Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains.
Madeleine R. Geisheker,Gabriel Heymann,Tianyun Wang,Bradley P. Coe,Tychele N. Turner,Holly A.F. Stessman,Kendra Hoekzema,Malin Kvarnung,Marie Shaw,Kathryn Friend,Kathryn Friend,Jan Liebelt,Christopher Barnett,Christopher Barnett,Elizabeth Thompson,Elizabeth Thompson,Eric Haan,Eric Haan,Hui Guo,Britt-Marie Anderlid,Ann Nordgren,Anna Lindstrand,Geert Vandeweyer,Antonino Alberti,Emanuela Avola,Mirella Vinci,Stefania Giusto,Tiziano Pramparo,Karen Pierce,Srinivasa Nalabolu,Jacob J. Michaelson,Zdenek Sedlacek,Gijs W. E. Santen,Hilde Peeters,Hakon Hakonarson,Eric Courchesne,Corrado Romano,R. Frank Kooy,Raphael Bernier,Magnus Nordenskjöld,Jozef Gecz,Kun Xia,Larry S. Zweifel,Evan E. Eichler,Evan E. Eichler +44 more
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Overall, significant clustering of de novo mutations in 200 genes is found, highlighting specific functional domains and synaptic candidate genes important in NDD pathology.Abstract:
Although de novo missense mutations have been predicted to account for more cases of autism than gene-truncating mutations, most research has focused on the latter. We identified the properties of de novo missense mutations in patients with neurodevelopmental disorders (NDDs) and highlight 35 genes with excess missense mutations. Additionally, 40 amino acid sites were recurrently mutated in 36 genes, and targeted sequencing of 20 sites in 17,688 patients with NDD identified 21 new patients with identical missense mutations. One recurrent site substitution (p.A636T) occurs in a glutamate receptor subunit, GRIA1. This same amino acid substitution in the homologous but distinct mouse glutamate receptor subunit Grid2 is associated with Lurcher ataxia. Phenotypic follow-up in five individuals with GRIA1 mutations shows evidence of specific learning disabilities and autism. Overall, we find significant clustering of de novo mutations in 200 genes, highlighting specific functional domains and synaptic candidate genes important in NDD pathology.read more
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Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity.
Bradley P. Coe,Holly A.F. Stessman,Arvis Sulovari,Madeleine R. Geisheker,Trygve E. Bakken,Allison M. Lake,Joseph D. Dougherty,Ed S. Lein,Fereydoun Hormozdiari,Raphael Bernier,Evan E. Eichler +10 more
TL;DR: Analysis of ~10,000 cases of developmental delay and autism identifies 253 candidate neurodevelopmental disease genes with an excess of missense and/or likely gene-disruptive mutations and highlights cell-specific enrichments of disease-related genes in the D1+ and D2+ spiny neurons of the striatum.
Journal ArticleDOI
Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels.
Kasper B. Hansen,Lonnie P. Wollmuth,Derek Bowie,Hiro Furukawa,Frank S. Menniti,Alexander I. Sobolevsky,Geoffrey T. Swanson,Sharon A. Swanger,Ingo H. Greger,Terunaga Nakagawa,Chris J. McBain,Vasanthi Jayaraman,Chian-Ming Low,Mark L. Dell’Acqua,Jeffrey S. Diamond,Chad R. Camp,Riley E. Perszyk,Hongjie Yuan,Stephen F. Traynelis +18 more
TL;DR: In this paper, the authors review insights from more than 3 decades of iGluR studies with an emphasis on the progress that has occurred in the past decade, covering structure, function, pharmacology, roles in neurophysiology, and therapeutic implications for all classes of receptors assembled from the subunits encoded by the 18 ionotropic glutamate receptor genes.
Journal ArticleDOI
The Autism-Associated Gene Scn2a Contributes to Dendritic Excitability and Synaptic Function in the Prefrontal Cortex
Perry W.E. Spratt,Roy Ben-Shalom,Caroline M. Keeshen,Kenneth J. Burke,Rebecca L. Clarkson,Stephen Sanders,Kevin J. Bender +6 more
TL;DR: It is shown that NaV1.2 is unexpectedly critical for dendritic excitability and synaptic function in mature pyramidal neurons in addition to regulating early developmental axonal excitability in ASD.
Journal ArticleDOI
AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders
Vincenzo Salpietro,Vincenzo Salpietro,Vincenzo Salpietro,Christine L Dixon,Hui Guo,Hui Guo,Oscar D. Bello,Jana Vandrovcova,Stephanie Efthymiou,Reza Maroofian,Gali Heimer,Lydie Burglen,Stéphanie Valence,Erin Torti,Moritz Hacke,Julia Rankin,Huma Tariq,Estelle Colin,Vincent Procaccio,Pasquale Striano,Pasquale Striano,Kshitij Mankad,Andreas Lieb,Sharon Chen,Laura Pisani,Conceição Bettencourt,Roope Männikkö,Andreea Manole,Alfredo Brusco,Enrico Grosso,Giovanni Battista Ferrero,Judith Armstrong-Moron,Sophie Gueden,Omer Bar-Yosef,Michal Tzadok,Kristin G. Monaghan,Teresa Santiago-Sim,Richard E. Person,Megan T. Cho,Rebecca Willaert,Yongjin Yoo,Jong-Hee Chae,Yingting Quan,Huidan Wu,Tianyun Wang,Tianyun Wang,Raphael Bernier,Kun Xia,Alyssa Blesson,Mahim Jain,M. Mahdi Motazacker,Bregje Jaeger,Amy L Schneider,Katja E. Boysen,Alison M. Muir,Candace T. Myers,Ralitza H. Gavrilova,Lauren Gunderson,Laura Schultz-Rogers,Eric W. Klee,David A. Dyment,Matthew Osmond,Matthew Osmond,Mara Parellada,Cloe Llorente,Javier González-Peñas,Angel Carracedo,Arie van Haeringen,Claudia A. L. Ruivenkamp,Caroline Nava,Delphine Héron,Rosaria Nardello,Michele Iacomino,Carlo Minetti,Carlo Minetti,Aldo Skabar,Antonella Fabretto,Miquel Raspall-Chaure,Michael Chez,Anne Tsai,Emily Fassi,Marwan Shinawi,John N. Constantino,Rita De Zorzi,Sara Fortuna,Fernando Kok,Boris Keren,Dominique Bonneau,Murim Choi,Bruria Ben-Zeev,Federico Zara,Heather C Mefford,Ingrid E. Scheffer,Jill Clayton-Smith,Jill Clayton-Smith,Alfons Macaya,James E. Rothman,James E. Rothman,Evan E. Eichler,Dimitri M. Kullmann,Henry Houlden +100 more
TL;DR: The results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission.
Journal ArticleDOI
Ionotropic Glutamate Receptors in Epilepsy: A Review Focusing on AMPA and NMDA Receptors.
TL;DR: It is suggested that a misunderstanding of the role of each glutamate receptor in the ictogenic process may underlie the failure of these drugs to demonstrate clinical efficacy and safety.
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Grant,Carla Gallo,Giovanni Poletti,Danish Saleheen,Asif Rasheed,Lisa D. Brooks,Adam Felsenfeld,Jean E. McEwen,Yekaterina Vaydylevich,Audrey Duncanson,Michael Dunn,Jeffery A. Schloss +517 more
TL;DR: The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations, and has reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-generation sequencing, deep exome sequencing, and dense microarray genotyping.
Journal ArticleDOI
Analysis of protein-coding genetic variation in 60,706 humans
Monkol Lek,Konrad J. Karczewski,Konrad J. Karczewski,Eric Vallabh Minikel,Eric Vallabh Minikel,Kaitlin E. Samocha,Eric Banks,Timothy Fennell,Anne H. O’Donnell-Luria,Anne H. O’Donnell-Luria,Anne H. O’Donnell-Luria,James S. Ware,Andrew J. Hill,Andrew J. Hill,Andrew J. Hill,Beryl B. Cummings,Beryl B. Cummings,Taru Tukiainen,Taru Tukiainen,Daniel P. Birnbaum,Jack A. Kosmicki,Laramie E. Duncan,Laramie E. Duncan,Karol Estrada,Karol Estrada,Fengmei Zhao,Fengmei Zhao,James Zou,Emma Pierce-Hoffman,Emma Pierce-Hoffman,Joanne Berghout,David Neil Cooper,Nicole A. Deflaux,Mark A. DePristo,Ron Do,Jason Flannick,Jason Flannick,Menachem Fromer,Laura D. Gauthier,Jackie Goldstein,Jackie Goldstein,Namrata Gupta,Daniel P. Howrigan,Daniel P. Howrigan,Adam Kiezun,Mitja I. Kurki,Mitja I. Kurki,Ami Levy Moonshine,Pradeep Natarajan,Lorena Orozco,Gina M. Peloso,Gina M. Peloso,Ryan Poplin,Manuel A. Rivas,Valentin Ruano-Rubio,Samuel A. Rose,Douglas M. Ruderfer,Khalid Shakir,Peter D. Stenson,Christine Stevens,Brett Thomas,Brett Thomas,Grace Tiao,María Teresa Tusié-Luna,Ben Weisburd,Hong-Hee Won,Dongmei Yu,David Altshuler,David Altshuler,Diego Ardissino,Michael Boehnke,John Danesh,Stacey Donnelly,Roberto Elosua,Jose C. Florez,Jose C. Florez,Stacey Gabriel,Gad Getz,Gad Getz,Stephen J. Glatt,Christina M. Hultman,Sekar Kathiresan,Markku Laakso,Steven A. McCarroll,Steven A. McCarroll,Mark I. McCarthy,Mark I. McCarthy,Dermot P.B. McGovern,Ruth McPherson,Benjamin M. Neale,Benjamin M. Neale,Aarno Palotie,Shaun Purcell,Danish Saleheen,Jeremiah M. Scharf,Pamela Sklar,Patrick F. Sullivan,Patrick F. Sullivan,Jaakko Tuomilehto,Ming T. Tsuang,Hugh Watkins,Hugh Watkins,James G. Wilson,Mark J. Daly,Mark J. Daly,Daniel G. MacArthur,Daniel G. MacArthur +106 more
TL;DR: The aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC) provides direct evidence for the presence of widespread mutational recurrence.
Journal ArticleDOI
A general framework for estimating the relative pathogenicity of human genetic variants
Martin Kircher,Daniela Witten,Preti Jain,Brian J. O'Roak,Brian J. O'Roak,Gregory M. Cooper,Jay Shendure +6 more
TL;DR: The ability of CADD to prioritize functional, deleterious and pathogenic variants across many functional categories, effect sizes and genetic architectures is unmatched by any current single-annotation method.
Journal ArticleDOI
Synaptic, transcriptional and chromatin genes disrupted in autism
Silvia De Rubeis,Xin-Xin He,Arthur P. Goldberg,Christopher S. Poultney,Kaitlin E. Samocha,A. Ercument Cicek,Yan Kou,Li Liu,Menachem Fromer,Menachem Fromer,R. Susan Walker,Tarjinder Singh,Lambertus Klei,Jack A. Kosmicki,Shih-Chen Fu,Branko Aleksic,Monica Biscaldi,Patrick Bolton,Jessica M. Brownfeld,Jinlu Cai,Nicholas G. Campbell,Angel Carracedo,Angel Carracedo,Maria H. Chahrour,Andreas G. Chiocchetti,Hilary Coon,Emily L. Crawford,Lucy Crooks,Sarah Curran,Geraldine Dawson,Eftichia Duketis,Bridget A. Fernandez,Louise Gallagher,Evan T. Geller,Stephen J. Guter,R. Sean Hill,R. Sean Hill,Iuliana Ionita-Laza,Patricia Jiménez González,Helena Kilpinen,Sabine M. Klauck,Alexander Kolevzon,Irene Lee,Jing Lei,Terho Lehtimäki,Chiao-Feng Lin,Avi Ma'ayan,Christian R. Marshall,Alison L. McInnes,Benjamin M. Neale,Michael John Owen,Norio Ozaki,Mara Parellada,Jeremy R. Parr,Shaun Purcell,Kaija Puura,Deepthi Rajagopalan,Karola Rehnström,Abraham Reichenberg,Aniko Sabo,Michael Sachse,Stephen Sanders,Chad M. Schafer,Martin Schulte-Rüther,David Skuse,David Skuse,Christine Stevens,Peter Szatmari,Kristiina Tammimies,Otto Valladares,Annette Voran,Li-San Wang,Lauren A. Weiss,A. Jeremy Willsey,Timothy W. Yu,Timothy W. Yu,Ryan K. C. Yuen,Edwin H. Cook,Christine M. Freitag,Michael Gill,Christina M. Hultman,Thomas Lehner,Aarno Palotie,Aarno Palotie,Aarno Palotie,Gerard D. Schellenberg,Pamela Sklar,Matthew W. State,James S. Sutcliffe,Christopher A. Walsh,Christopher A. Walsh,Stephen W. Scherer,Michael E. Zwick,Jeffrey C. Barrett,David J. Cutler,Kathryn Roeder,Bernie Devlin,Mark J. Daly,Mark J. Daly,Joseph D. Buxbaum +99 more
TL;DR: Using exome sequencing, it is shown that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate of < 0.05, plus a set of 107 genes strongly enriched for those likely to affect risk (FDR < 0.30).
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Synaptic, transcriptional and chromatin genes disrupted in autism
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Analysis of protein-coding genetic variation in 60,706 humans
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