Journal article
A case-control collapsing analysis identifies epilepsy genes implicated in trio sequencing studies focused on de novo mutations
X Zhu, R Padmanabhan, B Copeland, J Bridgers, Z Ren, S Kamalakaran, A O'Driscoll-Collins, SF Berkovic, IE Scheffer, A Poduri, D Mei, R Guerrini, DH Lowenstein, AS Allen, EL Heinzen, DB Goldstein
Plos Genetics | PUBLIC LIBRARY SCIENCE | Published : 2017
Abstract
Trio exome sequencing has been successful in identifying genes with de novo mutations (DNMs) causing epileptic encephalopathy (EE) and other neurodevelopmental disorders. Here, we evaluate how well a case-control collapsing analysis recovers genes causing dominant forms of EE originally implicated by DNM analysis. We performed a genome-wide search for an enrichment of "qualifying variants" in protein-coding genes in 488 unrelated cases compared to 12,151 unrelated controls. These "qualifying variants" were selected to be extremely rare variants predicted to functionally impact the protein to enrich for likely pathogenic variants. Despite modest sample size, three known EE genes (KCNT1, SCN2A..
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Grants
Awarded by European Commission
Funding Acknowledgements
This work was supported by grants from the National Institute of Neurological Disorders and Stroke (The Epilepsy Phenome/Genome Project NS053998; Epi4K-Administrative Core NS077274; Epi4K-Sequencing, Biostatistics and Bioinformatics Core NS077303; Epi4K-Multiplex Families & Pairs Project NS077367 and Epi4K-Phenotyping and Clinical Informatics Core NS077276, and K23NS069784 (AP)) and the European Union's Seventh Framework Programme grant (Health-Fs-602531-2013 - DESIRE, http://epilepsydesireproiect.eu/). The collection of control samples and data was funded in part by: Biogen, Inc.; Gilead Sciences, Inc.; UCB; Bryan ADRC NIA P30AG028377; B57 SAIC-Fredrick Inc M11-074; National Institute of Neurological Disorders and Stroke (RC2MH089915; U01NS077303; U01NS053998, U54NS078059, P01HD080642); National Human Genome Research Institute (Yale Mendelian Genomics Center - UM1HG006504, U01HG007672); National Institute of Mental Health (K01MH098126, R01MH097971, R01MH099216, RC2MH089915); National Institute of Diabetes and Digestive and Kidney Diseases (R01DK080099); National Institute of Allergy and Infectious Diseases (Division of Intramural Research, 1R56A1098588-01A1); National Institute of Allergy and Infectious Diseases Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (UM1AI100645, U19AI067854); National Center for Advancing Translational Sciences (UL1TR000040); Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD048805); the Ellison Medical Foundation New Scholar award AG-NS-0441-08; the Duke Chancellor's Discovery Program Research Fund 2014; Neil Molberger Brain Research Fund; Endocrine Fellows Foundation Grant; Bill and Melinda Gates Foundation; The Murdock Study Community Registry and Biorepository; The Stanley Institute for Cognitive Genomics at Cold Spring Harbor Laboratory; the Duke Genome Sequencing Clinic; New York-Presbyterian Hospital; Columbia University College Physicians and Surgeons; Columbia University Medical Center; The J. Willard and Alice S. Marriott Foundation; The Muscular Dystrophy Association; The Nicholas Nunno Foundation; The JDM Fund for Mitochondrial Research; The Arturo Estopinan TK2 Research Fund; and The Endocrine Fellows Foundation; Helaine B Allen and Emily Allen Wolff. Data collection and sharing for the WHICAP project (used as controls in this analysis) was supported by the Washington Heights-Inwood Columbia Aging Project (WHICAP, PO1AG07232, R01AG037212, RF1AG054023) funded by the National Institute on Aging (NIA) and by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant Number UL1TR001873. This manuscript has been reviewed by WHICAP investigators for scientific content and consistency of data interpretation with previous WHICAP Study publications. We acknowledge the WHICAP study participants and the WHICAP research and support staff for their contributions to this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.