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Polymicrogyria-associated epilepsy: a multicenter phenotypic study from the Epilepsy Phenome/Genome Project.

ABSTRACT: Polymicrogyria (PMG) is an epileptogenic malformation of cortical development. We describe the clinical epilepsy and imaging features of a large cohort with PMG-related epilepsy.Participants were recruited through the Epilepsy Phenome/Genome Project, a multicenter collaborative effort to collect detailed phenotypic data on individuals with epilepsy. We reviewed phenotypic data from participants with epilepsy and PMG.We identified 87 participants, 43 female and 44 male, with PMG and epilepsy. Median age of seizure onset was 3 years (range <1 month to 37 years). Most presented with focal epilepsy (87.4%), some in combination with seizures generalized from onset (23.0%). Focal seizures with dyscognitive features were most common (54.3%). Of those presenting with generalized seizure types, infantile spasms were most prevalent (45.2%). The most common topographic pattern was perisylvian PMG (77.0%), of which the majority was bilateral (56.7%). Generalized PMG presented with an earlier age of seizure onset (median age of 8 months) and an increased prevalence of developmental delay prior to seizure onset (57.1%). Of the unilateral, and asymmetric bilateral groups where PMG was more involved in one hemisphere, the majority (71.4%) of participants had seizures that lateralized to the same hemisphere as the PMG or the hemisphere with greater involvement.Participants with PMG had both focal and generalized onset of seizures. Our data confirm the involvement of known topographic patterns of PMG and suggest that more extensive distributions of PMG present with an earlier age of seizure onset and increased prevalence of developmental delay prior to seizure onset.

SUBMITTER: Shain C

PROVIDER: S-EPMC3851304 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Polymicrogyria-associated epilepsy: a multicenter phenotypic study from the Epilepsy Phenome/Genome Project.

Shain Catherine C Ramgopal Sriram S Fallil Zianka Z Parulkar Isha I Alongi Richard R Knowlton Robert R Poduri Annapurna A

Epilepsia 20130610 8

<h4>Purpose</h4>Polymicrogyria (PMG) is an epileptogenic malformation of cortical development. We describe the clinical epilepsy and imaging features of a large cohort with PMG-related epilepsy.<h4>Methods</h4>Participants were recruited through the Epilepsy Phenome/Genome Project, a multicenter collaborative effort to collect detailed phenotypic data on individuals with epilepsy. We reviewed phenotypic data from participants with epilepsy and PMG.<h4>Key findings</h4>We identified 87 participan ...[more]

PMID: 23750890

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Project description:ObjectiveWe 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.MethodsWe 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.ResultsAcross 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.SignificanceThis 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.

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Dataset Information

Polymicrogyria-associated epilepsy: a multicenter phenotypic study from the Epilepsy Phenome/Genome Project.

Publications

Polymicrogyria-associated epilepsy: a multicenter phenotypic study from the Epilepsy Phenome/Genome Project.

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