Molecular characteristics and pathogenic mechanisms
Pathogenic SCN2A variants are found throughout the gene. Missense, nonsense and frameshift variants are all reported.
Study of the most common recurrent missense variants (including Arg853Gln and Arg1882Gln) show a genotype-phenotype correlation. That is, the phenotype associated with these variants is consistent between affected individuals (e.g. Arg853Gln is associated with a mid-late infancy-onset phenotype and Arg1882Gln with a neonatal/early-infantile phenotype).
Further, biophysical analysis of mutant channels using voltage clamp and dynamic clamp modelling show that the functional impact of the pathogenic variants appears to correlate with the distinct clinical phenotypes, and suggests that the biophysical consequences of the variant are a major determinant of the clinical phenotype. Although study of additional variants is required to confirm this apparent genotype-phenotype correlation, evidence to date would support the hypothesis that different SCN2A phenotypes are distinct disorders (and may therefore require different treatments), rather than one condition with variable presentation.
The neonatal-infantile phenotypes are due to missense variants that appear to cause a gain-of-function (GOF) of the Nav1.2 channel and an associated increase in neuronal firing. The degree of increased neuronal firing was greater in the severe neonatal-infantile phenotype (eg due to Arg1882Gln mutation) than the milder BFNIS phenotype (e.g. due to Leu1563Val mutation). GOF is similarly reported with some EA-associated variants. These biophysical changes may explain the reported benefit of sodium channel blockers (SCBs) in these phenotypes.
In contrast, loss-of-function (LOF) of the Nav1.2 channel and reduced neuronal firing is reported in the mid-infancy onset phenotype. LOF of the Nav1.2 channel is also reported in the ID/ASD phenotype (without seizures). Missense variants are seen in the mid-infancy onset phenotype, whereas the ID/ASD phenotype can be caused by missense or nonsense/frameshift mutations. At this point, it is not known whether the type or degree of LOF of the Nav1.2 channel differs between variants causing these two phenotypes.
Diagnostic testing
Diagnosis is most commonly made with genomic testing such as a gene panel or whole exome sequencing as phenotypic features of SCN2A-related disorders overlap with those of other genetic aetiologies.
There are a number of differential diagnoses for each SCN2A phenotype, including:
- BFNIS: KCNQ2, KCNQ3, PRRT2 genes (KCNQ2/3 typically have seizure onset in the neonatal period and PRRT2 in infancy, SCN2A can present at either time point).
- Severe and intermediate neonatal/early-infantile phenotypes: KCNQ2 (main differential diagnosis), KCNT1, SCN8A, others.
- Mid-late infancy-onset phenotype: there are over 200 aetiologies reported for epilepsies presenting as West syndrome. Important ‘genetic’ (non-structural, non-metabolic) causes include STXBP1, CDKL5 and ARX.
- Episodic ataxia: KCNA1, CACNA1A, KCNA2, others.