Missense, MESH: Catalytic Domain, Neurodevelopmental disease, Protein Serine-Threonine Kinases, X-linked intellectual disability, MESH: Brain, WNK3, SDG 3 - Good Health and Well-being, Loss of Function Mutation, Catalytic Domain, MESH: Mental Retardation, X-Linked, Humans, Phosphorylation, MESH: Hemizygote, Genetics (clinical), Hemizygote, MESH: Mutation, Missense, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Phosphorylation, Symporters, Brain, MESH: Loss of Function Mutation, MESH: Protein Serine-Threonine Kinases, MESH: Male, Mental Retardation, X-Linked, Maternal Inheritance, MESH: Maternal Inheritance
Abstract: PURPOSE: WNK3 kinase (PRKWNK3) has been implicated in the development and function of the brain via its regulation of the cation-chloride cotransporters, but the role of WNK3 in human development is unknown. METHOD: We ascertained exome or genome sequences of individuals with rare familial or sporadic forms of intellectual disability (ID). RESULTS: We identified a total of 6 different maternally-inherited, hemizygous, 3 loss-of-function or 3 pathogenic missense variants (p.Pro204Arg, p.Leu300Ser, p.Glu607Val) in WNK3 in 14 male individuals from 6 unrelated families. Affected individuals had identifier with variable presence of epilepsy and structural brain defects. WNK3 variants cosegregated with the disease in 3 different families with multiple affected individuals. This included 1 large family previously diagnosed with X-linked Prieto syndrome. WNK3 pathogenic missense variants localize to the catalytic domain and impede the inhibitory phosphorylation of the neuronal-specific chloride cotransporter KCC2 at threonine 1007, a site critically regulated during the development of synaptic inhibition. CONCLUSION: Pathogenic WNK3 variants cause a rare form of human X-linked identifier with variable epilepsy and structural brain abnormalities and implicate impaired phospho-regulation of KCC2 as a pathogenic mechanism.
Published: 2022

8. The landscape of reported VUS in multi-gene panel and genomic testing: Time for a change

Author: Heidi L Rehm, Joseph T Alaimo, Swaroop Aradhya, Pinar Bayrak-Toydemir, Hunter Best, Rhonda Brandon, Jillian G Buchan, Elizabeth C Chao, Elaine Chen, Jacob Clifford, Ana S Cohen, Laura K Conlin, Soma Das, Kyle W Davis, Daniela del Gaudio, Florencia Del Viso, Christina DiVincenzo, Marcia Eisenberg, Lucia Guidugli, Monia B Hammer, Steven M Harrison, Kathryn E Hatchell, Lindsay Havens Dyer, Lily U Hoang, James M Holt, Vaidehi Jobanputra, Izabela D Karbassi, Hutton M Kearney, Melissa A Kelly, Jacob M Kelly, Michelle L Kluge, Timothy Komala, Paul Kruszka, Lynette Lau, Matthew S Lebo, Christian R Marshall, Dianalee McKnight, Kirsty McWalter, Yan Meng, Narasimhan Nagan, Christian S Neckelmann, Nir Neerman, Zhiyv Niu, Vitoria K Paolillo, Sarah A Paolucci, Denise Perry, Tina Pesaran, Kelly Radtke, Kristen J Rasmussen, Kyle Retterer, Carol J Saunders, Elizabeth Spiteri, Christine M Stanley, Anna Szuto, Ryan J Taft, Isabelle Thiffault, Brittany C Thomas, Amanda Thomas-Wilson, Erin Thorpe, Timothy J Tidwell, Meghan C Towne, and Hana Zouk
Abstract: Variants of uncertain significance (VUS) are a common result of diagnostic genetic testing and can be difficult to manage with potential misinterpretation and downstream costs, including time investment by clinicians. We investigated the rate of VUS reported on diagnostic testing via multi-gene panels (MGPs) and exome and genome sequencing (ES/GS) to measure the magnitude of uncertain results and explore ways to reduce their potentially detrimental impact. We collected data from over 1.5 million genetic tests from 19 clinical laboratories across the United States and Canada from during 2020-2021. We found a lower rate of inconclusive results due to VUS on ES/GS tests compared to MGPs (22.5% vs. 32.6%; p
Published: 2022

9. Uniparental disomy in a population of 32,067 clinical exome trios

Author: Jennifer Keller-Ramey, Kyle Retterer, Vladimir G. Gainullin, Jane Juusola, Ganka Douglas, Rebecca I. Torene, Lindsay Dyer, Julie Scuffins, and Jeanne Meck
Subjects: Genetics, congenital, hereditary, and neonatal diseases and abnormalities, education.field_of_study, DNA Copy Number Variations, Homozygote, Population, Uniparental Disomy, Biology, medicine.disease, Article, Uniparental disomy, Polymorphism (computer science), Exome Sequencing, medicine, Humans, SNP, Exome, Imprinting (psychology), education, Trisomy, Genetics (clinical), Exome sequencing
Abstract: Purpose Data on the clinical prevalence and spectrum of uniparental disomy (UPD) remain limited. Trio exome sequencing (ES) presents a comprehensive method for detection of UPD alongside sequence and copy-number variant analysis. Methods We analyzed 32,067 ES trios referred for diagnostic testing to create a profile of UPD events and their disease associations. ES single-nucleotide polymorphism (SNP) and copy-number data were used to identify both whole-chromosome and segmental UPD and to categorize whole-chromosome results as isodisomy, heterodisomy, or mixed. Results Ninety-nine whole-chromosome and 13 segmental UPD events were identified. Of these, 29 were associated with an imprinting disorder, and 16 were associated with a positive test result through homozygous sequence variants. Isodisomy was more commonly observed in large chromosomes along with a higher rate of homozygous pathogenic variants, while heterodisomy was more frequent in chromosomes associated with imprinting or trisomy mosaicism (14, 15, 16, 20, 22). Conclusion Whole-chromosome UPD was observed in 0.31% of cases, resulting in a diagnostic finding in 0.14%. Only three UPD-positive cases had a diagnostic finding unrelated to the UPD. Thirteen UPD events were identified in cases with prior normal SNP chromosomal microarray results, demonstrating the additional diagnostic value of UPD detection by trio ES.
Published: 2021

10. Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease

Author: Sarthak Gupta, Amanda K. Ombrello, Emily Rominger, Megan Trick, Karyl S. Barron, Ryan S. Laird, Sinisa Savic, Shuichiro Nakabo, Daniela Ospina Cardona, Ivona Aksentijevich, Carmelo Carmona-Rivera, Gustaf Wigerblad, Mariana J. Kaplan, Emma M. Groarke, Laura W. Dillon, Chyi-Chia Richard Lee, Kalpana Manthiram, Kristina V. Wells, Nicholas Balanda, Zhijie Wu, Helen J. Lachmann, Daniel L. Kastner, Fernanda Gutierrez-Rodrigues, Achim Werner, Michele Nehrebecky, Lisha Xu, Alina Dulau-Florea, Wanxia L. Tsai, Bhavisha A Patel, Stefania Dell'Orso, Weixin Wang, Anthony J. Asmar, Danica Novacic, Katherine R. Calvo, David B. Beck, Robert A. Colbert, Massimo Gadina, William A. Gahl, Wendy Goodspeed, Natalie Deuitch, Dorota Rowczenio, Peter C. Grayson, Daron L. Ross, Sofia Rosenzweig, Anne Jones, Christopher S. Hourigan, James C. Mullikin, Stephen R. Brooks, Jason C. Collins, Wuhong Pei, May Christine V. Malicdan, Neal S. Young, Shawn M. Burgess, Keith A. Sikora, Mones Abu-Asab, Kyle Retterer, Patrycja Hoffmann, Hirotsugu Oda, Marcela A. Ferrada, Zuoming Deng, Benjamin D. Solomon, and Jae Jin Chae
Subjects: Genetics, Mutation, Somatic cell, business.industry, Sequence analysis, General Medicine, UBA1, 030204 cardiovascular system & hematology, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Genotype, Medicine, Missense mutation, 030212 general & internal medicine, Age of onset, business, Gene
Abstract: Background Adult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated in autoinflammatory disease, may...
Published: 2020

11. Mobile element insertion detection in 89,874 clinical exomes

Author: Kyle Retterer, Carlos Borroto, Erin Beaver, Jane Juusola, Lorne A. Clarke, Kevin Galens, Zhancheng Zhang, Shuxi Liu, Jennifer Heeley, Kevin J. Arvai, Rebecca I. Torene, Jagdeep S. Walia, Julie Scuffins, Danna Hull, Bethany Friedman, Hana Sroka, and Sarah Neil
Subjects: 0301 basic medicine, mobile elements, rare disease, Binomial test, Computational biology, 030105 genetics & heredity, Brief Communication, DNA sequencing, 03 medical and health sciences, Exome Sequencing, medicine, diagnostics, Humans, Exome, Genetic Testing, Genetics (clinical), Exome sequencing, Genetic testing, medicine.diagnostic_test, business.industry, Sequence Analysis, DNA, Confidence interval, 030104 developmental biology, Mobile genetic elements, Mendelian disease, business, Founder effect
Abstract: Purpose Exome sequencing (ES) is increasingly used for the diagnosis of rare genetic disease. However, some pathogenic sequence variants within the exome go undetected due to the technical difficulty of identifying them. Mobile element insertions (MEIs) are a known cause of genetic disease in humans but have been historically difficult to detect via ES and similar targeted sequencing methods. Methods We developed and applied a novel MEI detection method prospectively to samples received for clinical ES beginning in November 2017. Positive MEI findings were confirmed by an orthogonal method and reported back to the ordering provider. In this study, we examined 89,874 samples from 38,871 cases. Results Diagnostic MEIs were present in 0.03% (95% binomial test confidence interval: 0.02–0.06%) of all cases and account for 0.15% (95% binomial test confidence interval: 0.08–0.25%) of cases with a molecular diagnosis. One diagnostic MEI was a novel founder event. Most patients with pathogenic MEIs had prior genetic testing, three of whom had previous negative DNA sequencing analysis of the diagnostic gene. Conclusion MEI detection from ES is a valuable diagnostic tool, reveals molecular findings that may be undetected by other sequencing assays, and increases diagnostic yield by 0.15%.
Published: 2020

12. Response to Hamosh et al

Author: John M. Graham, Joseph T. Shieh, Alan F. Rope, Philip F Giampietro, Lynne M. Bird, Roberta A Pagon, John C. Carey, Katta M. Girisha, Cathy A. Stevens, David D. Weaver, Margaret P. Adam, William B. Dobyns, Bryan D. Hall, Elaine H. Zackai, Chad R. Haldeman-Englert, Anne C. Tsai, A. Micheil Innes, Marc S. Williams, Ian A. Glass, David A. Stevenson, Kenjiro Kosaki, Beth A. Kozel, Jennifer M. Kalish, Michael J. Bamshad, John J. Mulvihill, Robin D. Clark, Anne Slavotinek, Kim M. Keppler-Noreuil, Anita E. Beck, Małgorzata J.M. Nowaczyk, Cynthia J. Curry, Fowzan S. Alkuraya, Ghayda M. Mirzaa, Timothy C. Cox, Anne Amemiya, Karen W. Gripp, Wen-Hann Tan, Andrew K. Sobering, Yuri A. Zarate, Mary Beth Dinulos, Laurie H. Seaver, James T. Bennett, Leslie G. Biesecker, Kyle Retterer, Tiong Yang Tan, Brian H.Y. Chung, and Pedro A. Sanchez-Lara
Subjects: Genetics, Biology, Letter to the Editor, Genetics (clinical)
Published: 2021

13. Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability

Author: Philippe M. Campeau, Katherine Agre, Vernon R. Sutton, Kirsty McWalter, Bertrand Isidor, Øystein L. Holla, Anna Lehman, Megha Desai, Jonathan Berg, Stéphane Bézieau, Rolph Pfundt, Jennifer Tarpinian, Jennifer B. Humberson, Holly A.F. Stessman, Madeleine R. Geisheker, Emma Bedoukian, Shalini N. Jhangiani, Marine I. Murphree, Annapurna Poduri, Anne-Sophie Denommé-Pichon, Christian Gilissen, Yaping Yang, Eliane Beauregard-Lacroix, Claude Férec, Francesca Filippini, Anne Guimier, Daryl A. Scott, Stephen Sanders, Julie C. Sapp, Ralitza H. Gavrilova, Slavé Petrovski, Ann Nordgren, Sylvia Redon, Ernie M.H.F. Bongers, Shelagh Joss, Jill A. Rosenfeld, Wallid Deb, Ingrid M. Wentzensen, Usha Kini, Vandana Shashi, Mindy H. Li, Stanislas Lyonnet, Thomas Garcia, Øyvind L. Busk, Christoffer Nellåker, Amber Begtrup, Brigitte Gilbert-Dussardier, Thomas Besnard, Francois V. Bolduc, Patrick R. Blackburn, Justine Rousseau, Frédéric Bilan, Eric W. Klee, Christopher T. Gordon, Pavel N. Pichurin, Peggy Kulch, Kevin P. Lally, Laurie Robak, Arnaud Picard, Kristian Tveten, Meredith Park, Sébastien Küry, Jaya Punetha, Moira Blyth, Asbjørg Stray-Pedersen, Jacqueline Harris, Erin L. Heinzen, Nicholas Stong, Cara M. Skraban, Julie S. Cohen, Aida Telegrafi, Xenia Latypova, Zeynep Coban Akdemir, Jacob Zyskind, Caitlin Troyer, Xiang-Jiao Yang, Tuula Rinne, Leslie G. Biesecker, Jennifer E. Posey, Kyle Retterer, Jeanne Amiel, Rui Xiao, Magnus Nordenskjöld, Tammie Dewan, Jennifer A. Sullivan, Charlotte von der Lippe, Evan E. Eichler, Anna Lindstrand, Dominique Bonneau, Yuri A. Zarate, Elaine H. Zackai, Fayth M. Kalb, Daniel H. Lowenstein, Shiri Avni, Benjamin Cogné, Jennifer J. Johnston, Kerri H. Whitlock, Catherine Shain, Séverine Audebert-Bellanger, Malin Kvarnung, Oana Caluseriu, David Goldstein, Annick Toutain, Andres Hernandez-Garcia, Brina Daniels, Sophie Ehresmann, James R. Lupski, Julie McGaughran, Ashley H Ebanks, Kévin Uguen, Marine Legendre, Sylvie Odent, Richard Redon, Erica H. Gerkes, Xiaofei Song, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Sainte Justine [Montréal], Université du Québec à Montréal = University of Québec in Montréal (UQAM), University of Oxford [Oxford], GeneDx [Gaithersburg, MD, USA], Mayo Clinic [Rochester], University of California [San Francisco] (UCSF), University of California, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Etablissement Français du Sang Bretagne, EFS, Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), Johns Hopkins University School of Medicine [Baltimore], Kennedy Krieger Institute [Baltimore], Chapel Allerton Hospital, University of British Columbia (UBC), University of Dundee, Rush University Medical Center [Chicago], Oxford University Hospitals NHS Trust, Queen Elizabeth University Hospital (Glasgow), Trondheim University, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), University of Virginia [Charlottesville], Texas Children's Hospital [Houston, USA], Baylor College of Medicine (BCM), Baylor University, University of Pennsylvania [Philadelphia], National Human Genome Research Institute (NHGRI), Harvard Medical School [Boston] (HMS), Karolinska University Hospital [Stockholm], Duke University Medical Center, University of Groningen [Groningen], University of Arkansas for Medical Sciences (UAMS), McGovern Medical School [Houston, Texas], The University of Texas Health Science Center at Houston (UTHealth), Phoenix Children's Hospital, Columbia University [New York], University of Southern Queensland (USQ), Telemark Hospital Trust [Skien, Norway], University of Washington [Seattle], Oslo University Hospital [Oslo], Children’s Hospital of Philadelphia (CHOP ), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Radboud University Medical Center [Nijmegen], Ann & Robert H. Lurie Children's Hospital of Chicago, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), 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), CHU Pontchaillou [Rennes], Centre de référence Maladies Rares CLAD-Ouest [Rennes], Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre hospitalier universitaire de Poitiers (CHU Poitiers), University of Alberta, Boston Children's Hospital, McGill University Health Center [Montreal] (MUHC), Hôpital Morvan - CHRU de Brest (CHU - BREST ), Creighton University Medical School [Omaha, NE, USA], Howard Hughes Medical Institute [Boston] (HHMI), Howard Hughes Medical Institute (HHMI)-Harvard Medical School [Boston] (HMS), National Institute of Neurological Disorders and Stroke, K08 HG008986, National Human Genome Research Institute, BC Children’s Hospital Foundation, Genome British Columbia, Fonds de Recherche du Québec - Santé, Canadian Institutes of Health Research, Center for Individualized Medicine, Mayo Clinic, Health Regional Agency from Poitou-Charentes, French Ministry of Health, RC14_0107, HUGODIMS, NS053998, The Epilepsy Phenome/Genome Project, NS077303, Epi4K, Duke Genome Sequencing Clinic, NINDS R35 NS105078, National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development, HG200328 12, intramural research program of the NHGRI, Dart NeuroScience, Kids Brain Health Network, Mining for Miracles, UM1 HG006542, National Heart, Lung, and Blood Institute, CIM Investigative and Functional Genomics Program, R01MH101221, National Institute of Mental Health, Unité de recherche de l'institut du thorax (ITX-lab), 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), University of Oxford, University of California [San Francisco] (UC San Francisco), University of California (UC), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Virginia, University of Pennsylvania, Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 ), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), CCSD, Accord Elsevier, Faculteit Medische Wetenschappen/UMCG, Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: CHROMATIN, Male, 0301 basic medicine, Autism, Sequence Homology, [SDV.GEN] Life Sciences [q-bio]/Genetics, Medical and Health Sciences, 0302 clinical medicine, SCHIZOPHRENIA, Gene expression, 2.1 Biological and endogenous factors, Missense mutation, Aetiology, Child, de novo variants, Genetics (clinical), Pediatric, Genetics & Heredity, Genetics, biology, neurodevelopmental disorders, histone acetylation, Adaptor Proteins, Nuclear Proteins, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Syndrome, Biological Sciences, Prognosis, Phenotype, Chromatin, Mental Health, Histone, intellectual disability, Child, Preschool, Female, REGULATOR, congenital malformations, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], BRAIN-DEVELOPMENT, Adult, Adolescent, Histone acetyltransferase complex, Intellectual and Developmental Disabilities (IDD), Mutation, Missense, Deciphering Developmental Disorders study, autism spectrum disorder, KAT6B, RNAI SCREEN, Young Adult, 03 medical and health sciences, CAUSES Study, Rare Diseases, Intellectual Disability, Report, COFACTOR, medicine, RUBINSTEIN-TAYBI-SYNDROME, Humans, Amino Acid Sequence, Autistic Disorder, Preschool, Gene, Genetic Association Studies, Adaptor Proteins, Signal Transducing, [SDV.GEN]Life Sciences [q-bio]/Genetics, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Rubinstein–Taybi syndrome, Signal Transducing, Neurosciences, Infant, medicine.disease, TRRAP, Brain Disorders, SELF-RENEWAL, 030104 developmental biology, DE-NOVO MUTATIONS, Mutation, biology.protein, Missense, 030217 neurology & neurosurgery
Abstract: Contains fulltext : 202928.pdf (Publisher’s version ) (Open Access) Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants.
Published: 2019

14. Molecular Diagnostic Yield of Exome Sequencing in Patients With Cerebral Palsy

Author: Vladimir G. Gainullin, Francisca Millan, Claire Teigen, Julie Scuffins, Andres Moreno-De-Luca, Kevin J. Arvai, H. Lester Kirchner, Matthew T. Oetjens, Houda Zghal Elloumi, Scott M. Myers, Karen E. Wain, Kyle Retterer, Rebecca I. Torene, Christa Lese Martin, Denis R. Pesacreta, and David H. Ledbetter
Subjects: Adult, Male, Pediatrics, medicine.medical_specialty, Adolescent, Cross-sectional study, 01 natural sciences, Cerebral palsy, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, Interquartile range, Exome Sequencing, medicine, Prevalence, Humans, 030212 general & internal medicine, Genetic Testing, 0101 mathematics, Child, Exome sequencing, Genetic testing, Original Investigation, Retrospective Studies, Asphyxia, medicine.diagnostic_test, business.industry, Cerebral Palsy, 010102 general mathematics, Obstetrics and Gynecology, Genetic Variation, Retrospective cohort study, General Medicine, Middle Aged, medicine.disease, Cross-Sectional Studies, Autism spectrum disorder, Neurodevelopmental Disorders, Child, Preschool, Cohort, Mutation, Female, medicine.symptom, business
Abstract: Importance Cerebral palsy is a common neurodevelopmental disorder affecting movement and posture that often co-occurs with other neurodevelopmental disorders. Individual cases of cerebral palsy are often attributed to birth asphyxia; however, recent studies indicate that asphyxia accounts for less than 10% of cerebral palsy cases. Objective To determine the molecular diagnostic yield of exome sequencing (prevalence of pathogenic and likely pathogenic variants) in individuals with cerebral palsy. Design, Setting, and Participants A retrospective cohort study of patients with cerebral palsy that included a clinical laboratory referral cohort with data accrued between 2012 and 2018 and a health care–based cohort with data accrued between 2007 and 2017. Exposures Exome sequencing with copy number variant detection. Main Outcomes and Measures The primary outcome was the molecular diagnostic yield of exome sequencing. Results Among 1345 patients from the clinical laboratory referral cohort, the median age was 8.8 years (interquartile range, 4.4-14.7 years; range, 0.1-66 years) and 601 (45%) were female. Among 181 patients in the health care–based cohort, the median age was 41.9 years (interquartile range, 28.0-59.6 years; range, 4.8-89 years) and 96 (53%) were female. The molecular diagnostic yield of exome sequencing was 32.7% (95% CI, 30.2%-35.2%) in the clinical laboratory referral cohort and 10.5% (95% CI, 6.0%-15.0%) in the health care–based cohort. The molecular diagnostic yield ranged from 11.2% (95% CI, 6.4%-16.2%) for patients without intellectual disability, epilepsy, or autism spectrum disorder to 32.9% (95% CI, 25.7%-40.1%) for patients with all 3 comorbidities. Pathogenic and likely pathogenic variants were identified in 229 genes (29.5% of 1526 patients); 86 genes were mutated in 2 or more patients (20.1% of 1526 patients) and 10 genes with mutations were independently identified in both cohorts (2.9% of 1526 patients). Conclusions and Relevance Among 2 cohorts of patients with cerebral palsy who underwent exome sequencing, the prevalence of pathogenic and likely pathogenic variants was 32.7% in a cohort that predominantly consisted of pediatric patients and 10.5% in a cohort that predominantly consisted of adult patients. Further research is needed to understand the clinical implications of these findings.
Published: 2021

15. A dyadic approach to the delineation of diagnostic entities in clinical genomics

Author: Wen-Hann Tan, Małgorzata J.M. Nowaczyk, Joseph T. Shieh, Anne Slavotinek, John M. Graham, Lynne M. Bird, David D. Weaver, Laurie H. Seaver, Anne Amemiya, Ghayda Mirzaa, Beth A. Kozel, Jennifer M. Kalish, John C. Carey, Anita E. Beck, Margaret P. Adam, Bryan D. Hall, Philip F Giampietro, Kim M. Keppler-Noreuil, David A. Stevenson, Karen W. Gripp, Robin D. Clark, Mary Beth Dinulos, William B. Dobyns, Pedro A. Sanchez-Lara, Roberta A Pagon, Andrew K. Sobering, Michael J. Bamshad, Fowzan S. Alkuraya, Tiong Yang Tan, Brian H.Y. Chung, Alan F. Rope, Elaine H. Zackai, Marc S. Williams, John J. Mulvihill, James T. Bennett, Leslie G. Biesecker, Kyle Retterer, Yuri A. Zarate, Timothy C. Cox, Chad R. Haldeman-Englert, Anne C. Tsai, Ian A. Glass, Cynthia J. Curry, Kenjiro Kosaki, A. Micheil Innes, Katta M. Girisha, and Cathy A. Stevens
Subjects: 0301 basic medicine, Cystic Fibrosis, Genotype, Computer science, Cystic Fibrosis Transmembrane Conductance Regulator, Disease, Computational biology, 030105 genetics & heredity, Medical and Health Sciences, 03 medical and health sciences, symbols.namesake, Rare Diseases, Genetics, medicine, Humans, Mendelian disorders, Letter to the Editor, Genetics (clinical), Simple (philosophy), Genetics & Heredity, Clinical genomics, Extramural, Genetic disorder, Genetic Diseases, Inborn, Genomics, Biological Sciences, medicine.disease, Inborn, 030104 developmental biology, Phenotype, Genetic Diseases, Perspective, Mutation, Mendelian inheritance, symbols
Abstract: The delineation of disease entities is complex, yet recent advances in the molecular characterization of diseases provide opportunities to designate diseases in a biologically valid manner. Here, we have formalized an approach to the delineation of Mendelian genetic disorders that encompasses two distinct but inter-related concepts: (1) the gene that is mutated and (2) the phenotypic descriptor, preferably a recognizably distinct phenotype. We assert that only by a combinatorial or dyadic approach taking both of these attributes into account can a unitary, distinct genetic disorder be designated. We propose that all Mendelian disorders should be designated as “GENE-related phenotype descriptor” (e.g., “CFTR-related cystic fibrosis”). This approach to delineating and naming disorders reconciles the complexity of gene-to-phenotype relationships in a simple and clear manner yet communicates the complexity and nuance of these relationships.
Published: 2021

16. eP281: SeqFirst-neo: Improving access equity for a precise genetic diagnosis in the NICU

Author: Tara Wenger, Abbey Scott, Megan Sikes, Chayna Davis, Kati Buckingham, Jessica Chong, Kyle Retterer, Jane Juusola, Deborah Copenheaver, Paul Kruszka, Katrina Dipple, and Michael Bamshad
Subjects: Genetics (clinical)
Published: 2022

17. Somatic Mutations in

Author: David B, Beck, Marcela A, Ferrada, Keith A, Sikora, Amanda K, Ombrello, Jason C, Collins, Wuhong, Pei, Nicholas, Balanda, Daron L, Ross, Daniela, Ospina Cardona, Zhijie, Wu, Bhavisha, Patel, Kalpana, Manthiram, Emma M, Groarke, Fernanda, Gutierrez-Rodrigues, Patrycja, Hoffmann, Sofia, Rosenzweig, Shuichiro, Nakabo, Laura W, Dillon, Christopher S, Hourigan, Wanxia L, Tsai, Sarthak, Gupta, Carmelo, Carmona-Rivera, Anthony J, Asmar, Lisha, Xu, Hirotsugu, Oda, Wendy, Goodspeed, Karyl S, Barron, Michele, Nehrebecky, Anne, Jones, Ryan S, Laird, Natalie, Deuitch, Dorota, Rowczenio, Emily, Rominger, Kristina V, Wells, Chyi-Chia R, Lee, Weixin, Wang, Megan, Trick, James, Mullikin, Gustaf, Wigerblad, Stephen, Brooks, Stefania, Dell'Orso, Zuoming, Deng, Jae J, Chae, Alina, Dulau-Florea, May C V, Malicdan, Danica, Novacic, Robert A, Colbert, Mariana J, Kaplan, Massimo, Gadina, Sinisa, Savic, Helen J, Lachmann, Mones, Abu-Asab, Benjamin D, Solomon, Kyle, Retterer, William A, Gahl, Shawn M, Burgess, Ivona, Aksentijevich, Neal S, Young, Katherine R, Calvo, Achim, Werner, Daniel L, Kastner, and Peter C, Grayson
Subjects: Aged, 80 and over, Inflammation, Male, Genotype, Giant Cell Arteritis, Immunoblotting, Mutation, Missense, Genetic Diseases, X-Linked, Sequence Analysis, DNA, Syndrome, Ubiquitin-Activating Enzymes, Middle Aged, Sweet Syndrome, Article, Autoimmune Diseases, Polyarteritis Nodosa, Myelodysplastic Syndromes, Cytokines, Humans, Exome, Polychondritis, Relapsing, Age of Onset, Multiple Myeloma, Aged
Abstract: Adult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated in autoinflammatory disease, may define new disorders.We analyzed peripheral-blood exome sequence data independent of clinical phenotype and inheritance pattern to identify deleterious mutations in ubiquitin-related genes. Sanger sequencing, immunoblotting, immunohistochemical testing, flow cytometry, and transcriptome and cytokine profiling were performed. CRISPR-Cas9-edited zebrafish were used as an in vivo model to assess gene function.We identified 25 men with somatic mutations affecting methionine-41 (p.Met41) in UBA1, the major E1 enzyme that initiates ubiquitylation. (The geneUsing a genotype-driven approach, we identified a disorder that connects seemingly unrelated adult-onset inflammatory syndromes. We named this disorder the VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. (Funded by the NIH Intramural Research Programs and the EU Horizon 2020 Research and Innovation Program.).
Published: 2020

18. Mutations disrupting neuritogenesis genes confer risk for cerebral palsy

Author: Jeff L. Waugh, Mahalia S.B. Frank, Xiaoyang Wang, Antigone Papavasileiou, Michael C. Sierant, Nadia Badawi, Bohao Zhang, Chongchen Zhou, Sheetal Shetty, Sheng Chih Jin, Susan M Reid, Changlian Zhu, Francisca Millan, Suzanna C. MacLennan, Julien Buratti, David J. Amor, Stephen Pastore, Lance H. Rodan, Timothy Feyma, Janice E. Brunstrom-Hernandez, Kylie E. Crompton, Megan Cho, Helen Magee, Sergio Padilla-Lopez, Julie S. Cohen, Daniela C. Zarnescu, Richard P. Lifton, Aureliane Elie, Michael C. Kruer, Qiongshi Lu, Sandra Whalen, Christopher Castaldi, John B. Vincent, Chao Gao, Irina Tikhonova, Ali Fatemi, Qinghe Xing, Dinah Reddihough, Lei Xia, Bethany Y. Norton, Shozeb Haider, Shrikant Mane, Yana A. Wilson, Dengna Zhu, Yangong Wang, Somayeh Bakhtiari, Francesc López-Giráldez, Michael C Fahey, Clare L. van Eyk, Sarah McIntyre, Jozef Gecz, Junhui Zhang, Xue Zeng, Jennifer Heim, Iona Novak, Spencer Vaughan, John P. Phillips, Sara A. Lewis, Angela E. Lin, Diane Doummar, Mark A. Corbett, Kyle Retterer, James R. Knight, Qing Shang, Boyang Li, Yiran Xu, James Liu, Boris Keren, Sandra M. Nordlie, Kaya Bilguvar, Amar H. Sheth, Dani L. Webber, Alastair H. MacLennan, Brandon S. Guida, Kelly Harper, and Jesia G. Berry
Subjects: Male, Cyclin D, RHOB, medicine.disease_cause, Article, Cerebral palsy, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Tubulin, Exome Sequencing, RhoB GTP-Binding Protein, Neurites, Genetics, medicine, Animals, Humans, Exome, Genetic Predisposition to Disease, rhoB GTP-Binding Protein, Cytoskeleton, beta Catenin, Exome sequencing, 030304 developmental biology, Focal Adhesions, 0303 health sciences, Mutation, biology, Genome, Human, Cerebral Palsy, F-Box Proteins, Tumor Suppressor Proteins, Sequence Analysis, DNA, medicine.disease, Human genetics, Extracellular Matrix, biology.protein, Drosophila, Female, 030217 neurology & neurosurgery, Signal Transduction
Abstract: In addition to commonly associated environmental factors, genomic factors may cause cerebral palsy. We performed whole-exome sequencing of 250 parent-offspring trios, and observed enrichment of damaging de novo mutations in cerebral palsy cases. Eight genes had multiple damaging de novo mutations; of these, two (TUBA1A and CTNNB1) met genome-wide significance. We identified two novel monogenic etiologies, FBXO31 and RHOB, and showed that the RHOB mutation enhances active-state Rho effector binding while the FBXO31 mutation diminishes cyclin D levels. Candidate cerebral palsy risk genes overlapped with neurodevelopmental disorder genes. Network analyses identified enrichment of Rho GTPase, extracellular matrix, focal adhesion and cytoskeleton pathways. Cerebral palsy risk genes in enriched pathways were shown to regulate neuromotor function in a Drosophila reverse genetics screen. We estimate that 14% of cases could be attributed to an excess of damaging de novo or recessive variants. These findings provide evidence for genetically mediated dysregulation of early neuronal connectivity in cerebral palsy.
Published: 2020

19. Histone H3.3 beyond cancer: Germline mutations in

Author: Laura, Bryant, Dong, Li, Samuel G, Cox, Dylan, Marchione, Evan F, Joiner, Khadija, Wilson, Kevin, Janssen, Pearl, Lee, Michael E, March, Divya, Nair, Elliott, Sherr, Brieana, Fregeau, Klaas J, Wierenga, Alexandrea, Wadley, Grazia M S, Mancini, Nina, Powell-Hamilton, Jiddeke, van de Kamp, Theresa, Grebe, John, Dean, Alison, Ross, Heather P, Crawford, Zoe, Powis, Megan T, Cho, Marcia C, Willing, Linda, Manwaring, Rachel, Schot, Caroline, Nava, Alexandra, Afenjar, Davor, Lessel, Matias, Wagner, Thomas, Klopstock, Juliane, Winkelmann, Claudia B, Catarino, Kyle, Retterer, Jane L, Schuette, Jeffrey W, Innis, Amy, Pizzino, Sabine, Lüttgen, Jonas, Denecke, Tim M, Strom, Kristin G, Monaghan, Zuo-Fei, Yuan, Holly, Dubbs, Renee, Bend, Jennifer A, Lee, Michael J, Lyons, Julia, Hoefele, Roman, Günthner, Heiko, Reutter, Boris, Keren, Kelly, Radtke, Omar, Sherbini, Cameron, Mrokse, Katherine L, Helbig, Sylvie, Odent, Benjamin, Cogne, Sandra, Mercier, Stephane, Bezieau, Thomas, Besnard, Sebastien, Kury, Richard, Redon, Karit, Reinson, Monica H, Wojcik, Katrin, Õunap, Pilvi, Ilves, A Micheil, Innes, Kristin D, Kernohan, Gregory, Costain, M Stephen, Meyn, David, Chitayat, Elaine, Zackai, Anna, Lehman, Hilary, Kitson, Martin G, Martin, Julian A, Martinez-Agosto, Stan F, Nelson, Christina G S, Palmer, Jeanette C, Papp, Neil H, Parker, Janet S, Sinsheimer, Eric, Vilain, Jijun, Wan, Amanda J, Yoon, Allison, Zheng, Elise, Brimble, Giovanni Battista, Ferrero, Francesca Clementina, Radio, Diana, Carli, Sabina, Barresi, Alfredo, Brusco, Marco, Tartaglia, Jennifer Muncy, Thomas, Luis, Umana, Marjan M, Weiss, Garrett, Gotway, K E, Stuurman, Michelle L, Thompson, Kirsty, McWalter, Constance T R M, Stumpel, Servi J C, Stevens, Alexander P A, Stegmann, Kristian, Tveten, Arve, Vøllo, Trine, Prescott, Christina, Fagerberg, Lone Walentin, Laulund, Martin J, Larsen, Melissa, Byler, Robert Roger, Lebel, Anna C, Hurst, Joy, Dean, Samantha A, Schrier Vergano, Jennifer, Norman, Saadet, Mercimek-Andrews, Juanita, Neira, Margot I, Van Allen, Nicola, Longo, Elizabeth, Sellars, Raymond J, Louie, Sara S, Cathey, Elly, Brokamp, Delphine, Heron, Molly, Snyder, Adeline, Vanderver, Celeste, Simon, Xavier, de la Cruz, Natália, Padilla, J Gage, Crump, Wendy, Chung, Benjamin, Garcia, Hakon H, Hakonarson, and Elizabeth J, Bhoj
Subjects: endocrine system, SciAdv r-articles, Forkhead Transcription Factors, Neurodegenerative Diseases, Zebrafish Proteins, Histones, fluids and secretions, mental disorders, Genetics, Animals, Humans, Molecular Biology, reproductive and urinary physiology, Germ-Line Mutation, Zebrafish, Research Articles, Research Article
Abstract: Germ line mutations in H3F3A and H3F3B cause a previously unidentified neurodevelopmental syndrome., Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation.
Published: 2020

20. Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases

Author: Nuzhat Rana, Edwin H. Jacobs, Ehsan Ghayoor Karimiani, Amber Begtrup, Jozef Hertecant, Evita Medici-van den Herik, Mohammad Doosti, Gouri Rao Passi, Mohammadreza Dehghani, Tjakko J. van Ham, Mariya Kozenko, Laila AlQuait, Mohammad Yahya Vahidi Mehrjardi, Dilek Colak, Herma C. van der Linde, Henry Houlden, Eleonora Aronica, Huma Arshad Cheema, Jennefer N. Kohler, Namik Kaya, Krishna Kumar Kandaswamy, Salem Alwadaee, Maysoon Alsagob, Woutje M. Berdowski, Zaynab Khazaei, Renjith Mani, Faisal Al Azri, Amna Al Futaisi, Stephanie Efthymiou, Majid Mojarrad, Aida M. Bertoli-Avella, Murat Gunel, Tahsin Stefan Barakat, Wilfred F. J. van IJcken, Kristin G. Monaghan, Rebecca I. Torene, Atieh Eslahi, Fathiya Al Murshedi, Khalid Awartani, Peter Bauer, Muddathir H. Hamad, Kyle Retterer, Reza Maroofian, Rawan Almass, Erik-Jan Kamsteeg, Serdar Coskun, Jonathan A. Bernstein, Elena Perenthaler, Anita Nikoncuk, Mohammed A. AlMuhaizea, Jana Vandrovcova, Anas M. Dababo, Soheil Yousefi, Fateme Massinaei Darmiyan, Mustafa A. Salih, Lauren Brick, A. Gulhan Ercan-Sencicek, Futwan Al-Mohanna, Ivan Čapo, Faisal Zafar, Khaled O. Alahmadi, Marjon van Slegtenhorst, Walter G. de Valk, Mazhor Al-Dosary, Wafa Qubbaj, Alice S. Brooks, Mehrnaz Ghazvini, Paul van den Berg, Darija Putar, Clinical Genetics, Cell biology, Neurology, Pathology, ANS - Cellular & Molecular Mechanisms, APH - Aging & Later Life, and APH - Mental Health
Subjects: Gene isoform, Protein isoform, Male, Microcephaly, Recurrent mutation, UTP-Glucose-1-Phosphate Uridylyltransferase, UGP2, medicine.disease_cause, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, epileptic encephalopathy, ATG mutations, start-loss mutation, genetics, whole exome sequencing, microcephaly, recurrent mutation, founder mutation, essential gene, medicine, Genetics, Missense mutation, Animals, Humans, Allele, Founder mutation, Zebrafish, Exome sequencing, 030304 developmental biology, 0303 health sciences, Mutation, Original Paper, Brain Diseases, Genes, Essential, biology, Epileptic encephalopathy, Whole exome sequencing, Infant, biology.organism_classification, medicine.disease, 3. Good health, Pedigree, Start-loss mutation, Essential gene, Child, Preschool, Female, Neurology (clinical), Epileptic Syndromes, 030217 neurology & neurosurgery
Abstract: Developmental and/or epileptic encephalopathies (DEEs) are a group of devastating genetic disorders, resulting in early-onset, therapy-resistant seizures and developmental delay. Here we report on 22 individuals from 15 families presenting with a severe form of intractable epilepsy, severe developmental delay, progressive microcephaly, visual disturbance and similar minor dysmorphisms. Whole exome sequencing identified a recurrent, homozygous variant (chr2:64083454A > G) in the essential UDP-glucose pyrophosphorylase (UGP2) gene in all probands. This rare variant results in a tolerable Met12Val missense change of the longer UGP2 protein isoform but causes a disruption of the start codon of the shorter isoform, which is predominant in brain. We show that the absence of the shorter isoform leads to a reduction of functional UGP2 enzyme in neural stem cells, leading to altered glycogen metabolism, upregulated unfolded protein response and premature neuronal differentiation, as modeled during pluripotent stem cell differentiation in vitro. In contrast, the complete lack of all UGP2 isoforms leads to differentiation defects in multiple lineages in human cells. Reduced expression of Ugp2a/Ugp2b in vivo in zebrafish mimics visual disturbance and mutant animals show a behavioral phenotype. Our study identifies a recurrent start codon mutation in UGP2 as a cause of a novel autosomal recessive DEE syndrome. Importantly, it also shows that isoform-specific start-loss mutations causing expression loss of a tissue-relevant isoform of an essential protein can cause a genetic disease, even when an organism-wide protein absence is incompatible with life. We provide additional examples where a similar disease mechanism applies. Electronic supplementary material The online version of this article (10.1007/s00401-019-02109-6) contains supplementary material, which is available to authorized users.
Published: 2020

21. Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients

Author: Thomas Besnard, Kristian Tveten, Hilary F Kitson, Jennifer A. Lee, Brieana Fregeau, Rachel Schot, Khadija Wilson, Katrin Õunap, Juliane Winkelmann, Anna Lehman, Nicola Longo, Servi J. C. Stevens, Megan T. Cho, Christina G.S. Palmer, Causes Study, Giovanni Battista Ferrero, Joy Dean, Lone W. Laulund, Grazia M.S. Mancini, Matias Wagner, Martin G. Martin, Sabine Lüttgen, Elizabeth J. Bhoj, Amanda J. Yoon, Thomas Klopstock, Janet S. Sinsheimer, Eric Vilain, Sébastien Küry, Francesca Clementina Radio, Jiddeke M. van de Kamp, Cameron Mrokse, Hakon Hakonarson, Samuel G. Cox, Jeanette C. Papp, Margot I. Van Allen, Raymond J. Louie, Constance T. R. M. Stumpel, Evan F. Joiner, Juanita Neira, Arve Vøllo, Amy Pizzino, Kelly Radtke, Celeste Simon, Michelle L. Thompson, Allison Zheng, Omar Sherbini, Marcia C. Willing, Tim M. Strom, Benjamin Garcia, Sara S. Cathey, Theresa A. Grebe, Dong Li, Marjan M. Weiss, Marco Tartaglia, Laura M Bryant, Sandra Mercier, Katherine L. Helbig, Martin Jakob Larsen, Ddd Study, Alexandrea Wadley, Alexander P.A. Stegmann, Sabina Barresi, A. Micheil Innes, Elaine H. Zackai, Gregory Costain, Davor Lessel, Molly Snyder, Heather P. Crawford, Richard Redon, Pearl Lee, Melissa Byler, Holly Dubbs, J. Gage Crump, K. E. Stuurman, Boris Keren, Stéphane Bézieau, Stan F. Nelson, Kristin G. Monaghan, Michael J. Lyons, Jeffrey W. Innis, Anna C.E. Hurst, Elizabeth A. Sellars, Samantha A. Schrier Vergano, Saadet Mercimek-Andrews, Monica H. Wojcik, Alison Ross, Heiko Reutter, Zuo-Fei Yuan, Dylan M. Marchione, Renee Bend, Diana Carli, Zöe Powis, Neil H. Parker, Jennifer Muncy Thomas, Luis A. Umaña, Adeline Vanderver, Julia Hoefele, Linda Manwaring, Christina Fagerberg, Elly Brokamp, M. Stephen Meyn, Pilvi Ilves, Xavier de la Cruz, Nina Powell-Hamilton, Caroline Nava, Garrett Gotway, Karit Reinson, Kristin D. Kernohan, Jennifer Norman, Alexandra Afenjar, Benjamin Cogné, Delphine Héron, Roman Günthner, Alfredo Brusco, John Dean, Kevin A. Janssen, Robert Roger Lebel, Divya Nair, Jijun Wan, Julian A. Martinez-Agosto, Elliott H. Sherr, Kyle Retterer, Claudia B. Catarino, Michael E. March, Natalia Padilla, Elise Brimble, Sylvie Odent, Jane L. Schuette, David Chitayat, Klaas J. Wierenga, Kirsty McWalter, Trine Prescott, Jonas Denecke, Wendy K. Chung, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Gastroenterology Endocrinology Metabolism, Klinische Genetica, MUMC+: DA KG Polikliniek (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Lab Centraal Lab (9), and Clinical Genetics
Subjects: metabolism [Zebrafish Proteins], RESIDUE, metabolism [Histones], GENES, Somatic cell, CODE, cancer mutation, histone, Biology, VARIANTS, medicine.disease_cause, progressive neurologic dysfunction, Histones, 03 medical and health sciences, Histone H3, 0302 clinical medicine, Germline mutation, SDG 3 - Good Health and Well-being, histone, neurodevelopmental disorder, progressive neurologic dysfunction, congenital anomalies, cancer mutation, medicine, Animals, Humans, H3-3A protein, human, metabolism [Zebrafish], TRANSCRIPTION, PHOSPHORYLATION, Gene, Zebrafish, Germ-Line Mutation, 030304 developmental biology, Genetics, genetics [Zebrafish], 0303 health sciences, Multidisciplinary, foxd3 protein, zebrafish, congenital anomalies, Forkhead Transcription Factors, Zebrafish Proteins, biology.organism_classification, genetics [Histones], neurodevelopmental disorder, H3F3B, Histone, genetics [Forkhead Transcription Factors], genetics [Neurodegenerative Diseases], biology.protein, ddc:500, Carcinogenesis, 030217 neurology & neurosurgery
Abstract: Germ line mutations in H3F3A and H3F3B cause a previously unidentified neurodevelopmental syndrome. Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation
Published: 2020

22. De novo missense variants in MEIS2 recapitulate the microdeletion phenotype of cardiac and palate abnormalities, developmental delay, intellectual disability and dysmorphic features

Author: Susan Winter, Linford Williams, Ganka Douglas, Theresa A. Grebe, Apostolos Psychogios, Matthew A. Deardorff, Angelika Erwin, Megan T. Cho, Jason Carmichael, Elaine H. Zackai, Margaret Harr, Jane Juusola, Aida Telegrafi, and Kyle Retterer
Subjects: Heart Defects, Congenital, Male, 0301 basic medicine, Hearing loss, Developmental Disabilities, Mutation, Missense, Short stature, 03 medical and health sciences, Gene Frequency, Intellectual Disability, Exome Sequencing, Intellectual disability, Genetics, medicine, Humans, Missense mutation, Abnormalities, Multiple, Child, Alleles, Genetic Association Studies, Genetics (clinical), Exome sequencing, Homeodomain Proteins, Palate, business.industry, Facies, Infant, Syndrome, medicine.disease, Hypotonia, Phenotype, 030104 developmental biology, Autism spectrum disorder, Child, Preschool, Failure to thrive, Female, Chromosome Deletion, medicine.symptom, business, Transcription Factors
Abstract: Gross deletions involving the MEIS2 gene have been described in a small number of patients with overlapping phenotypes of atrial or ventricular septal defects, cleft palate, and variable developmental delays and intellectual disability. Non-specific dysmorphic features were noted in some patients, including broad forehead with high anterior hairline, arched eyebrows, thin or tented upper lip, and short philtrum. Recently, a patient with a de novo single amino acid deletion, c.998_1000delGAA (p.Arg333del), and a patient with a de novo nonsense variant, (c.611C>G, p.Ser204*), were reported with a similar, but apparently more severe phenotypes. Clinical whole exome sequencing (WES) performed at our clinical molecular diagnostic laboratory identified four additional patients with predicted damaging de novo MEIS2 missense variants. Our patients' features closely resembled those previously reported in patients with gross deletions, but also included some less commonly reported features, such as autism spectrum disorder, hearing loss, and short stature, as well as features that may be unique to nucleotide-level variants, such as hypotonia, failure to thrive, gastrointestinal, skeletal, limb, and skin abnormalities. All of the observed missense variants, Pro302Leu, Gln322Leu, Arg331Lys, and Val335Ala, are located in the functionally important MEIS2 homeodomain. Pro302Leu is found in the region between helix 1 and helix 2, while the other three are located in the DNA-binding helix 3. To our knowledge, these are the first described de novo missense variants in MEIS2, expanding the known mutation spectrum of the newly recognized human disorder caused by aberrations in this gene.
Published: 2018

23. Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia

Author: Benjamin Cogné, Stephen Sanders, François Rivier, Tahir N. Khan, Mireille Claustres, Gaetan Lesca, Lihadh Al-Gazali, Annick Vogels, Sarah Weckhuysen, Nicholas Katsanis, Stéphane Bézieau, Thomas Besnard, Maxime Cadieux-Dion, Julitta de Bellescize, Katrin Õunap, Anne Boland, Aurora Pujol, Monica H. Wojcik, Maria J. Guillen Sacoto, Paul Rollier, Laurent Pasquier, Bertrand Isidor, Sébastien Küry, Hilde Van Esch, Aisha Al Shamsi, Megan T. Cho, Kyle Retterer, Michel Koenig, Christèle Dubourg, Andreas G. Chiocchetti, Damien Sanlaville, Erica E. Davis, Claire Guissart, Sander Pajusalu, Hannah Stamberger, Xenia Latypova, Shannon Sattler, Souphatta Sasorith, Isabelle Thiffault, Marie Vincent, Nicolas Leboucq, Irman Forghani, Lynn Schema, Sylvie Odent, Marie T. McDonald, Lauren E. Grote, Susanne Kjaergaard, Wilfrid Carré, Rena Pressman, Emily G. Farrow, Jean-François Deleuze, Carol J Saunders, Deborah Barbouth, Danielle Karlowicz, Nicole P. Safina, Kirsty McWalter, Christine M. Freitag, Wim Van Paesschen, Rebecca Willaert, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Clinical Genetics, Leicester Royal Infirmary, University Hospitals Leicester-University Hospitals Leicester, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Universitätsklinikum Leipzig, Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe-Universität Frankfurt am Main, Human Molecular Genetics, Institut de Génétique et Développement de Rennes (IGDR), Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Service de biologie moléculaire, Hôpital Pontchaillou, Centre National de Genotypage, Service de Génétique Médicale, Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Pediatrics, Faculty of Medicine and Health Sciences, UAE University, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Département de Neuroradiologie[Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Service de Génétique, Service de cytogénétique constitutionnelle, Hospices Civils de Lyon (HCL)-CHU de Lyon-Centre Neuroscience et Recherche, Service de génétique clinique [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Center for Human Disease Modeling, Duke University [Durham], Laboratoire de Diagnostic Génétique, CHU Strasbourg-Hopital Civil, Service de génétique clinique, hôpital Sud, National Human Genome Research Institute, UM1 HG008900, National Eye Institute, PUT355, Eesti Teadusagentuur, 2011-RARE-004-01, Agence Nationale pour la Recherche/E-rare Joint-Transnational-Call 2011, National Heart, Lung, and Blood Institute under the Trans-Omics for Precision Medicine (TOPMed) program, R01 MH106826, NIH, Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Unité de recherche de l'institut du thorax (ITX-lab), 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), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), and Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud
Subjects: Male, 0301 basic medicine, Autism, [SDV]Life Sciences [q-bio], Neurodegenerative, Medical and Health Sciences, RORA, Purkinje Cells, 0302 clinical medicine, Neurodevelopmental disorder, Group F, 80 and over, 2.1 Biological and endogenous factors, Missense mutation, Aetiology, Child, Zebrafish, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), Genes, Dominant, Pediatric, Genetics & Heredity, Aged, 80 and over, Genetics, Malalties neurodegeneratives, Brain, Nuclear Receptor Subfamily 1, Group F, Member 1, Neurodegenerative Diseases, Syndrome, Biological Sciences, Middle Aged, Magnetic Resonance Imaging, 3. Good health, Mental Health, intellectual disability, Child, Preschool, Larva, Neurological, Female, Cerebellar atrophy, medicine.symptom, Haploinsufficiency, Adult, Member 1, Ataxia, Cerebellar Ataxia, Nuclear Receptor Subfamily 1, Adolescent, DNA Copy Number Variations, Intellectual and Developmental Disabilities (IDD), Mutation, Missense, Biology, Article, 03 medical and health sciences, Rare Diseases, medicine, Animals, Humans, Dominant, Autistic Disorder, Allele, Preschool, Alleles, Aged, [SDV.GEN]Life Sciences [q-bio]/Genetics, Cerebellar ataxia, Animal, Point mutation, Genetic Complementation Test, Neurosciences, medicine.disease, neurodevelopmental disorder, Brain Disorders, Disease Models, Animal, 030104 developmental biology, Genes, autistic features, Disease Models, Mutation, epilepsy, Human medicine, cerebellar ataxia, Missense, Autisme, dual molecular effects, 030217 neurology & neurosurgery
Abstract: RORα, the RAR-related orphan nuclear receptor alpha, is essential for cerebellar development. The spontaneous mutant mouse staggerer, with an ataxic gait caused by neurodegeneration of cerebellar Purkinje cells, was discovered two decades ago to result from homozygous intragenic Rora deletions. However, RORA mutations were hitherto undocumented in humans. Through a multi-centric collaboration, we identified three copy-number variant deletions (two de novo and one dominantly inherited in three generations), one de novo disrupting duplication, and nine de novo point mutations (three truncating, one canonical splice site, and five missense mutations) involving RORA in 16 individuals from 13 families with variable neurodevelopmental delay and intellectual disability (ID)-associated autistic features, cerebellar ataxia, and epilepsy. Consistent with the human and mouse data, disruption of the D. rerio ortholog, roraa, causes significant reduction in the size of the developing cerebellum. Systematic in vivo complementation studies showed that, whereas wild-type human RORA mRNA could complement the cerebellar pathology, missense variants had two distinct pathogenic mechanisms of either haploinsufficiency or a dominant toxic effect according to their localization in the ligand-binding or DNA-binding domains, respectively. This dichotomous direction of effect is likely relevant to the phenotype in humans: individuals with loss-of-function variants leading to haploinsufficiency show ID with autistic features, while individuals with de novo dominant toxic variants present with ID, ataxia, and cerebellar atrophy. Our combined genetic and functional data highlight the complex mutational landscape at the human RORA locus and suggest that dual mutational effects likely determine phenotypic outcome. ispartof: American Journal of Human Genetics vol:102 issue:5 pages:744-759 ispartof: location:United States status: published
Published: 2018

24. Diagnostic outcomes for genetic testing of 70 genes in 8565 patients with epilepsy and neurodevelopmental disorders

Author: Anita Shanmugham, Courtney Downtain‐Pickersgill, Tracy Brandt, Dianalee McKnight, Elizabeth Butler, Gabriele Richard, Mary Beth Stosser, Kyle Retterer, and Amanda Lindy
Subjects: Adult, Male, 0301 basic medicine, Oncology, medicine.medical_specialty, Adolescent, CDKL5, MECP2, Young Adult, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Internal medicine, medicine, Humans, Genetic Testing, Child, Gene, Genetic testing, Comparative Genomic Hybridization, medicine.diagnostic_test, business.industry, Infant, Newborn, High-Throughput Nucleotide Sequencing, Infant, Middle Aged, medicine.disease, 030104 developmental biology, Molecular Diagnostic Techniques, Neurology, Neurodevelopmental Disorders, Child, Preschool, Cohort, Female, Neurology (clinical), business, 030217 neurology & neurosurgery, PRRT2, Comparative genomic hybridization
Abstract: Objective We evaluated >8500 consecutive, unselected patients with epilepsy and neurodevelopmental disorders who underwent multigene panel testing to determine the average age at molecular diagnosis and diagnostic yield of 70 genes. Methods We reviewed molecular test results for 70 genes known to cause epilepsy and neurodevelopmental disorders using next generation sequencing (NGS) and exon-level array comparative genomic hybridization (aCGH). A positive result was defined as the presence of 1 or 2 pathogenic or likely pathogenic (P/LP) variants in a single gene, depending on the mode of inheritance of the associated disorder. Results Overall, 22 genes were found to have a high yield of positive findings by genetic testing, with SCN1A and KCNQ2 accounting for the greatest number of positive findings. In contrast, there were no positive findings in 16 genes. Most of the P/LP variants were sequence changes identified by NGS (90.9%), whereas ~9% were gross deletions or duplications detected by exon-level aCGH. The mean age of molecular diagnosis for the cohort was 5 years, 8 months (ranging from 1 week to 47 years). Recurrent P/LP variants were observed in 14 distinct genes, most commonly in MECP2, KCNQ2, SCN1A, SCN2A, STXBP1, and PRRT2. Parental testing was performed in >30% of positive cases. All variants identified in CDKL5, STXBP1, SCN8A, GABRA1, and FOXG1 were de novo, whereas 85.7% of variants in PRRT2 were inherited. Significance Using a combined approach of NGS and exon-level aCGH, testing identified a genetic etiology in 15.4% of patients in this cohort and revealed the age at molecular diagnosis for patients. Our study highlights both high- and low-yield genes associated with epilepsy and neurodevelopmental disorders, indicating which genes may be considered for molecular diagnostic testing.
Published: 2018

25. Whole-exome sequencing on deceased fetuses with ultrasound anomalies: expanding our knowledge of genetic disease during fetal development

Author: Gabriele Richard, Bethany Friedman, Carin Yates, Julie Scuffins, Cathlin R Kucera, Kristin G. Monaghan, Kyle Retterer, Deborah Copenheaver, and Jane Juusola
Subjects: Male, 0301 basic medicine, medicine.medical_specialty, Candidate gene, Pathology, Prenatal diagnosis, Disease, 030105 genetics & heredity, Ultrasonography, Prenatal, Fetal Development, 03 medical and health sciences, Fetus, Pregnancy, Prenatal Diagnosis, Exome Sequencing, medicine, Humans, Exome, Fetal Death, Genetics (clinical), Exome sequencing, Ultrasonography, Obstetrics, business.industry, Abortion, Induced, Sequence Analysis, DNA, medicine.disease, Phenotype, Mutation, Etiology, Female, business
Abstract: PurposeThe aim of this study was to determine the diagnostic yield of whole-exome sequencing (WES) in fetuses with ultrasound anomalies that resulted in fetal demise or pregnancy termination. The results were also utilized to aid in the identification of candidate genes for fetal development and to expand the clinical phenotype of known genetic conditions.MethodsWES was performed on specimens from 84 deceased fetuses. Data were analyzed and final results were classified into one of four categories: positive, possible, negative, and candidate gene only. WES analysis was predominantly performed in fetus-parent trios or quads (61%, n=52).ResultsOverall, 20% (n = 17) of cases were positive, 45% (n=38) were possible, 9% (n=7) had only candidate gene variants and 26% (n = 22) tested negative. The diagnostic yield for definitive findings for trio analysis was 24% (n = 11) compared to 14% (n = 4) for singletons. The most frequently reported ultrasound anomalies were central nervous system (37%, n = 31), hydrops/edema (36%, n = 30), and cardiovascular anomalies (31%, n = 26).ConclusionOur experience supports the use of WES to identify the molecular etiology of fetal ultrasound anomalies, to identify candidate genes involved in fetal development, and to expand our knowledge of the clinical phenotype of known genetic conditions.
Published: 2017

26. Biallelic Mutations in MRPS34 Lead to Instability of the Small Mitoribosomal Subunit and Leigh Syndrome

Author: Agnès Rötig, Marlène Rio, Vamsi K. Mootha, Zhancheng Zhang, Nicole J. Lake, Benedetta Ruzzenente, David A. Stroud, Nathalie Bodaert, Elizabeth M. McCormick, Tara R. Richman, Zarazuela Zolkipli-Cunningham, Sander M. Houten, Marni J. Falk, Kyle Retterer, Alison G. Compton, Mingma D. Sherpa, Metodi D. Metodiev, James Byrnes, Katrina Haude, Zahra Assouline, Hayley S. Mountford, Juliette Pulman, Aleksandra Filipovska, John Christodoulou, Ingrid Cristian, Eric E. Schadt, Renkui Bai, Bryn D. Webb, Sarah E. Calvo, David R. Thorburn, Coralie Zangarelli, and Laboratory Genetic Metabolic Diseases
Subjects: Male, Proteomics, Ribosomal Proteins, 0301 basic medicine, Mitochondrial DNA, Mitochondrial Diseases, Adolescent, Mitochondrial translation, Protein subunit, RNA Splicing, Respiratory chain, Biology, Mitochondrion, Compound heterozygosity, DNA, Mitochondrial, Article, Oxidative Phosphorylation, Mitochondrial Proteins, 03 medical and health sciences, 0302 clinical medicine, Ribosomal protein, Genetics, Mitochondrial ribosome, medicine, Humans, Exome, Leigh disease, Child, Genetics (clinical), Ribosome Subunits, Small, Eukaryotic, Base Sequence, Correction, Infant, Sequence Analysis, DNA, medicine.disease, Molecular biology, Human genetics, Mitochondria, 3. Good health, 030104 developmental biology, Child, Preschool, Female, Leigh Disease, 030217 neurology & neurosurgery
Abstract: The synthesis of all 13 mitochondrial DNA (mtDNA)-encoded protein subunits of the human oxidative phosphorylation (OXPHOS) system is carried out by mitochondrial ribosomes (mitoribosomes). Defects in the stability of mitoribosomal proteins or mitoribosome assembly impair mitochondrial protein translation, causing combined OXPHOS enzyme deficiency and clinical disease. Here we report four autosomal-recessive pathogenic mutations in the gene encoding the small mitoribosomal subunit protein, MRPS34, in six subjects from four unrelated families with Leigh syndrome and combined OXPHOS defects. Whole-exome sequencing was used to independently identify all variants. Two splice-site mutations were identified, including homozygous c.321+1G>T in a subject of Italian ancestry and homozygous c.322−10G>A in affected sibling pairs from two unrelated families of Puerto Rican descent. In addition, compound heterozygous MRPS34 mutations were identified in a proband of French ancestry; a missense (c.37G>A [p.Glu13Lys]) and a nonsense (c.94C>T [p.Gln32∗]) variant. We demonstrated that these mutations reduce MRPS34 protein levels and the synthesis of OXPHOS subunits encoded by mtDNA. Examination of the mitoribosome profile and quantitative proteomics showed that the mitochondrial translation defect was caused by destabilization of the small mitoribosomal subunit and impaired monosome assembly. Lentiviral-mediated expression of wild-type MRPS34 rescued the defect in mitochondrial translation observed in skin fibroblasts from affected subjects, confirming the pathogenicity of MRPS34 mutations. Our data establish that MRPS34 is required for normal function of the mitoribosome in humans and furthermore demonstrate the power of quantitative proteomic analysis to identify signatures of defects in specific cellular pathways in fibroblasts from subjects with inherited disease.
Published: 2017

27. Integrating healthcare and research genetic data empowers the discovery of 28 novel developmental disorders

Author: Matthew E. Hurles, Deciphering Developmental Disorders Study, de Boer E, Jeffrey C. Barrett, Kevin J. Arvai, Stefan H. Lelieveld, Giuseppe Gallone, Patrick J. Short, Helen V. Firth, Hilary C. Martin, Christian Gilissen, Alison Yeung, Joanna Kaplanis, Petr Danecek, Ni Huang, Rebecca I. Torene, Kaitlin E. Samocha, R. Pfundt, Helger G. Yntema, Han G. Brunner, Caroline F. Wright, Ruth Y. Eberhardt, Jane Juusola, Reijnders Mrf., Inigo Martincorena, David R. FitzPatrick, Jeremy F. McRae, Eugene J. Gardner, Vissers Lelm, Zhancheng Zhang, Kyle Retterer, Jenny Lord, and Laurens Wiel
Subjects: 0303 health sciences, Genetic data, Computational biology, Biology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, chemistry, Penetrant (biochemical), Exome, Gene, 030217 neurology & neurosurgery, De novo mutations, 030304 developmental biology
Abstract: SummaryDe novo mutations (DNMs) in protein-coding genes are a well-established cause of developmental disorders (DD). However, known DD-associated genes only account for a minority of the observed excess of such DNMs. To identify novel DD-associated genes, we integrated healthcare and research exome sequences on 31,058 DD parent-offspring trios, and developed a simulation-based statistical test to identify gene-specific enrichments of DNMs. We identified 285 significantly DD-associated genes, including 28 not previously robustly associated with DDs. Despite detecting more DD-associated genes than in any previous study, much of the excess of DNMs of protein-coding genes remains unaccounted for. Modelling suggests that over 1,000 novel DD-associated genes await discovery, many of which are likely to be less penetrant than the currently known genes. Research access to clinical diagnostic datasets will be critical for completing the map of dominant DDs.
Published: 2019

28. Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform specific start-loss mutations of essential genes can cause genetic diseases

Author: Henry Houlden, Aida M. Bertoli-Avella, Marjon van Slegtenhorst, Edwin H. Jacobs, Ehsan Ghayoor Karimiani, Eleonora Aronica, Peter Bauer, Atieh Eslahi, Amna Al Futaisi, Tjakko J. van Ham, Jennefer N. Kohler, Stephanie Efthymiou, Reza Maroofian, Darija Putar, Mariya Kozenko, Jana Vandrovcova, Walter G. de Valk, Jonathan A. Bernstein, Amber Begtrup, Kyle Retterer, Renjith Mani, Jozef Hertecant, Evita Medici-van den Herik, Alice S. Brooks, Elena Perenthaler, Rebecca I. Torene, Woutje M. Berdowski, Wilfred F. J. van IJcken, Kristin G. Monaghan, Majid Mojarrad, Nuzhat Rana, Anita Nikoncuk, Faisal Zafar, Tahsin Stefan Barakat, Paul van den Berg, Soheil Yousefi, Krishna Kumar Kandaswamy, Ivan Čapo, Fathiya Al Murshedi, Fateme Massinaei Darmiyan, Faisal Al Azri, Lauren Brick, Erik-Jan Kamsteeg, Mehrnaz Ghazvini, Herma C. van der Linde, Mohammad Doosti, and Zaynab Khazaei
Subjects: Gene isoform, Protein isoform, Genetics, 0303 health sciences, Mutation, Biology, medicine.disease_cause, biology.organism_classification, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, medicine, Missense mutation, Allele, Gene, Zebrafish, 030217 neurology & neurosurgery, Exome sequencing, 030304 developmental biology
Abstract: Developmental and/or epileptic encephalopathies (DEEs) are a group of devastating genetic disorders, resulting in early onset, therapy resistant seizures and developmental delay. Here we report on 12 individuals from 10 families presenting with a severe form of intractable epilepsy, severe developmental delay, progressive microcephaly and visual disturbance. Whole exome sequencing identified a recurrent, homozygous variant (chr2:64083454A>G) in the essentialUDP-glucose pyrophosphorylase(UGP2) gene in all probands. This rare variant results in a tolerable Met12Val missense change of the longer UGP2 protein isoform but causes a disruption of the start codon of the shorter isoform. We show that the absence of the shorter isoform leads to a reduction of functional UGP2 enzyme in brain cell types, leading to altered glycogen metabolism, upregulated unfolded protein response and premature neuronal differentiation, as modelled during pluripotent stem cell differentiationin vitro. In contrast, the complete lack of all UGP2 isoforms leads to differentiation defects in multiple lineages in human cells. Reduced expression of Ugp2a/Ugp2bin vivoin zebrafish mimics visual disturbance and mutant animals show a behavioral phenotype. Our study identifies a recurrent start codon mutation inUGP2as a cause of a novel autosomal recessive DEE. Importantly, it also shows that isoform specific start-loss mutations causing expression loss of a tissue relevant isoform of an essential protein can cause a genetic disease, even when an organism-wide protein absence is incompatible with life. We provide additional examples where a similar disease mechanism applies.
Published: 2019

29. Sex-Based Analysis of De Novo Variants in Neurodevelopmental Disorders

Author: Trygve E. Bakken, Amy B. Wilfert, Evan E. Eichler, Micah R. Pepper, Rebecca I. Torene, Zhancheng Zhang, Kyle Retterer, Raphael Bernier, and Tychele N. Turner
Subjects: Genetic Markers, Male, SYNGAP1, Biology, Article, Cohort Studies, Neurodevelopmental disorder, Sex Factors, Genetics, medicine, Humans, Exome, Gene Regulatory Networks, Allele, Child, Gene, Genetics (clinical), X chromosome, Chromatin binding, medicine.disease, Phenotype, Neurodevelopmental Disorders, Mutation, Autism, Female, DDX3X, Genome-Wide Association Study
Abstract: While genes with an excess of de novo mutations (DNMs) have been identified in children with neurodevelopmental disorders (NDDs), few studies focus on DNM patterns where the sex of affected children is examined separately. We considered ∼8,825 sequenced parent-child trios (n ∼26,475 individuals) and identify 54 genes with a DNM enrichment in males (n = 18), females (n = 17), or overlapping in both the male and female subsets (n = 19). A replication cohort of 18,778 sequenced parent-child trios (n = 56,334 individuals) confirms 25 genes (n = 3 in males, n = 7 in females, n = 15 in both male and female subsets). As expected, we observe significant enrichment on the X chromosome for females but also find autosomal genes with potential sex bias (females, CDK13, ITPR1; males, CHD8, MBD5, SYNGAP1); 6.5% of females harbor a DNM in a female-enriched gene, whereas 2.7% of males have a DNM in a male-enriched gene. Sex-biased genes are enriched in transcriptional processes and chromatin binding, primarily reside in the nucleus of cells, and have brain expression. By downsampling, we find that DNM gene discovery is greatest when studying affected females. Finally, directly comparing de novo allele counts in NDD-affected males and females identifies one replicated genome-wide significant gene (DDX3X) with locus-specific enrichment in females. Our sex-based DNM enrichment analysis identifies candidate NDD genes differentially affecting males and females and indicates that the study of females with NDDs leads to greater gene discovery consistent with the female-protective effect.
Published: 2019

30. Age-adjusted association of homologous recombination genes with ovarian cancer using clinical exomes as controls

Author: Erica S. Rinella, Lisa R. Susswein, Megan L. Marshall, Lauren Yackowski, Zhancheng Zhang, Maegan E. Roberts, Kyle Retterer, Rebecca I. Torene, Kevin J. Arvai, Kathleen S. Hruska, Natalie J. Carter, and Rachel T. Klein
Subjects: 0301 basic medicine, Oncology, Exome sequencing, medicine.medical_specialty, lcsh:QH426-470, PALB2, Age adjustment, BRIP1, 030105 genetics & heredity, lcsh:RC254-282, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Allele, CHEK2, Genetics (clinical), business.industry, Research, Cancer, Odds ratio, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Confidence interval, Ovarian Cancer, lcsh:Genetics, 030220 oncology & carcinogenesis, RAD51C, business
Abstract: Background Genes in the homologous recombination pathway have shown varying results in the literature regarding ovarian cancer (OC) association. Recent case-control studies have used allele counts alone to quantify genetic associations with cancer. Methods A retrospective case-control study was performed on 6,182 women with OC referred for hereditary cancer multi-gene panel testing (cases) and 4,690 mothers from trios who were referred for whole-exome sequencing (controls). We present age-adjusted odds ratios (ORAdj) to determine association of OC with pathogenic variants (PVs) in homologous recombination genes. Results Significant associations with OC were observed in BRCA1, BRCA2, RAD51C and RAD51D. Other homologous recombination genes, BARD1, NBN, and PALB2, were not significantly associated with OC. ATM and CHEK2 were only significantly associated with OC by crude odds ratio (ORCrude) or by ORAdj, respectively. However, there was no significant difference between ORCrude and ORAdj for these two genes. The significant association of PVs in BRIP1 by ORCrude (2.05, CI = 1.11 to 3.94, P = 0.03) was not observed by ORAdj (0.87, CI = 0.41 to 1.93, P = 0.73). Interestingly, the confidence intervals of the two effect sizes were significantly different (P = 0.04). Conclusion The lack of association of PVs in BRIP1 with OC by ORAdj is inconsistent with some previous literature and current management recommendations, highlighted by the significantly older age of OC onset for BRIP1 PV carriers compared to non-carriers. By reporting ORAdj, this study presents associations that reflect more informed genetic contributions to OC when compared to traditional count-based methods. Electronic supplementary material The online version of this article (10.1186/s13053-019-0119-3) contains supplementary material, which is available to authorized users.
Published: 2019

31. Author Correction: Mutations disrupting neuritogenesis genes confer risk for cerebral palsy

Author: Mahalia S.B. Frank, Chao Gao, Brandon S. Guida, Dani L. Webber, Aureliane Elie, Bohao Zhang, Kelly Harper, Richard P. Lifton, Dengna Zhu, Jesia G. Berry, Iona Novak, Xiaoyang Wang, Antigone Papavasileiou, Yana A. Wilson, Francesc López-Giráldez, Michael C Fahey, Sergio Padilla-Lopez, Boris Keren, Jozef Gecz, Jeff L. Waugh, Shozeb Haider, Michael C. Sierant, Kyle Retterer, Sandra Whalen, Yangong Wang, Lance H. Rodan, Clare L. van Eyk, Megan Cho, Qiongshi Lu, Sheetal Shetty, John P. Phillips, Stephen Pastore, John B. Vincent, Chongchen Zhou, Sara A. Lewis, Bethany Y. Norton, Xue Zeng, Timothy Feyma, Qing Shang, Mark A. Corbett, Janice E. Brunstrom-Hernandez, Susan M Reid, Julie S. Cohen, Michael C. Kruer, Christopher Castaldi, Nadia Badawi, Spencer Vaughan, Qinghe Xing, Sandra M. Nordlie, Daniela C. Zarnescu, Angela E. Lin, David J. Amor, Sarah McIntyre, Julien Buratti, Jennifer Heim, Shrikant Mane, Yiran Xu, Suzanna C. MacLennan, Helen Magee, Somayeh Bakhtiari, Amar H. Sheth, Changlian Zhu, Alastair H. MacLennan, Kylie E. Crompton, Kaya Bilguvar, Sheng Chih Jin, Junhui Zhang, Diane Doummar, Francisca Millan, Irina Tikhonova, Ali Fatemi, Dinah Reddihough, Lei Xia, Hongyu Zhao, James Liu, James R. Knight, and Boyang Li
Subjects: Genetics, MEDLINE, medicine, Biology, Bioinformatics, medicine.disease, Gene, Cerebral palsy
Published: 2021

32. De novoloss of function mutations inKIAA2022are associated with epilepsy and neurodevelopmental delay in females

Author: Catherine Nowak, Megan T. Cho, Francisca Millan, Gerald V. Raymond, Aurora Pujol, Kyle Retterer, Amber Begtrup, Rachel Webster, Jessica Douglas, Orrin Devinsky, Wendy K. Chung, Dianalee McKnight, Ayesha Ahmad, and Maria R. Johnson
Subjects: 0301 basic medicine, Genetics, education.field_of_study, Population, Biology, medicine.disease, Phenotype, 03 medical and health sciences, Epilepsy, 030104 developmental biology, 0302 clinical medicine, Intellectual disability, medicine, Autism, education, 030217 neurology & neurosurgery, Genetics (clinical), Exome sequencing, Loss function, X chromosome
Abstract: Intellectual disability (ID) affects about 3% of the population and has a male gender bias. Of at least 700 genes currently linked to ID, more than 100 have been identified on the X chromosome, including KIAA2022. KIAA2022 is located on Xq13.3 and is expressed in the developing brain. The protein product of KIAA2022, X‐linked Intellectual Disability Protein Related to Neurite Extension (XPN), is developmentally regulated and is involved in neuronal migration and cell adhesion. The clinical manifestations of loss‐of‐function KIAA2022 mutations have been described previously in 15 males, born from unaffected carrier mothers, but few females. Using whole‐exome sequencing, we identified a cohort of five unrelated female patients with de novo probably gene damaging variants in KIAA2022 and core phenotypic features of ID, developmental delay, epilepsy refractory to treatment, and impaired language, of similar severity as reported for male counterparts. This study supports KIAA2022 as a novel cause of X‐linked dominant ID, and broadens the phenotype for KIAA2022 mutations.
Published: 2016

33. Variants in HNRNPH2 on the X Chromosome Are Associated with a Neurodevelopmental Disorder in Females

Author: Vidya Krishnamurthy, Orly Elpeleg, Kristin G. Monaghan, Aida Telegrafi, Marcia C. Willing, Yufeng Shen, Tomi L. Toler, Kyle Retterer, Wendy K. Chung, Jennifer M. Bain, Susan Sklower Brooks, Ashley Wilson, Gordon C. Gowans, Bruria Ben-Zev, Leigh Anne Autullo, Christina Botti, and Megan T. Cho
Subjects: Adult, Male, 0301 basic medicine, Microcephaly, Developmental Disabilities, Nuclear Localization Signals, Biology, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, Gene Frequency, Seizures, Intellectual Disability, Report, Genetics, medicine, Animals, Humans, Genetics(clinical), Exome, Amino Acid Sequence, Autistic Disorder, Child, Gene, Genetics (clinical), X chromosome, Chromosomes, Human, X, Sex Characteristics, Heterogeneous-Nuclear Ribonucleoprotein Group F-H, medicine.disease, Phenotype, Hypotonia, Alternative Splicing, 030104 developmental biology, Neurodevelopmental Disorders, Child, Preschool, Face, Mutation, Embryo Loss, Muscle Hypotonia, Autism, Female, medicine.symptom, Heterogeneous nuclear ribonucleoprotein H2, 030217 neurology & neurosurgery
Abstract: Via whole-exome sequencing, we identified six females from independent families with a common neurodevelopmental phenotype including developmental delay, intellectual disability, autism, hypotonia, and seizures, all with de novo predicted deleterious variants in the nuclear localization signal of Heterogeneous Nuclear Ribonucleoprotein H2, encoded by HNRNPH2, a gene located on the X chromosome. Many of the females also have seizures, psychiatric co-morbidities, and orthopedic, gastrointestinal, and growth problems as well as common dysmorphic facial features. HNRNPs are a large group of ubiquitous proteins that associate with pre-mRNAs in eukaryotic cells to produce a multitude of alternatively spliced mRNA products during development and play an important role in controlling gene expression. The failure to identify affected males, the severity of the neurodevelopmental phenotype in females, and the essential role of this gene suggests that male conceptuses with these variants may not be viable.
Published: 2016

34. Clinical application of whole-exome sequencing across clinical indications

Author: Francisca Millan, Megan T. Cho, Nizar Smaoui, Julie Neidich, Tracy Brandt, Gabriele Richard, Sherri J. Bale, Kyle Retterer, Wendy K. Chung, Kristin G. Monaghan, Renkui Bai, Eden Haverfield, Bethany Friedman, Sharon F. Suchy, Federica Gibellini, Annette Vertino-Bell, Patrik Vitazka, Dianalee McKnight, Jackie Tahiliani, Daniel E. Pineda-Alvarez, and Jane Juusola
Subjects: 0301 basic medicine, Proband, Candidate gene, medicine.medical_specialty, business.industry, Genetic heterogeneity, 03 medical and health sciences, 030104 developmental biology, Internal medicine, Medicine, Medical genetics, business, Exome, Genetics (clinical), Exome sequencing
Abstract: We report the diagnostic yield of whole-exome sequencing (WES) in 3,040 consecutive cases at a single clinical laboratory. WES was performed for many different clinical indications and included the proband plus two or more family members in 76% of cases. The overall diagnostic yield of WES was 28.8%. The diagnostic yield was 23.6% in proband-only cases and 31.0% when three family members were analyzed. The highest yield was for patients who had disorders involving hearing (55%, N = 11), vision (47%, N = 60), the skeletal muscle system (40%, N = 43), the skeletal system (39%, N = 54), multiple congenital anomalies (36%, N = 729), skin (32%, N = 31), the central nervous system (31%, N = 1,082), and the cardiovascular system (28%, N = 54). Of 2,091 cases in which secondary findings were analyzed for 56 American College of Medical Genetics and Genomics–recommended genes, 6.2% (N = 129) had reportable pathogenic variants. In addition to cases with a definitive diagnosis, in 24.2% of cases a candidate gene was reported that may later be reclassified as being associated with a definitive diagnosis. Our experience with our first 3,040 WES cases suggests that analysis of trios significantly improves the diagnostic yield compared with proband-only testing for genetically heterogeneous disorders and facilitates identification of novel candidate genes. Genet Med 18 7, 696–704.
Published: 2016

35. Mutations in TKT Are the Cause of a Syndrome Including Short Stature, Developmental Delay, and Congenital Heart Defects

Author: Nancy Kramer, Melissa Andrew, Birthe Roos, Vivian Hwa, Mirjam M.C. Wamelink, Kristin G. Monaghan, Jessica Douglas, Lia Boyle, Sulagna C. Saitta, Amber Begtrup, Andrew Dauber, Wendy K. Chung, Julia Wynn, Gajja S. Salomons, Ana Pop, Megan T. Cho, Murray Feingold, Kyle Retterer, Laboratory Medicine, and Amsterdam Neuroscience - Cellular & Molecular Mechanisms
Subjects: 0301 basic medicine, Adult, Heart Defects, Congenital, Male, neurodevelopmental disability, Developmental Disabilities, pentose phosphate pathway, Dwarfism, 030204 cardiovascular system & hematology, Biology, Transketolase, Compound heterozygosity, medicine.disease_cause, Short stature, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Cataracts, Report, medicine, Genetics, Missense mutation, Humans, Genetics(clinical), Child, Genetics (clinical), Mutation, Syndrome, transketolase deficiency, medicine.disease, Glutathione, congenital heart disease, Pedigree, TKT, 030104 developmental biology, Child, Preschool, Transketolase activity, Female, medicine.symptom, NADP
Abstract: Whole-exome sequencing (WES) is increasingly being utilized to diagnose individuals with undiagnosed disorders. Developmental delay and short stature are common clinical indications for WES. We performed WES in three families, using proband-parent trios and two additional affected siblings. We identified a syndrome due to an autosomal-recessively inherited deficiency of transketolase, encoded by TKT, on chromosome 3p21. Our series includes three families with a total of five affected individuals, ranging in age from 4 to 25 years. Two families of Ashkenazi Jewish ancestry were homozygous for an 18 base pair in-frame insertion in TKT. The third family was compound heterozygous for nonsense and missense variants in TKT. All affected individuals had short stature and were developmentally delayed. Congenital heart defects were noted in four of the five affected individuals, and there was a history of chronic diarrhea and cataracts in the older individuals with the homozygous 18 base pair insertion. Enzymatic testing confirmed significantly reduced transketolase activity. Elevated urinary excretion of erythritol, arabitol, ribitol, and pent(ul)ose-5-phosphates was detected, as well as elevated amounts of erythritol, arabitol, and ribitol in the plasma of affected individuals. Transketolase deficiency reduces NADPH synthesis and nucleic acid synthesis and cell division and could explain the problems with growth. NADPH is also critical for maintaining cerebral glutathione, which might contribute to the neurodevelopmental delays. Transketolase deficiency is one of a growing list of inborn errors of metabolism in the non-oxidative part of the pentose phosphate pathway.
Published: 2016
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36. Whole exome sequencing reveals de novo pathogenic variants inKAT6Aas a cause of a neurodevelopmental disorder

Author: Honey Nagakura, Victoria Roberts, Kyle Retterer, Elliott H. Sherr, Patrik Vitazka, Aida Telegrafi, LaDonna Immken, Sherri J. Bale, Brooke T. Smith, Marc DiFazio, Wendy K. Chung, Francisca Millan, Bethany Friedman, Megan T. Cho, Kristin G. Monaghan, Renkui Bai, Eden Haverfield, David B. Everman, Brad Angle, and Jane Juusola
Subjects: Adult, Male, 0301 basic medicine, Heterozygote, Population, KAT6A Gene, Biology, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual Disability, Genetics, medicine, Humans, Exome, Child, education, Genetics (clinical), Exome sequencing, Histone Acetyltransferases, education.field_of_study, High-Throughput Nucleotide Sequencing, Sequence Analysis, DNA, medicine.disease, Phenotype, Hypotonia, 030104 developmental biology, Neurodevelopmental Disorders, Child, Preschool, Mutation, Female, medicine.symptom, 030217 neurology & neurosurgery, Congenital disorder
Abstract: Neurodevelopmental disorders (NDD) are common, with 1-3% of general population being affected, but the etiology is unknown in most individuals. Clinical whole-exome sequencing (WES) has proven to be a powerful tool for the identification of pathogenic variants leading to Mendelian disorders, among which NDD represent a significant percentage. Performing WES with a trio-approach has proven to be extremely effective in identifying de novo pathogenic variants as a common cause of NDD. Here we report six unrelated individuals with a common phenotype consisting of NDD with severe speech delay, hypotonia, and facial dysmorphism. These patients underwent WES with a trio approach and de novo heterozygous predicted pathogenic novel variants in the KAT6A gene were identified. The KAT6A gene encodes a histone acetyltransfrease protein and it has long been known for its structural involvement in acute myeloid leukemia; however, it has not previously been associated with any congenital disorder. In animal models the KAT6A ortholog is involved in transcriptional regulation during development. Given the similar findings in animal models and our patient's phenotypes, we hypothesize that KAT6A could play a role in development of the brain, face, and heart in humans. © 2016 Wiley Periodicals, Inc.
Published: 2016

37. A recurrent de novo CTBP1 mutation is associated with developmental delay, hypotonia, ataxia, and tooth enamel defects

Author: Sara Halbach, Mark C. Hannibal, David B. Beck, Amber Begtrup, Bridget C. O’Connor, Darrel Waggoner, Carin Yates, Yufeng Shen, Marwan Shinawi, Brad Angle, Kyle Retterer, Wendy K. Chung, Victoria R. Sanders, Renkui Bai, Anne M. Connolly, Megan T. Cho, and Francisca Millan
Subjects: Adult, Male, 0301 basic medicine, Ataxia, Developmental Disabilities, Mutation, Missense, Biology, medicine.disease_cause, Bioinformatics, Young Adult, 03 medical and health sciences, Cellular and Molecular Neuroscience, Intellectual Disability, Exome Sequencing, Intellectual disability, Genetics, medicine, Humans, Missense mutation, Child, Dental Enamel, Genetics (clinical), Exome sequencing, Mutation, medicine.disease, Human genetics, Hypotonia, DNA-Binding Proteins, Alcohol Oxidoreductases, 030104 developmental biology, Failure to thrive, Muscle Hypotonia, Female, medicine.symptom
Abstract: Exome sequencing is an effective way to identify genetic causes of etiologically heterogeneous conditions such as developmental delay and intellectual disabilities. Using exome sequencing, we have identified four patients with similar phenotypes of developmental delay, intellectual disability, failure to thrive, hypotonia, ataxia, and tooth enamel defects who all have the same de novo R331W missense variant in C-terminal binding protein 1 (CTBP1). CTBP1 is a transcriptional regulator critical for development by coordinating different regulatory pathways. The R331W variant found in these patients is within the C-terminal portion of the PLDLS (Pro-Leu-Asp-Leu-Ser) binding cleft, which is the domain through which CTBP1, interacts with chromatin-modifying enzymes and mediates chromatin-dependent gene repression pathways. This is the first report of mutations within CTBP1 in association with any human disease.
Published: 2016

38. Additional de novo missense genetic variants in NALCN associated with CLIFAHDD syndrome

Author: Katelyn Payne, K. Mason, S. Debrosse, Megan T. Cho, Wendy K. Chung, Ingrid M. Wentzensen, Jane Juusola, Amber Begtrup, M. Vivero, Yuri A. Zarate, G B Schaefer, Kyle Retterer, K. Bosanko, L. Pollack, S. Deward, and Larry Walsh
Subjects: 0301 basic medicine, Genetics, 03 medical and health sciences, 030104 developmental biology, Neurodevelopmental disorder, medicine, Genetic variants, Missense mutation, Biology, medicine.disease, Genetics (clinical), Exome sequencing
Published: 2017

39. Association of the missense variant p.Arg203Trp in PACS1 as a cause of intellectual disability and seizures

Author: M.J. Guillen Sacoto, Kyle Retterer, Rashmi Chikarmane, Berivan Baskin, Barbara K. Burton, Emma Bedoukian, S Hopkins, Brooke E. Spangler, Heather M. McLaughlin, Wendy K. Chung, Fran Kendall, Matthew A. Deardorff, David Kronn, M. T. Cho, Marie T. McDonald, Rebecca Willaert, N Oundjian, D Stern, Ingrid M. Wentzensen, Anne Slavotinek, Dianalee McKnight, Allyn McConkie-Rosell, S Schrier Vergano, Katherine H. Kim, and N Chandy
Subjects: 0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Electroencephalography, behavioral disciplines and activities, 03 medical and health sciences, Internal medicine, mental disorders, Intellectual disability, Genetics, medicine, Attention deficit hyperactivity disorder, Missense mutation, cardiovascular diseases, Association (psychology), Genetics (clinical), medicine.diagnostic_test, business.industry, Fontanelle, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, Cardiology, Patent foramen ovale, business, psychological phenomena and processes, Patent ductus arteriosis
Abstract: Graphical abstract key: ADHD, attention deficit hyperactivity disorder; ASD, atrial septal defect; DD, developmental delay; EEG, electroencephalogram; Ht, height; ID, intellectual disability; OCD, obsessive-compulsive disorder; OFC, open fontanelle; PDA, patent ductus arteriosis; PFO, patent foramen ovale; VSD, ventricular septal defect; Wt, weight.
Published: 2017

40. De novo variants in HK1 associated with neurodevelopmental abnormalities and visual impairment

Author: Aida Telegrafi, Kwame Anyane-Yeboa, Megan T. Cho, Ian D. Krantz, Wendy K. Chung, Kinga M. Bujakowska, Kyle Retterer, Ganka Douglas, Ashley Wilson, Dorothy K. Grange, Kristin G. Monaghan, Linda Manwaring, Amber Begtrup, Brigitte A. van Oirschot, Eric A. Pierce, Peter J. Hulick, Holley May, Volkan Okur, Colleen Clark Muraresku, Richard van Wijk, Stephanie A. Coury, Emily Place, and Jonathan Picker
Subjects: Hemolytic anemia, Adult, Male, medicine.medical_specialty, Erythrocytes, Adolescent, Mutation, Missense, medicine.disease_cause, Article, 03 medical and health sciences, chemistry.chemical_compound, Neurodevelopmental disorder, Internal medicine, Hexokinase, Intellectual disability, Genetics, Medicine, Missense mutation, Humans, Glycolysis, Child, Genetics (clinical), 0303 health sciences, Mutation, business.industry, 030305 genetics & heredity, Infant, medicine.disease, eye diseases, Pedigree, Endocrinology, chemistry, Female, business, Hereditary motor and sensory neuropathy, Hereditary Sensory and Motor Neuropathy, Retinitis Pigmentosa
Abstract: Hexokinase 1 (HK1) phosphorylates glucose to glucose-6-phosphate, the first rate-limiting step in glycolysis. Homozygous and heterozygous variants in HK1 have been shown to cause autosomal recessive non-spherocytic hemolytic anemia, autosomal recessive Russe type hereditary motor and sensory neuropathy, and autosomal dominant retinitis pigmentosa (adRP). We report seven patients from six unrelated families with a neurodevelopmental disorder associated with developmental delay, intellectual disability, structural brain abnormality, and visual impairments in whom we identified four novel, de novo missense variants in the N-terminal half of HK1. Hexokinase activity in red blood cells of two patients was normal, suggesting that the disease mechanism is not due to loss of hexokinase enzymatic activity.
Published: 2018

41. Holoprosencephaly: A clinical genomics perspective

Author: Kyle Retterer, Benjamin D. Solomon, and Jane Juusola
Subjects: musculoskeletal diseases, 0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Genetics, Medical, Nerve Tissue Proteins, Computational biology, 030105 genetics & heredity, 03 medical and health sciences, Holoprosencephaly, Genetics, medicine, Humans, Exome, Hedgehog Proteins, Eye Proteins, Genetics (clinical), Exome sequencing, Homeodomain Proteins, Clinical genomics, business.industry, Perspective (graphical), Nuclear Proteins, medicine.disease, Repressor Proteins, Medical genetics, business, Transcription Factors
Abstract: New and rapidly evolving technologies have dramatically impacted the practice of clinical genetics as well as broader areas of medicine. To illustrate this trend from the perspective of a clinical molecular laboratory, we briefly summarize our general experience conducting exome testing for patients with holoprosencephaly (HPE). Though these cases are not representative of HPE more generally (i.e., cases undergoing exome sequencing represent a skewed sample), results include a 22% positive rate from exome testing. Of interest, 29% of reported results involved genes not considered to be classic HPE genes, indicating more evidence that HPE may fall within the severe spectrum of many other genetic conditions.
Published: 2018

42. Integrating healthcare and research genetic data empowers the discovery of 49 novel developmental disorders

Author: Joanna Kaplanis, Kaitlin E. Samocha, Laurens Wiel, Zhancheng Zhang, Kevin J. Arvai, Ruth Y. Eberhardt, Giuseppe Gallone, Stefan H. Lelieveld, Hilary C. Martin, Jeremy F. McRae, Patrick J. Short, Rebecca I. Torene, Elke de Boer, Petr Danecek, Eugene J. Gardner, Ni Huang, Jenny Lord, Iñigo Martincorena, Rolph Pfundt, Margot R. F. Reijnders, Alison Yeung, Helger G. Yntema, DDD Study, Lisenka E. L. M. Vissers, Jane Juusola, Caroline F. Wright, Han G. Brunner, Helen V. Firth, David R. FitzPatrick, Jeffrey C. Barrett, Matthew E. Hurles, Christian Gilissen, and Kyle Retterer
Subjects: Genetics, 0303 health sciences, biology, Variant type, Genomics, 3. Good health, 03 medical and health sciences, chemistry.chemical_compound, Negative selection, 0302 clinical medicine, chemistry, biology.protein, Missense mutation, Exome, Gene, 030217 neurology & neurosurgery, Polymerase, DNA, 030304 developmental biology
Abstract: Approximately 2% of de novo single nucleotide variants (SNVs) appear as part of clustered mutations that create multinucleotide variants (MNVs). MNVs are an important source of genomic variability as they are more likely to alter an encoded protein than a SNV, which has important implications in disease as well as evolution. Previous studies of MNVs have focused on their mutational origins and have not systematically evaluated their functional impact and contribution to disease. We identified 69,940 MNVs and 106 de novo MNVs in 6,688 exome sequenced parent-offspring trios from the Deciphering Developmental Disorders Study comprising families with severe developmental disorders. We replicated the previously described MNV mutational signatures associated with DNA polymerase zeta, an error-prone translesion polymerase, and the APOBEC family of DNA deaminases. We found that most MNVs within a single codon create a missense change that could not have been created by a SNV. MNV-induced missense changes were, on average, more physico-chemically divergent, more depleted in highly constrained genes (pLI>=0.9) and were under stronger purifying selection compared to SNV-induced missense changes. We found that de novo MNVs were significantly enriched in genes previously associated with developmental disorders in affected children. This demonstrates that MNVs can be more damaging than SNVs even when both induce missense changes and are an important variant type to consider in relation to human disease.
Published: 2018

43. Mutations in SPATA5 Are Associated with Microcephaly, Intellectual Disability, Seizures, and Hearing Loss

Author: Alisha Wilkins, Akemi J. Tanaka, Adolfo Garnica, Xilma R. Ortiz-Gonzalez, Kyle Retterer, Ada Hamosh, Jane Juusola, Catharina M L Volker-Touw, Kristin G. Monaghan, Charuta Joshi, Dianalee McKnight, Koen L.I. van Gassen, Megan T. Cho, Edward Gratz, Ellen van Binsbergen, Matthew A. Deardorff, Katherine D. Mathews, Nara Sobreira, Dmitriy Niyazov, Wendy K. Chung, Karin Panzer, Francisca Millan, and Eva H. Brilstra
Subjects: Male, Microcephaly, Hearing loss, Molecular Sequence Data, Genes, Recessive, Cortical visual impairment, Biology, Research Support, medicine.disease_cause, Bioinformatics, N.I.H, Gene Frequency, Research Support, N.I.H., Extramural, Seizures, Report, Intellectual Disability, Intellectual disability, Journal Article, medicine, Genetics, Humans, Abnormalities, Multiple, Exome, Genetics(clinical), Amino Acid Sequence, Hearing Loss, Non-U.S. Gov't, Genetics (clinical), Homeodomain Proteins, Mutation, Base Sequence, Research Support, Non-U.S. Gov't, Extramural, Sequence Analysis, DNA, medicine.disease, Hypotonia, ATPases Associated with Diverse Cellular Activities, Female, Sensorineural hearing loss, medicine.symptom, Sequence Alignment
Abstract: Using whole-exome sequencing, we have identified in ten families 14 individuals with microcephaly, developmental delay, intellectual disability, hypotonia, spasticity, seizures, sensorineural hearing loss, cortical visual impairment, and rare autosomal-recessive predicted pathogenic variants in spermatogenesis-associated protein 5 (SPATA5). SPATA5 encodes a ubiquitously expressed member of the ATPase associated with diverse activities (AAA) protein family and is involved in mitochondrial morphogenesis during early spermatogenesis. It might also play a role in post-translational modification during cell differentiation in neuronal development. Mutations in SPATA5 might affect brain development and function, resulting in microcephaly, developmental delay, and intellectual disability.
Published: 2015
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44. Mutations in ARID2 are associated with intellectual disabilities

Author: Alejandro Iglesias, Leandra Folk, Yufeng Shen, Jane Juusola, Wendy K. Chung, Luis Rohena, Anne H. O’Donnell-Luria, Jennifer B. Humberson, Alpa Sidhu, Patrik Vitazka, Sheila Saliganan, Linshan Shang, Kyle Retterer, and Megan T. Cho
Subjects: Male, Adolescent, Developmental Disabilities, Biology, Bioinformatics, Short stature, Cellular and Molecular Neuroscience, Intellectual Disability, Genetics, medicine, Humans, Attention deficit hyperactivity disorder, Exome, Child, Genetics (clinical), Loss function, Exome sequencing, Zinc finger, medicine.disease, Human genetics, Mutation, Etiology, Autism, Female, medicine.symptom, Transcription Factors
Abstract: The etiology of intellectual disabilities (ID) remains unknown for the majority of patients. Due to reduced reproductive fitness in many individuals with ID, de novo mutations account for a significant portion of severe ID. The ATP-dependent SWI/SNF chromatin modifier has been linked with neurodevelopmental disorders including ID and autism. ARID2 is an intrinsic component of polybromo-associated BAF (PBAF), the SWI/SNF subcomplex. In this study, we used clinical whole exome sequencing (WES) in proband-parent-trios to identify the etiology of ID. We identified four independent, novel, loss of function variants in ARID2 gene in four patients, three of which were confirmed to be de novo. The patients all have ID and share other clinical characteristics including attention deficit hyperactivity disorder, short stature, dysmorphic facial features, and Wormian bones. All four novel variants are predicted to lead to a premature termination with the loss of the two conservative zinc finger motifs. This is the first report of mutations in ARID2 associated with developmental delay and ID.
Published: 2015

45. Assessing copy number from exome sequencing and exome array CGH based on CNV spectrum in a large clinical cohort

Author: Daniel E. Pineda-Alvarez, Anastasia Kondakova, Julie Scuffins, Lindsay Schmidt, Daniel Schmidt, Eden Haverfield, Kyle Retterer, Ludmila Matyakhina, Swaroop Aradhya, Rachel Lewis, Jeanne Meck, Federica Gibellini, Amanda Stafford, Amanda Blair, Sherri J. Bale, and Stephanie Warren
Subjects: Comparative Genomic Hybridization, DNA Copy Number Variations, Clinical cohort, Microarray analysis techniques, Computational Biology, Genetic Variation, High-Throughput Nucleotide Sequencing, Context (language use), DNA, Computational biology, Biology, Cohort Studies, Exon, Genetic variation, Humans, Exome, Algorithms, Genetics (clinical), Exome sequencing, Comparative genomic hybridization
Abstract: Detection of copy-number variation (CNV) is important for investigating many genetic disorders. Testing a large clinical cohort by array comparative genomic hybridization provides a deep perspective on the spectrum of pathogenic CNV. In this context, we describe a bioinformatics approach to extract CNV information from whole-exome sequencing and demonstrate its utility in clinical testing. Exon-focused arrays and whole-genome chromosomal microarray analysis were used to test 14,228 and 14,000 individuals, respectively. Based on these results, we developed an algorithm to detect deletions/duplications in whole-exome sequencing data and a novel whole-exome array. In the exon array cohort, we observed a positive detection rate of 2.4% (25 duplications, 318 deletions), of which 39% involved one or two exons. Chromosomal microarray analysis identified 3,345 CNVs affecting single genes (18%). We demonstrate that our whole-exome sequencing algorithm resolves CNVs of three or more exons. These results demonstrate the clinical utility of single-exon resolution in CNV assays. Our whole-exome sequencing algorithm approaches this resolution but is complemented by a whole-exome array to unambiguously identify intragenic CNVs and single-exon changes. These data illustrate the next advancements in CNV analysis through whole-exome sequencing and whole-exome array. Genet Med 17 8, 623–629.
Published: 2015

46. Mutations inSLC1A4, encoding the brain serine transporter, are associated with developmental delay, microcephaly and hypomyelination

Author: Wendy K. Chung, Motee Al-Ashhab, Nadirah Damseh, Matthias A. Hediger, Barak Yaacov, Alexandre Simonin, Orly Elpeleg, Aida Telegrafi, Julie Neidich, Jane Juusola, John Pappas, Sherri J. Bale, Kyle Retterer, Joseph A. Picoraro, Bassam Abu-Libdeh, Ellen Moran, Kwame Anyane Yeboa, Avraham Shaag, Simon Edvardson, Megan T. Cho, Chaim Jalas, and Joshua Cappell
Subjects: Amino Acid Transport System ASC, Male, Heterozygote, medicine.medical_specialty, Microcephaly, Adolescent, Developmental Disabilities, DNA Mutational Analysis, Population, Biology, medicine.disease_cause, Serine, Molecular genetics, Genetics, medicine, Humans, Serine transport, Child, 610 Medicine & health, education, Exome, Myelin Sheath, Genetics (clinical), chemistry.chemical_classification, Mutation, education.field_of_study, Genetic Carrier Screening, Biological Transport, medicine.disease, Pedigree, Amino acid, Cell biology, HEK293 Cells, chemistry, Child, Preschool, 570 Life sciences, biology, Female
Abstract: Background L-serine plays an essential role in neuronal development and function. Although a non-essential amino acid, L-serine must be synthesised within the brain because of its poor permeability by the blood–brain barrier. Within the brain, its synthesis is confined to astrocytes, and its shuttle to neuronal cells is performed by a dedicated neutral amino acid transporter, ASCT1. Methods and results Using exome analysis we identified the recessive mutations, p.E256K, p.L315fs, and p.R457W, in SLC1A4 , the gene encoding ASCT1, in patients with developmental delay, microcephaly and hypomyelination; seizure disorder was variably present. When expressed in a heterologous system, the mutations did not affect the protein level at the plasma membrane but abolished or markedly reduced L-serine transport for p.R457W and p.E256K mutations, respectively. Interestingly, p.E256K mutation displayed a lower L-serine and alanine affinity but the same substrate selectivity as wild-type ASCT1. Conclusions The clinical phenotype of ASCT1 deficiency is reminiscent of defects in L-serine biosynthesis. The data underscore that ASCT1 is essential in brain serine transport. The SLC1A4 p.E256K mutation has a carrier frequency of 0.7% in the Ashkenazi-Jewish population and should be added to the carrier screening panel in this community.
Published: 2015

47. De novo missense variants inHECW2are associated with neurodevelopmental delay and hypotonia

Author: Megan T. Cho, Nathaniel H. Robin, Yufeng Shen, David A. Sweetser, Wendy K. Chung, Payam Mohassel, Kyle Retterer, Christine Moore, Martin G. Bialer, Carsten G. Bönnemann, Lynne A. Wolfe, Francisca Millan, Christine M. Eng, Yunru Shao, Jessica L. Waxler, Cynthia J. Tifft, Esther R. Berko, Fallon Brewer, and Sandra Donkervoort
Subjects: Male, 0301 basic medicine, Proband, Muscle Hypotonia, Ubiquitin-Protein Ligases, Mutation, Missense, Cortical visual impairment, Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Intellectual Disability, Intellectual disability, Genetics, medicine, Humans, Missense mutation, Exome, Child, Genetics (clinical), Exome sequencing, High-Throughput Nucleotide Sequencing, Tumor Protein p73, medicine.disease, Hypotonia, 030104 developmental biology, Neurodevelopmental Disorders, Child, Preschool, Female, medicine.symptom, 030217 neurology & neurosurgery
Abstract: Background The causes of intellectual disability (ID) are diverse and de novo mutations are increasingly recognised to account for a significant proportion of ID. Methods and results In this study, we performed whole exome sequencing on a large cohort of patients with ID or neurodevelopmental delay and identified four novel de novo predicted deleterious missense variants in HECW2 in six probands with ID/developmental delay and hypotonia. Other common features include seizures, strabismus, nystagmus, cortical visual impairment and dysmorphic facial features. HECW2 is an ubiquitin ligase that stabilises p73, a crucial mediator of neurodevelopment and neurogenesis. Conclusion This study implicates pathogenic genetic variants in HECW2 as potential causes of neurodevelopmental disorders in humans.
Published: 2016

48. De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder

Author: Jill A. Rosenfeld, Dominique Bonneau, Deborah Barbouth, Stephen Sanders, Kimberly Nugent, Kimberly Glaser, Ignacio Briceño, Kyle Retterer, Sylvain Simon, Weimin Bi, Yaping Yang, Holly A.F. Stessman, Kristin G. Monaghan, Pawel Stankiewicz, Caroline Rooryck, Sébastien Küry, James R. Lupski, Xenia Latypova, Carlos A. Bacino, Stephanie Sacharow, Sandra Mercier, Evan E. Eichler, Marie Vincent, Elizabeth Roeder, Sébastien Schmitt, Thomas Besnard, Alberto Gómez, Ankita Patel, Brigitte Gilbert-Dussardier, Valérie Malan, Mathilde Nizon, Jessica Douglas, Annick Toutain, Peter-Michael Kloetzel, Anne-Sophie Denommé-Pichon, Frédéric Ebstein, Fan Xia, Laurent Pasquier, Megan T. Cho, Mathilde Pacault, Laurence Perrin-Sabourin, James B. Gibson, Bertrand Isidor, William J. Craigen, Bo Yuan, Stéphane Bézieau, Chad A. Shaw, Richard Redon, Janice L. Smith, Benjamin Cogné, Eric Bieth, Wallid Deb, Kamal Khan, Sylvie Odent, Andrea Lehmann, Tahir N. Khan, Philippe Parent, Christelle Golzio, Nicholas Katsanis, Marie-Line Jacquemont, Tomasz Gambin, Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Boston Children's Hospital, Department of Medicine, Karolinska Institutet [Stockholm], Service de Génétique [Purpan], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Department of Pediatrics, The University of Texas at San Antonio (UTSA), LabEX IGO Immunothérapie Grand Ouest, Service de Cancéro-Dermatologie, Centre hospitalier universitaire de Nantes (CHU Nantes), Anti-tumor immunosurveillances and immunotherapy (CRCINA - Département INCIT - Equipe 3), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers (CRCINA), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Mitochondrie : Régulations et Pathologie, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Génétique Médicale, Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Centre de Référence Anomalies du Développement Ouest, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de génétique clinique [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-Hôpital Sud, CHU Pontchaillou [Rennes], Service de génétique [Tours], Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Imagerie et cerveau, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Laboratoire Histologie Embryologie Cytogénétique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Instituto de Genetica Humana, Pontificia Universidad Javeriana, Universitad de la Sabana, Baylor College of Medicine (BCM), Baylor University, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Center for Human Disease Modeling, Duke University [Durham], National Heart, Lung, and Blood Institute, Wellcome Trust, French Ministry of Health, HUGODIMS, 2013, RC14_0107, Health Regional Agency from Poitou-Charentes, U54HG006542, US National Human Genome Research Institute, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Duke University Medical Center, Warsaw University of Technology [Warsaw], University of California [San Francisco] (UC San Francisco), University of California (UC), University of Miami, Service Génétique Médicale [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hôpital Robert Debré, GeneDx [Gaithersburg, MD, USA], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Nantes Université (Nantes Univ), Anti-Tumor Immunosurveillance and Immunotherapy (CRCINA-ÉQUIPE 3), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire de Biologie Neurovasculaire Intégrée [Angers] (CNRS UMR6214 - INSERM U771), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre hospitalier universitaire de Poitiers (CHU Poitiers), 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 ), Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Pontificia Universidad Javeriana (PUJ), University of Washington [Seattle], Howard Hughes Medical Institute [Seattle], Howard Hughes Medical Institute (HHMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Jonchère, Laurent, Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Centre Hospitalier Universitaire de La Réunion ( CHU La Réunion ), The University of Texas at San Antonio ( UTSA ), Centre hospitalier universitaire de Nantes ( CHU Nantes ), Anti-tumor immunosurveillances and immunotherapy ( CRCINA - Département INCIT - Equipe 3 ), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers ( CRCINA ), Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Université d'Angers ( UA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université d'Angers ( UA ) -CHU Angers, Centre hospitalier universitaire de Poitiers ( CHU Poitiers ) -Centre de Référence Anomalies du Développement Ouest, Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -CHU Pontchaillou [Rennes]-Hôpital Sud, Hôpital Bretonneau-CHRU Tours, Université de Tours-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Universidad de la Sabana, Baylor College of Medicine ( BCM ), Baylor College of Medicine, unité de recherche de l'institut du thorax UMR1087 UMR6291 ( ITX ), Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), and Duke university [Durham]
Subjects: Male, 0301 basic medicine, Microcephaly, Intellectual disability, [SDV.GEN] Life Sciences [q-bio]/Genetics, 030105 genetics & heredity, 0302 clinical medicine, Neurodevelopmental disorder, Ubiquitin, PSMD12, Syndromic neurodevelopmental disorder, Child, Zebrafish, Genetics (clinical), Genetics, Proteasome 26S, Phenotype, proteasome 26S, intellectual disability, Child, Preschool, Female, Proteasome Endopeptidase Complex, Adolescent, DNA Copy Number Variations, syndromic neurodevelopmental disorder, Protein subunit, Down-Regulation, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Report, RPN5, ubiquitin, medicine, Animals, Humans, [SDV.GEN]Life Sciences [q-bio]/Genetics, Point mutation, Infant, Correction, biology.organism_classification, medicine.disease, Human genetics, Disease Models, Animal, 030104 developmental biology, Proteasome, Neurodevelopmental Disorders, biology.protein, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Gene Deletion, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract: 12 páginas Trichosporon asahii es un hongo patógeno emergente reportado en la literatura médica principalmente en pacientes inmunocomprometidos. No obstante, el presente caso es inusual debido a que se trata de un paciente adulto joven inmunocompetente que presentó fungemia por T. asahii y al mismo tiempo desarrolló insuficiencia respiratoria aguda por bronquiolitis respiratoria y neumonía descamativa, la cual resolvió posterior al tratamiento antimicótico instaurado, soporte ventilatorio y vigilancia en Unidad de Cuidado Intesivo (UCI). Degradation of proteins by the ubiquitin-proteasome system (UPS) is an essential biological process in the development of eukaryotic organisms. Dysregulation of this mechanism leads to numerous human neurodegenerative or neurodevelopmental disorders. Through a multi-center collaboration, we identified six de novo genomic deletions and four de novo point mutations involving PSMD12, encoding the non-ATPase subunit PSMD12 (aka RPN5) of the 19S regulator of 26S proteasome complex, in unrelated individuals with intellectual disability, congenital malformations, ophthalmologic anomalies, feeding difficulties, deafness, and subtle dysmorphic facial features. We observed reduced PSMD12 levels and an accumulation of ubiquitinated proteins without any impairment of proteasome catalytic activity. Our PSMD12 loss-of-function zebrafish CRISPR/Cas9 model exhibited microcephaly, decreased convolution of the renal tubules, and abnormal craniofacial morphology. Our data support the biological importance of PSMD12 as a scaffolding subunit in proteasome function during development and neurogenesis in particular; they enable the definition of a neurodevelopmental disorder due to PSMD12 variants, expanding the phenotypic spectrum of UPS-dependent disorders.
Published: 2017

49. High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies

Author: Patrick Cossette, Zoha Kibar, Maxime Cadieux-Dion, Helen Brittain, Andrew E. Fry, Emily Fassi, Edward Blair, Simone Martinelli, Paul J. Benke, Guy D'Anjou, Alexandre D. Laporte, Berge A. Minassian, Sylvia Stockler, Tyson L Ware, David R. FitzPatrick, Weimin Bi, Amy L Schneider, Jill A. Rosenfeld, Shekeeb S. Mohammad, Jacques L. Michaud, Carlos A. Bacino, Joss Shelagh, Samuel F. Berkovic, Stéphane Auvin, Yunru Shao, Sylvia Dobrzeniecka, Kelly Mo, Cory Tam, Nicole Corsten-Janssen, Wendy K. Chung, Renee-Myriam Boucher, Alain Verloes, Fadi F. Hamdan, Bronwyn Kerr, Frédéric Tran Mau-Them, Martina Bebin, Philippe M. Campeau, Dara V.F. Albert, Guy A. Rouleau, Quinn Stein, Anne Lortie, Susan M. Hiatt, Lubov Blumkin, Boris Keren, Dan Spiegelman, Saadet Mercimek-Mahmutoglu, Ronald G. Lafrenière, Marie-Christine Nougues, Rhys H. Thomas, Erica H. Gerkes, Elsa Rossignol, Bruno Dallapiccola, Klaas J. Wierenga, Natalie Canham, Monica H. Wojcik, Caroline Meloche, Moira Blyth, Cyril Mignot, Heather C Mefford, Ledia Brunga, D. L. Jones, François Dubeau, Kyle Retterer, James J. O'Byrne, Christine Massicotte, Vincenzo Leuzzi, Caroline Nava, Ingrid E. Scheffer, Erik-Jan Kamsteeg, Cyrus Boelman, Megan T. Cho, Gabriela Purcarin, Brigid M. Regan, Jean Monlong, Simon Girard, Philippe Major, Marguerite Miguet, Katrin Õunap, Yu Chi Liu, Guillaume Bourque, Myriam Srour, Ousmane Diallo, Emilie Riou, Lionel Carmant, Seema R. Lalani, Christina Nassif, Robert Roger Lebel, Anna Lehman, Georgie Hollingsworth, Stéphanie Jacques, Sunita Venkateswaran, Marco Tartaglia, Candace T. Myers, Ange-Line Bruel, Danielle M. Andrade, Imad Jarjour, Peyman Bizargity, Sara J. Dorison, Jane A. Hurst, Richard E. Frye, Lynette G. Sadleir, Alan Donaldson, Fernando Scaglia, Philippe Lemay, Paola Diadori, Laura Davis-Keppen, Division of Genetic Medicine [Seattle], University of Washington [Seattle], Centre hospitalier universtaire de Montréal, Université de Montréal, Baylor College of Medicine ( BCM ), Baylor College of Medicine, Laboratoire de Diagnostic Génétique, CHU Strasbourg-Hopital Civil, Clinical Genetics Department, St Michael's Hospital, Department of Clinical Genetics, Oxford Regional Genetics Service, The Churchill hospital, Regional Genetic Service, St Mary's Hospital, Manchester, SUNY Upstate Medical University, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpital Robert Debré, Universitätsklinikum Leipzig, Institute of Plant and Microbial Biology, Academia Sinica, Istituto di Genetica Medica, Medical Genetics and Pediatric Cardiology, IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanita', Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], 'Personal Protection Against Vectors' working group ( PPAV ), PPAV working group, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute ( ICM ), Centre National de la Recherche Scientifique ( CNRS ) -CHU Pitié-Salpêtrière [APHP]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Département de Mathématiques, Université de Sherbrooke, Université de Sherbrooke [Sherbrooke], McGill University and Genome Quebec Innovation Centre, Center of Excellence in Neuromics, University of Montreal, The Hospital for sick children [Toronto] ( SickKids ), CHU Sainte Justine [Montréal], Genome Canada Genome Quebec Jeanne and Jean-Louis Levesque Foundation Michael Bahen Chair in Epilepsy Research Ontario Brain Institute McLaughlin Foundation University of Toronto National Institute of Neurological Disorders and Stroke RO1 NS069605 University of Toronto McLaughlin Accelerator Grant in Genomic Medicine MC-2013-08, Baylor College of Medicine (BCM), Baylor University, State University of New York (SUNY), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Istituto Superiore di Sanità (ISS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 'Personal Protection Against Vectors' working group (PPAV), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Centre National de la Recherche Scientifique (CNRS), Département de mathématiques [Sherbrooke] (UdeS), Faculté des sciences [Sherbrooke] (UdeS), Université de Sherbrooke (UdeS)-Université de Sherbrooke (UdeS), The Hospital for sick children [Toronto] (SickKids), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC)
Subjects: Male, 0301 basic medicine, Candidate gene, medicine.medical_specialty, medical genetics, glycosylation, Nonsense mutation, Genome-wide association study, Gene mutation, Biology, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Article, severe intellectual disability, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, children, Recurrence, Seizures, Genetic linkage, Intellectual Disability, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Journal Article, Genetics, medicine, Humans, Child, disorders, Genetics (clinical), Genetic association, Brain Diseases, disease, cis-prenyltransferase, Genome, Human, structural basis, medicine.disease, diphosphate synthase, 030104 developmental biology, Child, Preschool, Mutation, Medical genetics, Female, nogo-b receptor, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Genome-Wide Association Study, Meta-Analysis
Abstract: Item does not contain fulltext Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. We focused our attention on de novo mutations (DNMs) and identified candidate genes containing such variants. We sought to identify additional subjects with DNMs in these genes by performing targeted sequencing in another series of individuals with DEE and by mining various sequencing datasets. We also performed meta-analyses to document enrichment of DNMs in candidate genes by leveraging our WGS dataset with those of several DEE and ID series. By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25. Overall, we established a molecular diagnosis in 63/197 (32%) individuals in our WGS series. The main cause of DEE in these individuals was de novo point mutations (53/63 solved cases), followed by inherited mutations (6/63 solved cases) and de novo CNVs (4/63 solved cases). De novo missense variants explained a larger proportion of individuals in our series than in other series that were primarily ascertained because of ID. Moreover, these DNMs were more frequently recurrent than those identified in ID series. These observations indicate that the genetic landscape of DEE might be different from that of ID without epilepsy.
Published: 2017

50. De novo missense variants in PPP1CB are associated with intellectual disability and congenital heart disease

Author: Zöe Powis, Janson White, Rhonda E. Schnur, Andrea M. Lewis, Sherri J. Bale, Joann Bodurtha, Neda Zadeh, Alyson Krokosky, Shalani N. Jhangiani, Megan T. Cho, Caleb Bupp, Seema R. Lalani, Elif Yilmaz Gulec, Heather M. McLaughlin, Weiyi Mu, Kristin Lindstrom, Wendy Alcaraz, Veronique Weinstein, Kyle Retterer, Yunru Shao, Katey Mayberry, Clesson Turner, Yavuz Bayram, Ingrid M. Wentzensen, Lijiang Ma, Daryl A. Scott, James R. Lupski, and Wendy K. Chung
Subjects: 0301 basic medicine, Adult, Heart Defects, Congenital, Male, Adolescent, Protein subunit, Mutation, Missense, Biology, medicine.disease_cause, Article, 03 medical and health sciences, Intellectual Disability, Protein Phosphatase 1, Intellectual disability, Genetics, medicine, Missense mutation, Humans, Exome, Genetic Predisposition to Disease, Phosphorylation, Child, Gene, Genetics (clinical), Genetic Association Studies, Mutation, Genetic heterogeneity, medicine.disease, 030104 developmental biology, Child, Preschool, Female
Abstract: Intellectual disabilities are genetically heterogeneous and can be associated with congenital anomalies. Using whole-exome sequencing (WES), we identified five different de novo missense variants in the protein phosphatase-1 catalytic subunit beta (PPP1CB) gene in eight unrelated individuals who share an overlapping phenotype of dysmorphic features, macrocephaly, developmental delay or intellectual disability (ID), congenital heart disease, short stature, and skeletal and connective tissue abnormalities. Protein phosphatase-1 (PP1) is a serine/threonine-specific protein phosphatase involved in the dephosphorylation of a variety of proteins. The PPP1CB gene encodes a PP1 subunit that regulates the level of protein phosphorylation. All five altered amino acids we observed are highly conserved among the PP1 subunit family, and all are predicted to disrupt PP1 subunit binding and impair dephosphorylation. Our data suggest that our heterozygous de novo PPP1CB pathogenic variants are associated with syndromic intellectual disability.
Published: 2016

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