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 Wolff et al., 2017 reported the phenotypes of 71 previously unpublished patients with SCN2A mutations; ASD was reported as a phenotype in 23 of these patients (PMID 28379373).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

para-VDRC104775 mutants showed increased embryonic lethality. para-VDRC6131 mutants showed no change in habituation.

References