Opposing Effects on NaV1.2 Function Underlie Differences Between SCN2A Variants Observed in Individuals with Autism Spectrum Disorder or Infantile Seizures
Objectives: 1) To perform a literature search of SCN2A mutations and to assess genotype-phenotype correlations. 2) To characterize the missense mutations observed in ASD electro-physiologically.
Methods: To assess the allelic spectrum of SCN2A mutations, genotypes and phenotypes were collated from all papers with SCN2A in their title or abstract and all large exome studies (>50 cases) in neuropsychiatric disorders. Electrophysiological assessment was performed for all missense variants observed in the Simons Simplex Collection or Autism Sequencing Consortium using voltage-clamp recordings from HEK293 cells.
Results: The literature review revealed 117 unique SCN2A variants in 148 families. The 118 families with sufficient phenotypic data clustered in four phenotypic groups: 20 variants in families with benign infantile familial seizures (BIFS); 8 variants in individuals with infantile seizures and mild developmental delay; 51 variants in individuals with epileptic encephalopathy (EE) characterized by infantile seizures and moderate to severe developmental delay; and 39 variants in individuals with a developmental disorder characterized by ASD and/or intellectual disability. Of note, loss of function variants were only observed in this last category. Electrophysiology analysis shows that all loss of function variants completely prevent sodium conductance, as do five of the eight missense variants in ASD. The remaining three missense variants altered channel function in three different ways, all of which reduced neuronal excitability in pyramidal cell simulations to the same degree of loss of function variants. In contrast, variants associated with infantile seizures increased neuronal excitability.
Conclusions: While SCN2A variants in infantile seizures lead to gain of function in NaV1.2, ASD variants lead to loss of function. Numerous genetic loci associated with neuropsychiatric disorders are observed across a range of diagnoses including developmental delay, ASD, and schizophrenia. Here, we show that functional analysis of apparently similar SCN2A missense mutations can distinguish two neuropsychiatric phenotypes: infantile seizures and ASD/developmental delay. This observation suggests that distinct neurobiological processes relating to specific neuropsychiatric disorders may be characterized through the investigation of single gene mutations, the first such example to our knowledge.
These data allow us to revise our estimate of the contribution of SCN2A mutations to ASD risk. We observe SCN2A mutations in 0.29% of ASD cases, a figure marginally higher than that for CHD8 (0.24%), making SCN2A the gene with the strongest evidence for ASD-association based on exome analysis and second only to Fragile X Syndrome as a single gene cause of ASD.
Examination of the neurobiology consequent to SCN2A haploinsufficiency, alongside parallel analysis of genes related to chromatin regulation, synaptic structure, and Fragile X Syndrome, is likely to provide critical insights into the etiology of ASD.
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