SCN2A, encoding a brain sodium channel responsible for regulation of excitability, has emerged as a major single gene implicated in neurogenetic disorders. The spectrum of SCN2A conditions includes mild and severe forms of early or childhood-onset epilepsy, autism, intellectual disability and schizophrenia. Severe epilepsy is often combined with cognitive and behavioural impairments and these highly severe conditions are called developmental and epileptic encephalopathies (DEEs). Analyses of SCN2A variants suggests a correlation between the clinical presentation, the pharmacosensitivity and the functional impact measured in different disease models. Given the high phenotypic heterogeneity, the mechanisms underlying the SCN2A pathophysiology have not been fully unravelled.
In this study, we interrogated two of the most recurrent SCN2A variants detected in early (<2 weeks) and late (>3 months) onset DEE, respectively: R1882Q and R853Q. Patient-derived iPSC lines and the corresponding isogenic controls were differentiated using the NGN2 overexpression protocol to obtain cortical glutamatergic neurons. Electrophysiological properties and expression profile were assessed to identify any functional abnormality. The results suggest increased activity of R1882Q neurons and no significant changes for R853Q compared to the controls.
Overall, our data show the validity of a iPSC-derived in vitro model to investigate genetic epilepsies and subsequently to test/screen innovative therapies.