Neurodevelopmental phenotypes associated with pathogenic variants in SLC6A1

Abstract

BackgroundSLC6A1 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.MethodsMedical 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.ResultsWe 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.ConclusionPathogenic 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.

Molecular and Clinical Repercussions of GABA Transporter 1 Variants Gone Amiss: Links to Epilepsy and Developmental Spectrum Disorders

“…Over recent years, a compendium of SLC6A1 mutations ( Figure 1 ) have been associated with a range of neurodevelopmental disorders, including autism, variable degrees of ID and a spectrum of epilepsy syndromes ( Table 1 ) ( Carvill et al, 2015 ; Johannesen et al, 2018 ; Mattison et al, 2018 ; Goodspeed et al, 2020 ; Kahen et al, 2021 ). Point mutations in SLC6A1 were first identified in patients suffering from epilepsy with myoclonic-atonic seizures (also known as Doose syndrome) ( Carvill et al, 2015 ).…”

“…Soon after, SLC6A1 variants were also reported in individuals afflicted with other forms of generalized epilepsies (e.g., childhood absence epilepsy) as well as in some patients with focal epilepsies (e.g., temporal lobe epilepsy) ( Johannesen et al, 2018 ). Detailed data on seizure semiology revealed that absence, atonic and myoclonic seizures are the most frequently observed seizure types ( Johannesen et al, 2018 ; Goodspeed et al, 2020 ; Kahen et al, 2021 ).…”

GenIDA: an international participatory database to gain knowledge on health issues related to genetic forms of neurodevelopmental disorders

“…Primarily aimed at English speakers, it currently offers study participation in Spanish, French and Dutch. For instance, the neurobehavioural phenotype of 28 individuals with de novo pathogenic/likely pathogenic variants in SLC6A1 was recently refined (Kahen et al 2021 ). If the types and frequency of clinical features reported (including hypotonia, ID/developmental delay, language disorder/speech delay, seizures, ASD, high pain tolerance, and sleep issues) are consistent with previous observations, it was also possible to clarify the strengths and weaknesses of these patients, and more specifically the specific areas of relative strength (socialisation and life skills) and weakness (communication and motor skills) by means of standardised behavioural measures (Vineland Adaptive Behaviour Scales—VABS, Child Behavior Checklist).…”

Clinical, neuroimaging and molecular characteristics ofPPP2R5D-related neurodevelopmental disorders: an expanded series with functional characterisation and genotype–phenotype analysis

“…Data on participant phenotypes are available from the PPP2R5D Simons Searchlight Single Gene Dataset V.7. Standardised medical history interviews were performed by telephone with certified genetic counsellors using previously published methods 33 . PPP2R5D genetic variants were identified through clinical exome sequencing or multigene panel sequencing for intellectual disability (ID), developmental delay (DD), autism spectrum disorder (ASD), and clinical genetic test reports were reviewed and verified through Simons Searchlight.…”