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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Heinzen, EL; O'Neill, AC; Zhu, X; Allen, AS; Bahlo, M; Chelly, J; Chen, MH; Dobyns, WB; Freytag, S; Guerrini, R; Leventer, RJ; Poduri, A; Robertson, SP; Walsh, CA; Zhang, M; Epi4K Consortium, ; Epilepsy Phenome/Genome Project,

Published Date

  • May 2018

Published In

Volume / Issue

  • 14 / 5

Start / End Page

  • e1007281 -

PubMed ID

  • 29738522

Pubmed Central ID

  • PMC5965900

Electronic International Standard Serial Number (EISSN)

  • 1553-7404

Digital Object Identifier (DOI)

  • 10.1371/journal.pgen.1007281


  • eng

Conference Location

  • United States