Epilepsy Phenome/Genome Project, Epi4K Consortium
Researchers with the Epilepsy Phenome/Genome Project (EPGP) report the genetic findings of a large cohort of patients with polymicrogyria and epilepsy analyzed with a trio-based, genome-wide approach. Ten individuals had variants in known polymicrogyria-related genes PIK3R2, CCND2, DYNC1H1, and WDR62. In a gene level assessment of genome-wide enrichment of de novo variants and overall rare variant enrichment, PIK3R2, a gene previously implicated in polymicrogyria, was significantly associated with polymicrogyria. Although the genes CCND2, DYNC1H1, and WDR62 did not reach statistical significance for an association with polymicrogyria in the cohort-wide analysis, the authors considered the variants in these three genes pathogenic or likely pathogenic given in silico predictions, clinical phenotype, and the reported association with polymicrogyria in the literature.
The study findings support a role for clinical genetic testing for patients with polymicrogyria, particularly those with epilepsy. Specifically, this study suggests that germline or mosaic variants in PIK3R2, or related PI3K-AKT-mTOR pathway genes, may be clinically relevant to polymicrogyria with macrocephaly. As treatment trials emerge for neurodevelopmental disorders related to this pathway, a genetic diagnosis may provide the opportunity for patients with polymicrogyria to participate in clinical trials.
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