TWO VARIANTS OF SLC6A1 ON AMINO ACID 451 (D451E AND D451G) ASSOCIATED WITH DEVELOPMENTAL DELAY AND EPILEPSY

Abstract

We present two case studies on the same allele and amino acid. The result of both variants is early onset of developmental delay and seizures. SLC6A1 is associated with an autosomal dominant early onset seizure and epileptic encephalopathy and intellectual disability. Genomic studies reported in ClinVar revealed two variants D451E and D451G. The amino acid substitution suggests that glycine would be predicted to be slightly more detrimental simply based on the physical differences between aspartic acid and glycine. Glutamic acid is similar to aspartic acid in structure and both are negatively charged amino acids. Structural and evolutionary assessments establish these variants represent a loss of function to the protein. Compiled metrics through custom tools on sequence, structure, and protein dynamics combined with PolyPhen2, Provean, SIFT, and Align-GVGD reveal these variants to rank in the top functional outcome changes relative to gnomAD, TOPMed, and ClinVar variants known to date. It is not known if these patients are resistant to multiple epileptic drugs; however, it has been noted that other variants in the same vicinity as these two respond better to valproic acid in controlling the seizures. This is consistent with additional groups studying SLC6A1 variants within patients.