SLC6A1 G443D associated with developmental delay and epilepsy

SLC6A1 is associated with an autosomal dominant early-onset seizure and epileptic encephalopathy associated with intellectual disability. We present a two-year-old girl with developmental delay and epilepsy, using a new computational filtering impact score to show the patients' variant ranks with other pathogenic variants. Genomic studies within the patient revealed a G443D variant of uncertain significance. Structural and evolutionary assessments establish this variant as a loss-of-function to the protein. Compiled metrics through our custom tools on sequence, structure, and protein dynamics combined with PolyPhen2, Provean, SIFT, and Align-GVGD reveal this variant to rank in the top functional outcome changes relative to gnomAD, TOPMed, and ClinVar variants known to date. The patient was resistant to multiple epileptic drugs, finally finding that valproic acid controls the seizures. This is consistent with additional groups studying SLC6A1 variants within patients.