SCN2A – SCN2A-Related Intellectual Disability

SCN2A encodes the voltage-gated sodium channel Nav1.2, which is critical for neuronal excitability. While SCN2A variants have been widely associated with epilepsy and autism spectrum disorder, multiple studies have demonstrated that heterozygous loss-of-function variants in SCN2A cause primary intellectual disability without seizures ([PMID:30813884]; [PMID:34247411]).

Inheritance is autosomal dominant, with most pathogenic variants arising de novo in affected individuals. In a cohort of 671 patients with intellectual disability only, two carried de novo SCN2A variants, a rate significantly higher than in developmental and epileptic encephalopathy cohorts (2/671 vs 0/830; pA (p.Trp1716Ter), c.2809C>T (p.Arg937Cys)) that produced no measurable current in heterologous cells ([PMID:30813884]).

Segregation data are limited by de novo occurrence; no additional affected relatives have been reported, consistent with fully penetrant, dominant-acting alleles.

The variant spectrum in intellectual disability consists predominantly of loss-of-function alleles, including frameshift, nonsense, and splice-site changes. No recurrent or founder variants have been reported in this cohort. Clinically, carrier frequency in outbred populations is extremely low (<0.001%), and intellectual disability manifests globally without early-onset seizures in these patients.

Functional assays using whole-cell patch-clamp in HEK293T cells uniformly show absence of Nav1.2 currents for truncating variants. Structural modeling supports disrupted channel folding and trafficking, consistent with a haploinsufficiency mechanism ([PMID:30813884]; [PMID:34247411]).

No reports have disputed the role of SCN2A loss-of-function in intellectual disability. Alternative phenotypes such as benign familial neonatal-infantile seizures involve gain-of-function variants, underscoring phenotype specificity of variant classes.

Together, genetic and functional data establish a strong association between heterozygous SCN2A loss-of-function variants and autosomal dominant intellectual disability. Comprehensive SCN2A testing should be considered in unexplained intellectual disability, as identification of haploinsufficiency may inform prognosis and potential future therapies.

Key Take-home: SCN2A haploinsufficiency is a clinically actionable cause of autosomal dominant intellectual disability without seizures; targeted genetic testing enables accurate diagnosis and management.

References

• Developmental Medicine and Child Neurology | 2021 | Genetic convergence of developmental and epileptic encephalopathies and intellectual disability PMID:34247411
• Molecular Medicine (Cambridge, Mass.) | 2019 | Further corroboration of distinct functional features in SCN2A variants causing intellectual disability or epileptic phenotypes PMID:30813884
• Lancet (London, England) | 2012 | Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study PMID:23020937

Evidence Based Scoring (AI generated)