Journal
PLOS GENETICS
Volume 14, Issue 5, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1007281
Keywords
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Categories
Funding
- National Institute of Neurological Disorders and Stroke [NS053998, NS077274, NS077303, NS077364, NS077276, RC2NS070344, RC2MH089915, U01NS077303, U01NS053998, U54NS078059, P01HD080642]
- Curekids NZ
- Health Research Council of NZ [14/200]
- European Union through the Seventh Framework Programme (FP7) under the project DESIRE [N602531]
- NINDS [K23NS069784, RO1 NS 35129]
- Boston Children's Hospital Translational Research Program
- Melbourne Childrens Clinician Scientist Fellowship
- Victorian Government's Operational Infrastructure Support Program
- Australian Government NHMRC IRIIS
- NHMRC [110297, 1054618, GNT1032364]
- Biogen, Inc.
- Gilead Sciences, Inc.
- UCB
- Bryan ADRC NIA [P30AG028377]
- B57 SAIC-Fredrick Inc [M11-074]
- National Human Genome Research Institute [UM1HG006504, U01HG007672]
- National Institute of Mental Health [RC2MH089915, K01MH098126, R01MH097971, R01MH099216]
- National Institute of Diabetes and Digestive and Kidney Diseases [R01DK080099]
- National Institute of Allergy and Infectious Diseases [1R56AI098588-01A1]
- 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]
- Ellison Medical Foundation New Scholar award [AG-NS-0441-08]
- Duke Chancellor's Discovery Program Research Fund 2014
- Neil Molberger Brain Research Fund
- Endocrine Fellows Foundation Grant
- Bill and Melinda Gates Foundation
- Murdock Study Community Registry and Biorepository
- Stanley Institute for Cognitive Genomics at Cold Spring Harbor Laboratory
- Duke Genome Sequencing Clinic
- New York-Presbyterian Hospital
- Columbia University College Physicians and Surgeons
- Columbia University Medical Center
- J. Willard and Alice S. Marriott Foundation
- Muscular Dystrophy Association
- Nicholas Nunno Foundation
- JDM Fund for Mitochondrial Research
- Arturo Estopinan TK2 Research Fund
- Endocrine Fellows Foundation
- Washington Heights-Inwood Columbia Aging Project (WHICAP) - National Institute on Aging (NIA) [P01AG07232, R01AG037212, RF1AG054023]
- National Center for Advancing Translational Sciences, National Institutes of Health [UL1TR001873]
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Periventricular nodular heterotopia (PVNH) is a malformation of cortical development commonly associated with epilepsy. We exome sequenced 202 individuals with sporadic PVNH to identify novel genetic risk loci. We first performed a trio-based analysis and identified 219 de novo variants. Although no novel genes were implicated in this initial analysis, PVNH cases were found overall to have a significant excess of nonsynonymous de novo variants in intolerant genes (p = 3.27x10(-7)), suggesting a role for rare new alleles in genes yet to be associated with the condition. Using a gene-level collapsing analysis comparing cases and controls, we identified a genome-wide significant signal driven by four ultrarare loss-of-function heterozygous variants in MAP1B, including one de novo variant. In at least one instance, the MAP1B variant was inherited from a parent with previously undiagnosed PVNH. The PVNH was frontally predominant and associated with perisylvian polymicrogyria. These results implicate MAP1B in PVNH. More broadly, our findings suggest that detrimental mutations likely arising in immediately preceding generations with incomplete penetrance may also be responsible for some apparently sporadic diseases.
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