Relevance to Autism

A de novo missense variant in the SLC6A1 gene was identified in an ASD proband from the Simons Simplex Collection (Sanders et al., 2012). This same variant was recently found in two patients (a mother and her female offspring) presenting with myoclonic atonic epilepsy (Carvill et al., 2015). Additional de novo variants in SLC6A1 were identified in patients with myoclonic atonic epilepsy in this report, many of whom also presented with autistic features. This gene was identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of <0.1 (Sanders et al., 2015). Four de novo missense variants that were predicted to be deleterious (defined as having an MPC score 2) were identified in the SLC6A1 gene in ASD probands from the Autism Sequencing Consortium in Satterstrom et al., 2020; subsequent TADA analysis of de novo variants from the Simons Simplex Collection and the Autism Sequencing Consortium and protein-truncating variants from iPSYCH in this report identified SLC6A1 as a candidate gene with a false discovery rate (FDR) 0.01. A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified SLC6A1 as a gene reaching exome-wide significance (P < 2.5E-06). Phenotypic evaluation of 34 individuals (30 novel, 4 previously published) with SLC6A1 mutations in Johannesen et al., 2018 demonstrated that impaired cognitive development (intellectual disability or learning disability) and epilepsy were the most common phenotypes; in addition, behavioral problems were frequently observed in individuals in this study, with eight patients presenting with ASD or autistic features. Mermer et al., 2021 experimentally assessed twenty-two SLC6A1 variants identified in patients with a broad spectrum of phenotypes, including SLC6A1 missense variants identified in ASD probands, and found that partial or complete loss of function (characterized by reduced GABA uptake and surface expression) was a common disease mechanism regardless of disease phenotype.

Molecular Function

The SLC6A1 gene encodes a gamma-aminobutyric acid (GABA) transporter, which removes GABA from the synaptic cleft.

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References

Model Summary

Slc6a1 null mice have impaired learning and memory of contextual fear conditioning, spatial learning that correlates with reduced theta burst stimulation induced LTP in the hippocampus.

References