Diverse genetic causes of polymicrogyria with epilepsy

Abstract

Objective: We sought to identify novel genes and to establish the contribution of known genes in a large cohort of patients with nonsyndromic sporadic polymicrogyria and epilepsy.

Methods: We enrolled participants with polymicrogyria and their parents through the Epilepsy Phenome/Genome Project. We performed phenotyping and whole exome sequencing (WES), trio analysis, and gene-level collapsing analysis to identify de novo or inherited variants, including germline or mosaic (postzygotic) single nucleotide variants, small insertion-deletion (indel) variants, and copy number variants present in leukocyte-derived DNA.

Results: Across the cohort of 86 individuals with polymicrogyria and epilepsy, we identified seven with pathogenic or likely pathogenic variants in PIK3R2, including four germline and three mosaic variants. PIK3R2 was the only gene harboring more than expected de novo variants across the entire cohort, and likewise the only gene that passed the genome-wide threshold of significance in the gene-level rare variant collapsing analysis. Consistent with previous reports, the PIK3R2 phenotype consisted of bilateral polymicrogyria concentrated in the perisylvian region with macrocephaly. Beyond PIK3R2, we also identified one case each with likely causal de novo variants in CCND2 and DYNC1H1 and biallelic variants in WDR62, all genes previously associated with polymicrogyria. Candidate genetic explanations in this cohort included single nucleotide de novo variants in other epilepsy-associated and neurodevelopmental disease-associated genes (SCN2A in two individuals, GRIA3, CACNA1C) and a 597-kb deletion at 15q25, a neurodevelopmental disease susceptibility locus.

Significance: This study confirms germline and postzygotically acquired de novo variants in PIK3R2 as an important cause of bilateral perisylvian polymicrogyria, notably with macrocephaly. In total, trio-based WES identified a genetic diagnosis in 12% and a candidate diagnosis in 6% of our polymicrogyria cohort. Our results suggest possible roles for SCN2A, GRIA3, CACNA1C, and 15q25 deletion in polymicrogyria, each already associated with epilepsy or other neurodevelopmental conditions without brain malformations. The role of these genes in polymicrogyria will be further understood as more patients with polymicrogyria undergo genetic evaluation.

Keywords: de novo variant; epilepsy; exome sequencing; polymicrogyria; trio.

FIGURE 1

(A) Location of previously reported brain malformation variants in PIK3R2 are shown^,– in maroon above the protein diagram with the number of times the variant has been reported. Below the protein diagram are the variants identified in this study. Gray shading indicates the exon level intolerance score (LIMBR). Higher numbers indicate more tolerance to functional variation. Both previously reported and new cases are enriched in regions of lower tolerance. (B) Magnetic resonance images from PIK3R2 cases. VAF, variant allele frequency

FIGURE 2

Quantile-quantile plot for gene-level association tests interrogating ultrarare functional variants. Black dots represent transformed p values against the expected transformed p values for genes with qualifying variants. The red line indicates the expectation under the null model of no effect on risk

FIGURE 3

De novo 597-k b deletion at 15q25 in pmgnd33808qu1