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genes in a large cohort of patients with nonsyndromic sporadic polymicrogyria and epilepsy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>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\u2010level collapsing analysis to identify de novo or inherited variants, including germline or mosaic (postzygotic) single nucleotide variants, small insertion\u2010deletion (indel) variants, and copy number variants present in leukocyte\u2010derived DNA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Across the cohort of 86 individuals with polymicrogyria and epilepsy, we identified seven with pathogenic or likely pathogenic variants in <jats:italic>PIK3R2<\/jats:italic>, including four germline and three mosaic variants. <jats:italic>PIK3R2<\/jats:italic> was the only gene harboring more than expected de novo variants across the entire cohort, and likewise the only gene that passed the genome\u2010wide threshold of significance in the gene\u2010level rare variant collapsing analysis. Consistent with previous reports, the <jats:italic>PIK3R2<\/jats:italic> phenotype consisted of bilateral polymicrogyria concentrated in the perisylvian region with macrocephaly. Beyond <jats:italic>PIK3R2<\/jats:italic>, we also identified one case each with likely causal de novo variants in <jats:italic>CCND2<\/jats:italic> and <jats:italic>DYNC1H1<\/jats:italic> and biallelic variants in <jats:italic>WDR62<\/jats:italic>, all genes previously associated with polymicrogyria. Candidate genetic explanations in this cohort included single nucleotide de novo variants in other epilepsy\u2010associated and neurodevelopmental disease\u2010associated genes (<jats:italic>SCN2A<\/jats:italic> in two individuals, <jats:italic>GRIA3<\/jats:italic>, <jats:italic>CACNA1C<\/jats:italic>) and a 597\u2010kb deletion at 15q25, a neurodevelopmental disease susceptibility locus.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>This study confirms germline and postzygotically acquired de novo variants in <jats:italic>PIK3R2<\/jats:italic> as an important cause of bilateral perisylvian polymicrogyria, notably with macrocephaly. In total, trio\u2010based WES identified a genetic diagnosis in 12% and a candidate diagnosis in 6% of our polymicrogyria cohort. Our results suggest possible roles for <jats:italic>SCN2A<\/jats:italic>, <jats:italic>GRIA3<\/jats:italic>, <jats:italic>CACNA1C<\/jats:italic>, 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.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.16854","type":"journal-article","created":{"date-parts":[[2021,4,5]],"date-time":"2021-04-05T09:58:25Z","timestamp":1617616705000},"page":"973-983","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Diverse genetic causes of polymicrogyria with epilepsy"],"prefix":"10.1111","volume":"62","author":[{"name":"Epilepsy Phenome\/Genome Project, Epi4K 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