TY - JOUR
T1 - SLC6A1 variant pathogenicity, molecular function and phenotype: a genetic and clinical analysis.
T2 - a genetic and clinical analysis
AU - Stefanski, Arthur
AU - Pérez-Palma, Eduardo
AU - Brünger, Tobias
AU - Montanucci, Ludovica
AU - Gati, Cornelius
AU - Klöckner, Chiara
AU - Johannesen, Katrine M.
AU - Goodspeed, Kimberly
AU - Macnee, Marie
AU - Deng, Alexander T.
AU - Aledo-Serrano, Ángel
AU - Borovikov, Artem
AU - Kava, Maina
AU - Bouman, Arjan M.
AU - Hajianpour, M. J.
AU - Pal, Deb K.
AU - Engelen, Marc
AU - Hagebeuk, Eveline E.O.
AU - Shinawi, Marwan
AU - Heidlebaugh, Alexis R.
AU - Oetjens, Kathryn
AU - Hoffman, Trevor L.
AU - Striano, Pasquale
AU - Freed, Amanda S.
AU - Futtrup, Line
AU - Balslev, Thomas
AU - Abulí, Anna
AU - Danvoye, Leslie
AU - Lederer, Damien
AU - Balci, Tugce
AU - Nouri, Maryam Nabavi
AU - Butler, Elizabeth
AU - Drewes, Sarah
AU - van Engelen, Kalene
AU - Howell, Katherine B.
AU - Khoury, Jean
AU - May, Patrick
AU - Trinidad, Marena
AU - Froelich, Steven
AU - Lemke, Johannes R.
AU - Tiller, Jacob
AU - Freed, Amber N.
AU - Kang, Jing Qiong
AU - Wuster, Arthur
AU - Møller, Rikke S.
AU - Lal, Dennis
N1 - Funding Information: D.L.’s work was supported by funds from the Dravet Syndrome Foundation (grant number, 272016), the BMBF (Treat-ION grant, 01GM1907), National Institute of Neurological Disorders and Stroke (Channelopathy-Associated Epilepsy Research Center, 5-U54-NS108874). E.P-P. is supported by Chilean National Agency for Investigation and Development, ANID Fondecyt grant 1221464 and the FamilieSCN2A foundation 2020 Action Potential Grant. P.M. received support by the BMBF (Treat-Ion2, 01GM2210B) and the Fonds National de la Recherche Luxembourg in Luxembourg (Research Unit FOR-2715, FNR grant NTER/DFG/21/16394868 MechEPI2). Publisher Copyright: © 2023 The Author(s). Published by Oxford University Press on behalf of the Guarantors of Brain.
PY - 2023/12/1
Y1 - 2023/12/1
N2 - 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 versus non-severe disease (P = 2.9 × 10-3, 95% confidence interval: 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/).
AB - 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 versus non-severe disease (P = 2.9 × 10-3, 95% confidence interval: 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/).
KW - SLC6A1
KW - autism
KW - epilepsy
KW - genetics
KW - neurodevelopmental disorder
UR - http://www.scopus.com/inward/record.url?scp=85169582892&partnerID=8YFLogxK
U2 - https://doi.org/10.1093/brain/awad292
DO - https://doi.org/10.1093/brain/awad292
M3 - Article
C2 - 37647852
SN - 0006-8950
VL - 146
SP - 5198
EP - 5208
JO - Brain
JF - Brain
IS - 12
ER -