De novo and inherited private variants in MAP1B in periventricular nodular heterotopia

PLoS Genet. 2018 May 8;14(5):e1007281. doi: 10.1371/journal.pgen.1007281.

Erin L Heinzen ¹, Adam C O'Neill ², Xiaolin Zhu ¹, Andrew S Allen ³ ⁴, Melanie Bahlo ⁵ ⁶, Jamel Chelly ⁷ ⁸, Ming Hui Chen ⁹, William B Dobyns ¹⁰ ¹¹, Saskia Freytag ¹², Renzo Guerrini ¹³, Richard J Leventer ¹⁴ ¹⁵ ¹⁶, Annapurna Poduri ¹⁷, Stephen P Robertson ², Christopher A Walsh ¹⁸ ¹⁹ ²⁰, Mengqi Zhang ⁴ ²¹, Epi4K Consortium, Epilepsy Phenome/Genome Project

Affiliations

1 Institute for Genomic Medicine, Columbia University Medical Center, New York, New York, United States of America.
2 Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
3 Center for Statistical Genetics and Genomics, Duke University Medical Center, Durham, North Carolina, United States of America.
4 Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina, United States of America.
5 Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
6 Department of Medical Biology, School of Mathematics and Statistics, University of Melbourne, Parkville, Victoria, Australia.
7 Pôle de Biologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
8 IGBMC, INSERM U964, CNRS UMR 7104, Université de Strasbourg, Illkirch, France.
9 Department of Cardiology and Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, United States of America.
10 Departments of Pediatrics and Neurology, University of Washington, Seattle, Washington, United States of America.
11 Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, United States of America.
12 Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
13 Neuroscience Department, Children's Hospital Anna Meyer-University of Florence, Florence, Italy.
14 Department of Neurology Royal Children's Hospital, University of Melbourne, Parkville, Victoria, Australia.
15 Murdoch Children's Research Institute, University of Melbourne, Parkville, Victoria, Australia.
16 Department of Pediatrics, University of Melbourne, Parkville, Victoria, Australia.
17 Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, Massachusetts, United States of America.
18 Division of Genetics and Genomics, Manton Center for Orphan Disease Research and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, Massachusetts, United States of America.
19 Departments of Pediatrics and Neurology, Harvard Medical School, Boston, Massachusetts, United States of America.
20 Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
21 Program in Computational Biology and Bioinformatics, Duke University, Durham, NC, United States of America.

PMID: 29738522 DOI: 10.1371/journal.pgen.1007281

Abstract

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 ultra-rare 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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