Relevance to Autism

Recurrent mutations in the SCN2A gene have been identified in multiple individuals with ASD as described below. Rare ASD-associated variants in the SCN2A gene were initially identified in a study by Weiss and colleagues in 2003 based on exon screening in a region of linkage with autism (PMID 12610651). Sanders et al., 2012 subsequently reported 2 de novo loss-of-function (LoF) variants in SCN2A among 200 ASD families from the Simons Simplex Collection (PMID 22495306). A third de novo LoF variant in the SCN2A gene was identified in a simplex ASD case in Tavassoli et al., 2014; this variant was not observed in dbSNP or other genomic databases (PMID 24650168). A fourth de novo LoF variant in SCN2A was identified in a female ASD proband with intellectual disability in Jiang et al., 2013; this variant was not present in a female sibling with ASD but normal IQ (PMID 23849776). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified SCN2A as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified SCN2A as a gene reaching exome-wide significance (P < 2.5E-06). Functional analysis of ASD-associated de novo missense and likely gene disruptive SCN2A variants identified in probands from the Simons Simplex Collection and the Autism Sequencing Consortium using whole-cell voltage-clamp electrophysiology in Ben-Shalom et al., 2017 found that these variants dampened or eliminated channel function, consistent with a loss-of-function effect (PMID 28256214). Wolff et al., 2017 reported the phenotypes of 71 previously unpublished patients with SCN2A mutations; ASD was reported as a phenotype in 23 of these patients (PMID 28379373).

Molecular Function

voltage-gated ion channel essential for the generation and propagation of action potentials, chiefly in nerve and muscle.

External Links

References

Model Summary

Scn2a expression is, therefore, redundant for embryonic development but essential for postnatal survival.

References