Commonalities and distinctions between two neurodevelopmental disorder subtypes associated with SCN2A and SCN8A variants and literature review

• Published in: Molecular genetics & genomic medicine 2022-05, Vol.10 (5), p.e1911-n/a
• Main Authors: Mangano, Giuseppe Donato, Fontana, Antonina, Antona, Vincenzo, Salpietro, Vincenzo, Mangano, Giuseppa Renata, Giuffrè, Mario, Nardello, Rosaria
• Format: Article
• Language: English
• Subjects: Age; Autism; Autism Spectrum Disorder - genetics; autism spectrum disorders; Channels; Clinical Report; Clinical Reports; Convulsions & seizures; Disorders; EEG; Epilepsy; Epilepsy - genetics; Genetic diversity; Genetic variance; Genotype & phenotype; Humans; Intellectual disabilities; intellectual disability; Intellectual Disability - genetics; Literature reviews; Memory; Mutation; NAV1.2 Voltage-Gated Sodium Channel - genetics; NAV1.6 Voltage-Gated Sodium Channel - genetics; Neurodevelopmental disorders; Neurodevelopmental Disorders - genetics; Neuropsychology; Observational studies; Observational Studies as Topic; Patients; Phenotype; Phenotypes; SCN2A; SCN8A; Sodium channels (voltage-gated); Standard scores; whole‐exome sequencing
• ISSN: 2324-9269; 2324-9269
• DOI: 10.1002/mgg3.1911

This study was aimed to analyze the commonalities and distinctions of voltage‐gated sodium channels, Nav1.2, Nav1.6, in neurodevelopmental disorders. An observational study was performed including two patients with neurodevelopmental disorders. The demographic, electroclinical, genetic, and neuropsychological characteristics were analyzed and compared with each other and then with the subjects carrying the same genetic variants reported in the literature. The clinical features of one of them argued for autism spectrum disorder and developmental delay, the other for intellectual disability, diagnoses confirmed by the neuropsychological assessment. The first patient was a carrier of SCN2A (p.R379H) variant while the second was carrier of SCN8A (p.E936K) variant, both involving the pore loop of the two channels. The results of this study suggest that the neurodevelopmental disorders without overt epilepsy of both patients can be the consequences of loss of function of Nav1.2/Nav1.6 channels. Notably, the SCN2A variant, with an earlier expression timing in brain development, resulted in a more severe phenotype as autism spectrum disorder and developmental delay, while the SCN8A variant, with a later expression timing, resulted in a less severe phenotype as intellectual disability. The recent identification of variants of the genes encoding voltage‐gated sodium channels, leading to their loss of function, are broadening the phenotypic spectrum of these channelopathies. Increasing the number of recurrent variants can be an effective surrogate of functional examination. The genes encoding voltage‐gated sodium channels should now be included in the genetic panels for the diagnosis of neurodevelopmental disorders, notably the intellectual disability and autism spectrum disorder.