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

Heinzen, EL; O&#39;Neill, AC; Zhu, X; Allen, AS; Bahlo, M; Chelly, J; Dobyns, WB; Freytag, S; Guerrini, R; Leventer, RJ; Poduri, A; Robertson, SP; Walsh, CA; Zhang, M; Epi, KConsortium; Epilepsy Phenome/Genome, Project

Author(s): Heinzen, EL; O'Neill, AC; Zhu, X; Allen, AS; Bahlo, M; Chelly, J; Dobyns, WB; Freytag, S; Guerrini, R; Leventer, RJ; Poduri, A; Robertson, SP; Walsh, CA; Zhang, M; Epi, KConsortium; Epilepsy Phenome/Genome, Project;
Details: Publication Year 2018-05-08,Volume 14,Issue #5,Page e1007281
Journal Title: PLoS Genetics
Publication Type: Journal Article
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.
Publisher: PLOS
Research Division(s): Population Health And Immunity
PubMed ID: 29738522
Publisher's Version: https://doi.org/10.1371/journal.pgen.1007281
Open Access at Publisher's Site: https://doi.org/10.1371/journal.pgen.1007281
NHMRC Grants: NHMRC/1054618,
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2018-05-18 09:33:26

Last Modified: 2018-06-27 09:43:44