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Deep phenotyping of a patient with atypical Dravet syndrome revealed a new pathogenic variant putatively affecting splicing at the SCN2A gene

Febrile seizure-associated epileptic encephalopathy is a genetically heterogeneous group of diseases caused by pathogenic variants in the SCN1A, PCDH19, SCN2A, SCN8A, and other genes. The onset of the disease can vary from neonatal or early infancy to a later onset of epilepsy after 18 months of life. Some forms of genetically determined epilepsy have targeted therapies that may be the key to a correct diagnosis.

The paper presents clinical and molecular genetic data of a patient with epileptic encephalopathy caused by a previously undescribed pathogenic variant in the SCN2A gene. Primary bioinformatics analysis revealed a likely pathogenic variant in the KDM6A gene and a previously described missense variant in the SCN1A gene in the proband. Given the patient's significant therapeutic response to treatment with sodium channel blockers, a different genetic etiology was suggested by the epileptologist. Repeated bioinformatics analysis revealed a previously undescribed intron variant in the SCN2A gene. With the help of functional analysis, the pathogenicity of the variant leading to disruption of splicing was confirmed.

Sharkov A, Sparber P, Stepanova A, Pyankov D, Korostelev S, Skoblov M. Case Report: phenotype-driven diagnosis of atypical Dravet-like syndrome caused by a novel splicing variant in the SCN2A gene. Frontiers in Genetics.:1123. (Q2, IF - 3.789)