SCN2A-related disorders are caused by pathogenic variants in the SCN2A gene on chromosome 2. The SCN2A gene encodes the sodium ion channel subunit protein Nav1.2, which is important for the movement of sodium ions across the cell membrane. Nav1.2 is expressed predominantly in the central nervous system, where it has a major role in the generation of action potentials. It is the main sodium channel in excitatory neurons in early life, before this role is assumed by the Nav1.6 protein (encoded by the SCN8A gene) in late infancy or early childhood. SCN2A-related disorders belong to a group of conditions that impact on ion channel function, collectively known as channelopathies.
Pathogenic variants in the SCN2A gene cause a number of neurodevelopmental disorders, with a broad spectrum of severity. Epilepsy, DD/ID, ASD and movement disorders are the most frequent, albeit not universal, symptoms. There are distinct patterns of clinical features (phenotypes), broadly distinguished by the absence or presence of epilepsy, and by the epilepsy type.
SCN2A is estimated to be the most common single gene cause of neurodevelopmental disorders, and is a major cause of severe epilepsy (also known as developmental and epileptic encephalopathy (DEE)). The incidence of SCN2A-related disorders was reported to be 1:78,000, although this is likely an underestimate.
SCN2A-related disorders are autosomal dominant. Most commonly pathogenic variants either arise de novo (occur spontaneously during early development in an affected individual) or are inherited from an affected parent.
Inherited variants are primarily seen in the context of the SCN2A phenotypes of benign familial neonatal-infantile seizures (BFNIS) and episodic ataxia (EA) (see the Professionals – Clinical characteristics section for discussion of phenotypes).
Other SCN2A-related phenotypes are generally due to de novo variants in the proband. However, inheritance from an unaffected or mildly affected parent who has mosaicism for the variant has been reported. Parental mosaicism may be more common than previously thought; a recent study of epileptic encephalopathies (Myers et al. 2018) found that low level parental somatic mosaicism could be detected with very sensitive genetic testing technology in 8% of families where it was previously thought the proband had a de novo variant. Recurrence in a sibling in the absence of detection of the variant in any tested parental somatic tissue has also been reported, which is thought to be due to confined gonadal mosaicism (presence of the variant in a patch of eggs or sperm but not in other body cells).
Genetic counselling is recommended for parents of a child with a SCN2A-related disorder who may be planning further children. The detection of parental somatic mosaicism and the possibility of gonadal mosaicism has important genetic counselling implications.