Abstracts

Rationale:
SLC6A1-related neurodevelopmental disorder (NDD) is characterized by childhood onset epilepsy, mild to severe developmental delay and behavioral disorders including autism. SLC6A1 encodes for the GABA transporter protein type 1 (GAT1), a membrane protein responsible for GABA neurotransmitter reuptake from the synaptic cleft in inhibitory synapses. A complete or partial loss-of-function (LoF) of GAT1 is thought to be the primary underlying disease mechanism disrupting reuptake of GABA. Recent publications have helped provide further details regarding clinical features and genotype-phenotype correlations in this disorder. These efforts often require extensive collaborations at a multi-center level to collate relatively large amounts of data over a long period of time. Alternatively, de-identified digital registries such as Ciitizen (copyright), provide a relatively easily accessible platform for the availability of medical records from for delineating rare disease phenotypes. We review and characterize the clinical and genomic data for SLC6A1-related disorders through Ciitizen data registry.




Methods:
We reviewed de-identified patient data from a digital online database consisting of clinical and genetic data collected from medical records. Clinical phenotype for patients with Pathogenic (P) and Likely Pathogenic (LP) variants were evaluated by reviewing their neurodevelopmental, clinical neurological, neurobehavioral and epilepsy phenotypes.




Results:
A total of n=47 patients(females=30;males=17) at a median age of 6 years with P/LP SLC6A1 variants were included. We observed a total of 33 missense, 4 splice, 6 frameshift, 2 nonsense and 2 deletions(whole gene/exon) variants(Fig1). The diagnosis of epilepsy was present in 24(51%), global developmental delay in 42(83%) and autism in 26(55%). Intellectual disability was diagnosed in 14(29%). Median age at seizure onset was 3.4 years(SD=1.89). Seizure types included absence in 19(40%), atonic in 10(21%) and myoclonic in 8(17%). Developmental regression was noted in 24(51%). Domains associated with developmental regression included fine motor(n=4; 8%), gross motor(n=7; 14%) and language(n=13; 27%). Both motor and language regression were noted in 5(10%). Most common neurobehavioral diagnoses in the cohort included autism in 24(51%), aggressive behavior in 19(40%) and ADHD in 14(29%). Clinical neurological abnormalities included hypotonia in 28(59%), hyporeflexia in 15 (31%), abnormal gait in 29(61%), and tremor in 12(25%). Other systems abnormalities included constipation in 22(46%) and sleep disturbance in 19(40%). Most common anti-seizure medications included Sodium Valproate in 24(51%), Ethosuximide in 13(27%), Lamotrigine in 15(32%) and Levetiracetam in 25(53%).




Conclusions: We describe clinical phenotype for patients with SLC6A1-related NDD from a de-identified digital data registry. The phenotypic spectrum consisted of generalized epilepsy, autism, developmental delay, intellectual disability and developmental regression, in concordance with previously described clinical features of this disorder. Our findings support the use of de-identified digital data registries for delineating phenotypic spectrum of rare diseases.

Funding: None