Pathogenic significance of SCN1A splicing variants causing Dravet syndrome: Improving diagnosis with targeted...

Genetic heterogeneity of epileptic encephalopathy (IEE) mandates the use of gene-panels for diagnosis.

A 36-gene-panel next-generation sequencing was applied for IEE in two Iranian families. A literature search was performed using keywords to identify reported splicing mutations in SCN1A and perform genotype-phenotype correlation.

An update of splicing mutations revealed 147 variants with 65.75% of them de novo mutations. Most of the familial variants were of parental origin. The structure of the protein was often affected in the linker and transmembrane segments. 92% of intronic variants were pathogenic. A de novo heterozygous mutation was found in the first patient, but not in her sibling and parents. In the second family, a novel de novo heterozygous mutation was found at position c.1210insT leading to a truncated protein.

Gene-panel sequencing is helpful for reducing the time and cost, guiding early treatment, and estimating the recurrence risks. The importance of characterization of intronic variants was noticed; though bioinformatics analysis of novel intronic variants should be of concern for rapid reporting the pathogenic effect of variants.