De novo and inherited private variants in MAP1B in periventricular nodular heterotopia.
Fiche publication
Date publication
mai 2018
Journal
PLoS genetics
Auteurs
Membres identifiés du Cancéropôle Est :
Pr CHELLY Jamel
Tous les auteurs :
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, ,
Lien Pubmed
Résumé
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.
Mots clés
Brain, abnormalities, Female, Genetic Predisposition to Disease, genetics, Heterozygote, Humans, Loss of Function Mutation, Magnetic Resonance Imaging, Male, Microtubule-Associated Proteins, genetics, Periventricular Nodular Heterotopia, genetics, Whole Exome Sequencing, methods
Référence
PLoS Genet.. 2018 May 8;14(5):e1007281