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Author: search.filters.author.Arthur StefanskiSubject: search.filters.subject.epilepsy

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    <i>SLC6A1</i> variant pathogenicity, molecular function and phenotype: a genetic and clinical analysis
    (2023)
    Arthur Stefanski
    ;
    Eduardo Pérez-Palma
    ;
    Tobias Brünger
    ;
    Ludovica Montanucci
    ;
    Cornelius Gati
    <jats:title>Abstract</jats:title> <jats:p>Genetic variants in the SLC6A1 gene can cause a broad phenotypic disease spectrum by altering the protein function. Thus, systematically curated clinically relevant genotype-phenotype associations are needed to understand the disease mechanism and improve therapeutic decision-making.</jats:p> <jats:p>We aggregated genetic and clinical data from 172 individuals with likely pathogenic/pathogenic (lp/p) SLC6A1 variants and functional data for 184 variants (14.1% lp/p). Clinical and functional data were available for a subset of 126 individuals. We explored the potential associations of variant positions on the GAT1 3D structure with variant pathogenicity, altered molecular function and phenotype severity using bioinformatic approaches.</jats:p> <jats:p>The GAT1 transmembrane domains 1, 6 and extracellular loop 4 (EL4) were enriched for patient over population variants. Across functionally tested missense variants (n = 156), the spatial proximity from the ligand was associated with loss-of-function in the GAT1 transporter activity. For variants with complete loss of in vitro GABA uptake, we found a 4.6-fold enrichment in patients having severe disease versus non-severe disease (P = 2.9 × 10−3, 95% confidence interval: 1.5–15.3).</jats:p> <jats:p>In summary, we delineated associations between the 3D structure and variant pathogenicity, variant function and phenotype in SLC6A1-related disorders. This knowledge supports biology-informed variant interpretation and research on GAT1 function. All our data can be interactively explored in the SLC6A1 portal (https://slc6a1-portal.broadinstitute.org/).</jats:p>
    Scopus© Citations 3  3
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    Identification and quantification of oligogenic loss-of-function disorders
    (2022)
    Arthur Stefanski
    ;
    Eduardo Pérez-Palma
    ;
    Marko Mrdjen
    ;
    Megan McHugh
    ;
    Costin Leu
    Scopus© Citations 3  1
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    Incidence and prevalence of major epilepsy-associated brain lesions
    (2022)
    Javier A. López-Rivera
    ;
    Victoria Smuk
    ;
    Costin Leu
    ;
    Gaelle Nasr
    ;
    Deborah Vegh
    Scopus© Citations 15  1