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.
Bibliographical noteFunding Information:
This work was supported by grants from the National Institute of Neurological Disorders and Stroke (The Epilepsy Phenome/Genome Project NS053998; Epi4K—Administrative Core NS077274; Epi4K—Sequencing, Biostatistics and Bioinformatics Core NS077303; Epi4K— Project 1 – Epileptic Encephalopathies NS077364, Epi4K—Phenotyping and Clinical Informatics Core NS077276), Curekids NZ and the Health Research Council of NZ 14/200, and the European Union through the Seventh Framework Programme (FP7) under the project DESIRE (N602531). AP was supported by NINDS K23NS069784 and the Boston Children’s Hospital Translational Research Program. RJL is supported by a Melbourne Childrens Clinician Scientist Fellowship.