Whole-exome sequencing studies utilizing samples from the Simons Simplex Collection and other autism cohorts have identified multiple variants in SCN2A, a gene encoding a neuronal voltage-gated sodium channel (Na_v1.2) previously associated with a range of neurodevelopmental disorders that typically feature epilepsy or epileptic encephalopathy. Approximately half of these SCN2A variants are predicted to truncate the encoded protein and are likely loss of function. The other variants are nonsynonymous, and it’s not possible to reliably predict their functional consequences. Some nonsynonymous variants may, in fact, be benign variants without relevance to the associated neurodevelopmental condition. Distinguishing benign from truly pathogenic variants is an ongoing challenge.

The goal of this study is to elucidate the functional consequences of a large set of SCN2A variants of unknown clinical significance associated with neurodevelopmental disorders including autism, intellectual disability and epileptic encephalopathy. Alfred George’s team will use a novel, automated electrophysiological platform capable of making hundreds of measurements per day to test the hypothesis that functional analyses of SCN2A variants will discriminate groups with or without functional defects and enable better assessment of pathogenicity. George hypothesizes that a systematic experimental approach to annotate the functional consequence of SCN2A variants will help discriminate pathogenic from non-pathogenic variants and reveal molecular defects underlying autism, epilepsy and related SCN2A-associated disorders. These experimental data will enable evaluations of in silico variant annotation algorithms to determine if any can accurately predict dysfunction caused by variants in this gene.

This work will also further the elucidation of important genotype-molecular phenotype correlations and provide new information regarding the molecular mechanisms contributing to the pathogenesis of neurodevelopmental disorders. Results from these studies could also validate sodium channels as potential therapeutic targets in a subset of cases. George expects that these experiments will provide the basis for future studies funded by the National Institutes of Health or other sponsors, utilizing transgenic animals with which electrophysiological and behavioral tests can be used to investigate neurodevelopmental phenotypes.