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 536 OP 543 DO 10.1136/jmedgenet-2021-107694 VO 59 IS 6 A1 Kahen, Ashley A1 Kavus, Haluk A1 Geltzeiler, Alexa A1 Kentros, Catherine A1 Taylor, Cora A1 Brooks, Elizabeth A1 Green Snyder, LeeAnne A1 Chung, Wendy YR 2022 UL http://jmg.bmj.com/content/59/6/536.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.