RT Journal Article SR Electronic T1 Neurodevelopmental phenotypes associated with pathogenic variants in SLC6A1 JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP jmedgenet-2021-107694 DO 10.1136/jmedgenet-2021-107694 A1 Ashley Kahen A1 Haluk Kavus A1 Alexa Geltzeiler A1 Catherine Kentros A1 Cora Taylor A1 Elizabeth Brooks A1 LeeAnne Green Snyder A1 Wendy Chung YR 2021 UL http://jmg.bmj.com/content/early/2021/05/18/jmedgenet-2021-107694.abstract AB Background SLC6A1 encodes GAT-1, a major gamma-aminobutyric acid (GABA) transporter in the brain. GAT-1 maintains neurotransmitter homeostasis by removing excess GABA from the synaptic cleft. Pathogenic variants in SLC6A1 disrupt the reuptake of GABA and are associated with a neurobehavioural phenotype.Methods Medical history interviews, seizure surveys, Vineland Adaptive Behavior Scales Second Edition and other behavioural surveys were completed by primary care givers of 28 participants in Simons Searchlight. All participants underwent clinical whole exome sequencing or gene panel sequencing. Additional cases from the medical literature with comparable data were included.Results We identified 28 individuals with largely de novo pathogenic/likely pathogenic variants including missense (15/21 or 71%) and truncating variants (6/21 or 29%). Missense variants were largely clustered around the sixth and seventh transmembrane domains, which functions as a GABA binding pocket. The phenotype of individuals with pathogenic variants in SLC6A1 includes hypotonia, intellectual disability/developmental delay, language disorder/speech delay, autism spectrum disorder, sleep issues and seizures.Conclusion Pathogenic variants in SLC6A1 are associated with a clinical phenotype of developmental delay, behaviour problems and seizures. Understanding of the genotype–phenotype correlation within SLC6A1 may provide opportunities to develop new treatments for GABA-related conditions.All data relevant to the study are included in the article or uploaded as online supplemental information. Our research is based on deidentified participant data from the Simons Searchlight. All data relevant to the study are included in the article or uploaded as online supplemental information and can be obtained on request (https://base.sfari.org). Reuse of the data is permitted on submission of a data request.