SCN2A, which encodes the alpha subunit of the neuronal voltage-gated sodium channel 1.2 (Na_v1.2), is a high-confidence risk gene for autism spectrum disorders (ASD). More than 70 SCN2A variants have been identified by exome and genome sequencing of ASD and intellectual disability (ID) probands. The functional consequences of most SCN2A variants identified by clinical sequencing and large-scale research studies are not known, and their contribution to the associated phenotypes remains unclear.

Alfred George’s laboratory has optimized a high-throughput experimental platform that exploits automated electrophysiological (patch clamp) recording for elucidating the functional consequences of SCN2A variants at an unprecedented scale. This work was funded in part by a previous SFARI Director Award.

In the current project, George and colleagues aim to determine the function of all SCN2A missense and small indel variants, as well as certain truncating variants, associated with ASD/ID that have been identified to date, as well as any new variants discovered within the funding period. They also plan to investigate the functional consequences of a limited set of rare population missense variants. In total, they plan to determine the functional consequences of up to 96 variants.

This work will leverage existing infrastructure and workflows that have been established for studying ion channel variants using automated patch clamp recording. The data generated by these studies will be curated using a new standardized functional ontology. Variant-specific functional information will be deposited in the public database ClinVar and appropriate SFARI databases for dissemination.

Results from this work will enable better categorization of variant pathogenicity, help to distinguish benign from disease-causing variants and contribute to elucidating the pathophysiological contribution of SCN2A dysfunction to risk of ASD/ID.