< i > De novo < /i > and inherited private variants in < i > MAP1B < /i > in periventricular nodular heterotopia

by Erin L. Heinzen, Adam C. O'Neill, Xiaolin Zhu, Andrew S. Allen, Melanie Bahlo, Jamel Chelly, William B. Dobyns, Saskia Freytag, Renzo Guerrini, Richard J. Leventer, Annapurna Poduri, Stephen P. Robertson, Christopher A. Walsh, Mengqi Zhang, for the Epi4K Consortium , Epilepsy Phenome/Genome Project

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 219de novo variants. Although no novel genes were implicated in this initial analysis, PVNH cases were found overall to have a significant excess of nonsynonymousde 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 inMAP1B, including onede novo variant. In at least one instance, theMAP1B variant was inherited from a parent with previously undiagnosed PVNH. The PVNH was frontally predominant and associated with perisylvian polymicrogyria. These results implicateMAP1B 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 appa...

Source: PLoS Genetics - May 8, 2018 Category: Genetics & Stem Cells Authors: Erin L. Heinzen Source Type: research