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SCN2A is one of top candidate genes strongly associated with autism. SCN2A encodes the neuronal voltage-gated sodium channel NaV1.2, a sodium channel isoform that is involved in the action potential initiation and propagation in a range of neuron classes.
Relevance to autism:
Over the last five years, whole exome sequencing has successfully identified over 50 genes associated with autism spectrum disorders. The gene SCN2A has the strongest evidence for association with autism with 8 de novo protein truncating variants and 12 de novo missense mutations in autism cohorts1,2,3. In addition, as of March 2018, total 193 genetic variations with various variant effect, transmission and familial structure of autism have been reported from 49 studies.
SCN2A exhibits strong genotype-phenotype correlation. SCN2A has also been associated with seizures in the first year of life, ranging from benign infantile familial seizures without obvious neuropsychiatric symptom to epileptic encephalopathy with long-term neurodevelopmental delay. In contrast, in autism, only 2 of the 20 cases have been reported to have seizures, and these occur after one year of age. Subsequently, replicated results, including ~80 variants, have been reported from the Canadian Epilepsy Network, East Asian cohort, and European clinics4,5,6.
Given the well-characterized electrophysiology of this gene, a study published Apr 2017 in Biological Psychiatry characterized the strong genotype-phenotype correlations associated with specific SCN2A mutations, and proposed different genetic etiology of the gene over a range of neurodevelopmental disorders7,8.
SCN2A is crucial for early neurodevelopment and has function implication in therapeutic intervention. From the animal study, SCN2A knockouts (Scn2a-/–) is perinatally lethal with severe hypoxia and massive neuronal apoptosis. In contrast, heterozygous deletion mice (Scn2a+/–) showed ~50 percent reductions for the level of Nav1.2 mRNA expression and sodium currents in hippocampal neurons9.