Pathogenic significance of SCN1A splicing variants causing Dravet syndrome; improving diagnosis with targeted sequencing for variants by in silico analysis

Publication date: Available online 31 January 2018
Source:Clinical Neurology and Neurosurgery
Author(s): Nejat Mahdieh, Sepideh Mikaeeli, Reza Shervin Badv, Azadeh Gharehzadeh Shirazi, Majid Maleki, Bahareh Rabbani
ObjectivesGenetic heterogeneity of epileptic encephalopathy (IEE) mandates the use of gene-panels for diagnosis.Patients and MethodsA 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.ResultsAn 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.ConclusionGene-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.



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