SLC6A1 variant pathogenicity, molecular function, and phenotype: a genetic and clinical analysis.
Arthur StefanskiEduardo Pérez-PalmaTobias BrüngerLudovica MontanucciCornelius GatiChiara KlöcknerKatrine Marie JohannesenKimberly GoodspeedMarie MacneeAlexander T DengÁngel Aledo-SerranoArtem BorovikovMaina KavaArjan M BoumanM J HajianpourDeb K PalMarc EngelenEveline E O HagebeukMarwan ShinawiAlexis R HeidlebaughKathryn OetjensTrevor L HoffmanPasquale StrianoAmanda S FreedLine FuttrupThomas BalslevAnna AbulíLeslie DanvoyeDamien LedererTugce BalciMaryam Nabavi NouriElizabeth ButlerSarah DrewesKalene van EngelenKatherine B HowellJean KhouryPatrick MayMarena TrinidadSteven FroelichJohannes R LemkeJacob TillerAmber N FreedJing Qiong KangArthur WusterRikke S MøllerDennis LalPublished in: Brain : a journal of neurology (2023)
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. 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. 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 vs. non-severe disease (P = 2.9e-3, 95% CI: 1.5 - 15.3). 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/).