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

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.
Author summary Almost 20 years ago the first gene responsible for periventricular nodular heterotopia (PVNH), a disorder that leads to abnormal migration of neurons during fetal brain development, was discovered. Since that time additional genes have been identified, but collectively they only explain a minority of cases. In this work we sought to further elucidate the genetic basis of this disorder using exome sequencing of 202 individuals with PVNH. We found a clear role for de novo mutations in PVNH, although with this analysis alone we were unable to pinpoint which of the de novo mutations in novel genes caused the disease. One patient was found to have a de novo variant in MAP1B, a gene that encodes a protein that plays a role at several key steps of brain development. With further analysis of the exome sequence data we found an additional three cases with a very rare inherited variant in MAP1B. This pattern is not expected to occur by chance and therefore indicates that these variants are likely responsible for the PVNH in these patients. Further strengthing the association of MAP1B in PVNH, all of the patients with a MAP1B variant had a similar brain abnormality, and at least one of the parents who transmitted the variant to their child was also similarly affected. This work adds to a growing list of genes responsible for PVNH, illuminates new genes involved in brain development, and importantly informs us about the types of genetic variants involved in PVNH.