Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1
Gemma L. Carvill,Sinéad Heavin,Simone C. Yendle,Jacinta M McMahon,Brian J. O'Roak,Joseph Cook,Adiba Khan,Michael O. Dorschner,Michael O. Dorschner,Molly Weaver,Molly Weaver,Sophie Calvert,Stephen M. Malone,Geoffrey Wallace,Thorsten Stanley,Ann M. E. Bye,Andrew Bleasel,Katherine B. Howell,Sara Kivity,Mark T Mackay,Victoria Rodriguez-Casero,Richard Webster,Amos D. Korczyn,Zaid Afawi,Nathanel Zelnick,Tally Lerman-Sagie,Tally Lerman-Sagie,Dorit Lev,Rikke S. Møller,Deepak Gill,Danielle M. Andrade,Jeremy L. Freeman,Lynette G. Sadleir,Jay Shendure,Samuel F. Berkovic,Ingrid E. Scheffer,Heather C Mefford +36 more
TLDR
Target massively parallel resequencing of 19 known and 46 candidate genes for epileptic encephalopathy in 500 affected individuals (cases) to identify new genes involved and to investigate the phenotypic spectrum associated with mutations in known genes.Abstract:
Epileptic encephalopathies are a devastating group of epilepsies with poor prognosis, of which the majority are of unknown etiology. We perform targeted massively parallel resequencing of 19 known and 46 candidate genes for epileptic encephalopathy in 500 affected individuals (cases) to identify new genes involved and to investigate the phenotypic spectrum associated with mutations in known genes. Overall, we identified pathogenic mutations in 10% of our cohort. Six of the 46 candidate genes had 1 or more pathogenic variants, collectively accounting for 3% of our cohort. We show that de novo CHD2 and SYNGAP1 mutations are new causes of epileptic encephalopathies, accounting for 1.2% and 1% of cases, respectively. We also expand the phenotypic spectra explained by SCN1A, SCN2A and SCN8A mutations. To our knowledge, this is the largest cohort of cases with epileptic encephalopathies to undergo targeted resequencing. Implementation of this rapid and efficient method will change diagnosis and understanding of the molecular etiologies of these disorders.read more
Citations
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ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology.
Ingrid E. Scheffer,Samuel F. Berkovic,Giuseppe Capovilla,Mary B. Connolly,Jacqueline A. French,Laura Maria de Figueiredo Ferreira Guilhoto,Edouard Hirsch,Satish Jain,Gary W. Mathern,Solomon L. Moshé,Douglas R. Nordli,Emilio Perucca,Torbjörn Tomson,Samuel Wiebe,Yuehua Zhang,Sameer M. Zuberi,Sameer M. Zuberi +16 more
TL;DR: The International League Against Epilepsy (ILAE) Classification of the Epilepsies has been updated to reflect our gain in understanding of the epilepsies and their underlying mechanisms following the major scientific advances that have taken place since the last ratified classification in 1989 as mentioned in this paper.
Journal ArticleDOI
Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals
James J. Lee,Robbee Wedow,Aysu Okbay,Edward Kong,Omeed Maghzian,Meghan Zacher,Tuan Anh Nguyen-Viet,Peter Bowers,Julia Sidorenko,Julia Sidorenko,Richard Karlsson Linnér,Richard Karlsson Linnér,Mark Alan Fontana,Mark Alan Fontana,Tushar Kundu,Chanwook Lee,Hui Li,Ruoxi Li,Rebecca Royer,Pascal Timshel,Pascal Timshel,Raymond K. Walters,Raymond K. Walters,Emily A. Willoughby,Loic Yengo,Maris Alver,Yanchun Bao,David W. Clark,Felix R. Day,Nicholas A. Furlotte,Peter K. Joshi,Peter K. Joshi,Kathryn E. Kemper,Aaron Kleinman,Claudia Langenberg,Reedik Mägi,Joey W. Trampush,Shefali S. Verma,Yang Wu,Max Lam,Jing Hua Zhao,Zhili Zheng,Zhili Zheng,Jason D. Boardman,Harry Campbell,Jeremy Freese,Kathleen Mullan Harris,Caroline Hayward,Pamela Herd,Pamela Herd,Meena Kumari,Todd Lencz,Todd Lencz,Jian'an Luan,Anil K. Malhotra,Anil K. Malhotra,Andres Metspalu,Lili Milani,Ken K. Ong,John R. B. Perry,David J. Porteous,Marylyn D. Ritchie,Melissa C. Smart,Blair H. Smith,Joyce Y. Tung,Nicholas J. Wareham,James F. Wilson,Jonathan P. Beauchamp,Dalton Conley,Tõnu Esko,Steven F. Lehrer,Steven F. Lehrer,Steven F. Lehrer,Patrik K. E. Magnusson,Sven Oskarsson,Tune H. Pers,Tune H. Pers,Matthew R. Robinson,Matthew R. Robinson,Kevin Thom,Chelsea Watson,Christopher F. Chabris,Michelle N. Meyer,David Laibson,Jian Yang,Magnus Johannesson,Philipp Koellinger,Philipp Koellinger,Patrick Turley,Patrick Turley,Peter M. Visscher,Daniel J. Benjamin,Daniel J. Benjamin,David Cesarini,David Cesarini +94 more
TL;DR: A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11–13% of the variance ineducational attainment and 7–10% ofthe variance in cognitive performance, which substantially increases the utility ofpolygenic scores as tools in research.
Journal ArticleDOI
Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders
Dalila Pinto,Elsa Delaby,Elsa Delaby,Elsa Delaby,Daniele Merico,Mafalda Barbosa,Alison K. Merikangas,Lambertus Klei,Bhooma Thiruvahindrapuram,Xiao Xu,Robert Ziman,Zhuozhi Wang,Jacob A. S. Vorstman,Ann P. Thompson,Regina Regan,Regina Regan,Marion Pilorge,Marion Pilorge,Marion Pilorge,Giovanna Pellecchia,Alistair T. Pagnamenta,Bárbara Oliveira,Bárbara Oliveira,Christian R. Marshall,Tiago R. Magalhaes,Tiago R. Magalhaes,Jennifer K. Lowe,Jennifer L. Howe,Anthony J. Griswold,John R. Gilbert,Eftichia Duketis,Beth A. Dombroski,Maretha de Jonge,Michael L. Cuccaro,Emily L. Crawford,Catarina Correia,Catarina Correia,Judith Conroy,Inȇs C. Conceição,Inȇs C. Conceição,Andreas G. Chiocchetti,Jillian P. Casey,Jillian P. Casey,Guiqing Cai,Christelle Cabrol,Christelle Cabrol,Christelle Cabrol,Nadia Bolshakova,Elena Bacchelli,Richard Anney,Steven Gallinger,Michelle Cotterchio,Graham Casey,Lonnie Zwaigenbaum,Kerstin Wittemeyer,Kirsty Wing,Simon Wallace,Herman van Engeland,Ana Tryfon,Susanne Thomson,Latha Soorya,Bernadette Rogé,Wendy Roberts,Fritz Poustka,Susana Mouga,Nancy J. Minshew,L. Alison McInnes,Susan G. McGrew,Catherine Lord,Marion Leboyer,Ann Le Couteur,Alexander Kolevzon,Patricia Jiménez González,Suma Jacob,Suma Jacob,Richard Holt,Stephen J. Guter,Jonathan Green,Andrew Green,Andrew Green,Christopher Gillberg,Bridget A. Fernandez,Frederico Duque,Richard Delorme,Geraldine Dawson,Pauline Chaste,Cátia Café,Sean Brennan,Thomas Bourgeron,Patrick Bolton,Patrick Bolton,Sven Bölte,Raphael Bernier,Gillian Baird,Anthony J. Bailey,Evdokia Anagnostou,Joana Almeida,Ellen M. Wijsman,Veronica J. Vieland,Astrid M. Vicente,Astrid M. Vicente,Gerard D. Schellenberg,Margaret A. Pericak-Vance,Andrew D. Paterson,Jeremy R. Parr,Guiomar Oliveira,John I. Nurnberger,Anthony P. Monaco,Anthony P. Monaco,Elena Maestrini,Sabine M. Klauck,Hakon Hakonarson,Jonathan L. Haines,Daniel H. Geschwind,Christine M. Freitag,Susan E. Folstein,Sean Ennis,Sean Ennis,Hilary Coon,Agatino Battaglia,Peter Szatmari,James S. Sutcliffe,Joachim Hallmayer,Michael Gill,Edwin H. Cook,Joseph D. Buxbaum,Bernie Devlin,Louise Gallagher,Catalina Betancur,Catalina Betancur,Catalina Betancur,Stephen W. Scherer +131 more
TL;DR: For example, the authors analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability.
Journal ArticleDOI
The genetic landscape of the epileptic encephalopathies of infancy and childhood
Amy McTague,Amy McTague,Katherine B. Howell,Katherine B. Howell,J. Helen Cross,J. Helen Cross,Manju A. Kurian,Manju A. Kurian,Ingrid E. Scheffer +8 more
TL;DR: Gene discovery provides the basis for neurobiological insights, often showing convergence of mechanistic pathways that underpin the development of targeted therapies, which are essential to improve the outcome of these devastating disorders.
Journal ArticleDOI
Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders.
Markus Wolff,Katrine M Johannesen,Ulrike B. S. Hedrich,Silvia Masnada,Guido Rubboli,Elena Gardella,Gaetan Lesca,Gaetan Lesca,Dorothée Ville,Mathieu Milh,Laurent Villard,Alexandra Afenjar,Sandra Chantot-Bastaraud,Cyril Mignot,Caroline Lardennois,Caroline Nava,Niklas Schwarz,Marion Gérard,Laurence Perrin,Diane Doummar,Stéphane Auvin,Maria J Miranda,Maja Hempel,Eva H. Brilstra,Nine V A M Knoers,Nienke E. Verbeek,Marjan J. A. van Kempen,Kees P.J. Braun,Grazia M.S. Mancini,Saskia Biskup,Konstanze Hörtnagel,Miriam Döcker,Thomas Bast,Tobias Loddenkemper,Lily C. Wong-Kisiel,Friedrich A. M. Baumeister,Walid Fazeli,Pasquale Striano,Robertino Dilena,Elena Fontana,Federico Zara,Gerhard Kurlemann,Joerg Klepper,Jess G. Thoene,Daniel H. Arndt,Nicolas Deconinck,Thomas Schmitt-Mechelke,Oliver Maier,Hiltrud Muhle,Beverly Wical,Claudio Finetti,Reinhard Brückner,Joachim Pietz,Günther Golla,Dinesh V Jillella,Karen Markussen Linnet,Perrine Charles,Ute Moog,Eve Õiglane-Shlik,John F Mantovani,Kristen Park,Marie Deprez,Damien Lederer,Sandrine Mary,Emmanuel Scalais,Laila Selim,Rudy Van Coster,Lieven Lagae,Marina Nikanorova,Helle Hjalgrim,G. Christoph Korenke,Marina Trivisano,Nicola Specchio,Berten Ceulemans,Thomas Dorn,Katherine L. Helbig,Katia Hardies,Hannah Stamberger,Peter De Jonghe,Sarah Weckhuysen,Johannes R. Lemke,Ingeborg Krägeloh-Mann,Ingo Helbig,Ingo Helbig,Gerhard Kluger,Holger Lerche,Rikke S. Møller +86 more
TL;DR: Clinical and experimental data suggest a correlation between age at disease onset, response to sodium channel blockers and the functional properties of mutations in children with SCN2A-related epilepsy, and suggest that mutations associated with early infantile epilepsy result in increased sodium channel activity with gain-of-function.
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Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.
Brian J. O'Roak,Laura Vives,Wenqing Fu,Jarrett D. Egertson,Ian B. Stanaway,Ian G. Phelps,Ian G. Phelps,Gemma L. Carvill,Gemma L. Carvill,Akash Kumar,Choli Lee,Katy Ankenman,Jeff Munson,Joseph B. Hiatt,Emily H. Turner,Roie Levy,Diana R. O’Day,Niklas Krumm,Bradley P. Coe,Beth Martin,Elhanan Borenstein,Elhanan Borenstein,Deborah A. Nickerson,Heather C Mefford,Heather C Mefford,Dan Doherty,Dan Doherty,Joshua M. Akey,Raphael Bernier,Evan E. Eichler,Evan E. Eichler,Jay Shendure +31 more
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