Abstracts

Rationale: Periventricular nodular heterotopia (PVNH) is a malformation of cortical development where neurons fail to migrate properly from the lateral ventricles to the cerebral cortex. Seven loci have been implicated to date, but only about 25% of patients have a genetic diagnosis. In this study, we studied individuals with sporadic PVNH to identify novel genetic risk loci for PVNH.  Methods: We exome sequenced 202 trios with sporadic PVNH and performed two analyses. First, we searched for de novo and bi-allelic genotypes using a trio-based analysis. Second, we performed a gene-level case-control collapsing analysis of 196 probands (excluding six individuals sequenced from lymphoblastoid cell line DNA) and controls to look for enrichment of rare, putatively deleterious variants (inherited or de novo) within the protein-coding sequence of individual genes. Results: Other than FLNA harboring nine de novo variants, no other gene was found to have more than expected de novo variants in a cohort of this size after taking into account the size and mutability of the protein-coding sequence. PVNH cases were found overall to have a significant excess of nonsynonymous de novo variants in genes that rarely carry protein-altering genetic variation in the general population (p= 3.27x10-7), suggesting a role for de novo variants in genes not yet associated with the condition. This excess suggests that some of these de novo variants are disease-causing despite our inability to pinpoint these specific mutations in this small cohort. To further support this finding, a number of the de novo variants were located in genes that are co-expressed with other known PVNH genes.Using a gene-level collapsing analysis comparing cases and controls, we identified a genome-wide significant signal driven by four ultra-rare heterozygous variants in MAP1B, including one de novo variant. Three of the four patients with a MAP1B variant have bilateral anterior PVNH, and two of the four presented with perisylvian polymicrogyria. The pattern of PVNH is unique in that the nodules are small and frontal-predominant, unlike what is typically seen in FLNA-associated PVNH where the nodules are larger and maximal along the bodies of the lateral ventricles and the posterior, or infrasylvian PVNH in which the nodules are maximal along the atria and temporal horns. In one case, the MAP1B variant was inherited from a parent with previously undiagnosed and milder PVNH having the same bilateral anterior pattern with medial perisylvian and insular polymicrogyria. The transmitting parent for the two other PNVH probands with inherited variants reported no neurological disease and MRI imaging was not available. Conclusions: These results implicate MAP1B in PVNH. MAP1B, encoding microtubule associated protein 1B, is involved in regulating both microtubule and actin dynamics, processes important to neurodevelopment. More broadly, our findings suggest that detrimental mutations with incomplete penetrance, likely arising in immediately preceding generations, may also be responsible for some apparently sporadic diseases.  Funding: 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), and Curekids NZ and the Health Research Council of NZ 14/200.