Dataset Information

Role of the phosphoinositide phosphatase FIG4 gene in familial epilepsy with polymicrogyria.

ABSTRACT:

Objective

The aim of this study was to identify the causal gene in a consanguineous Moroccan family with temporo-occipital polymicrogyria, psychiatric manifestations, and epilepsy, previously mapped to the 6q16-q22 region.

Methods

We used exome sequencing and analyzed candidate variants in the 6q16-q22 locus, as well as a rescue assay in Fig4-null mouse fibroblasts and immunohistochemistry of Fig4-null mouse brains.

Results

A homozygous missense mutation (p.Asp783Val) in the phosphoinositide phosphatase gene FIG4 was identified. Pathogenicity of the variant was supported by impaired rescue of the enlarged vacuoles in transfected fibroblasts from Fig4-deficient mice. Histologic examination of Fig4-null mouse brain revealed neurodevelopmental impairment in the hippocampus, cortex, and cerebellum as well as impaired cerebellar gyration/foliation reminiscent of human cortical malformations.

Conclusions

This study extends the spectrum of phenotypes associated with FIG4 mutations to include cortical malformation associated with seizures and psychiatric manifestations, in addition to the previously described Charcot-Marie-Tooth disease type 4J and Yunis-Varón syndrome.

SUBMITTER: Baulac S

PROVIDER: S-EPMC3962989 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Publications

Role of the phosphoinositide phosphatase FIG4 gene in familial epilepsy with polymicrogyria.

Baulac Stéphanie S Lenk Guy M GM Dufresnois Béatrice B Ouled Amar Bencheikh Bouchra B Couarch Philippe P Renard Julie J Larson Peter A PA Ferguson Cole J CJ Noé Eric E Poirier Karine K Hubans Christine C Ferreira Stéphanie S Guerrini Renzo R Ouazzani Reda R El Hachimi Khalid Hamid KH Meisler Miriam H MH Leguern Eric E

Neurology 20140305 12

<h4>Objective</h4>The aim of this study was to identify the causal gene in a consanguineous Moroccan family with temporo-occipital polymicrogyria, psychiatric manifestations, and epilepsy, previously mapped to the 6q16-q22 region.<h4>Methods</h4>We used exome sequencing and analyzed candidate variants in the 6q16-q22 locus, as well as a rescue assay in Fig4-null mouse fibroblasts and immunohistochemistry of Fig4-null mouse brains.<h4>Results</h4>A homozygous missense mutation (p.Asp783Val) in th ...[more]

PMID: 24598713

Similar Datasets

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.

Dataset Information

Role of the phosphoinositide phosphatase FIG4 gene in familial epilepsy with polymicrogyria.

Objective

Methods

Results

Conclusions

Publications

Role of the phosphoinositide phosphatase FIG4 gene in familial epilepsy with polymicrogyria.

Similar Datasets

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