New Mutation Linked to Dravet Syndrome Identified in Case Report

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by Diogo Pinto |

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A new mutation associated with Dravet syndrome was identified in an Iranian family with suspected disease, according to case report.

The study, “Pathogenic significance of SCN1A splicing variants causing Dravet syndrome: improving diagnosis with targeted sequencing for variants by in silico analysis,” was published in Clinical Neurology and Neurosurgery.

Dravet syndrome is one of the most severe epileptic encephalopathies. It is caused by mutations in the SCN1A gene, which provides instructions to build a protein that forms a subunit of a sodium channel found on the surface of nerve cells. This channel controls the flow of sodium ions into the cells, activating them and allowing them to pass nerve signals onto other cells.

Hundreds of mutations in this gene have been identified, making the use of gene panels a necessity for an accurate diagnosis.

Mutations in the SCNA1 gene can be divided into de novo mutations — those observed for the first time in a family member as a result of a mutation in the egg or sperm of one of the parents during fertilization — or familiar mutations that are transmitted from family members.

De novo mutations represent 90 to 95 percent of all the currently known mutations in the SCNA1 gene.

In this study, researchers report on two suspected cases of Dravet syndrome in Iran — one involving a a 2.5-year-old girl and another involving identical twins, both from consanguineous marriages, meaning the parents were related to one another.

A total of 36 genes for infantile epileptic encephalopathy were analyzed in these patients using a DNA-sequencing technology called targeted next-generation sequencing (NGS). A total of 147 mutations were identified and divided into previously reported mutations (based on the literature) and new mutations.

Sixty-six percent of all mutations were de novo mutations. Of those, two were associated with Dravet syndrome, and one of them had not yet been reported. Seven percent of the mutations were familial and 29.45 percent were unspecified. Sixty percent of all familial mutations were transmitted by the parents.

A more detailed analysis of each family detected a de novo mutation in the 2.5-year-old girl but not in her sibling or parents. This mutation had already been reported by researchers, and it is known to result in Dravet syndrome.

However, a previously unidentified de novo mutation was found in one of the twins, which was thought to cause the disease because it creates an abnormal version of the protein encoded by the SCN1A gene.

SCN1A gene may have a major role among Iranian patients. However, because of heterogenous etiology of [Dravet syndrome], targeted sequencing of patients provides clue for the cause of disease, genetic counseling and prenatal diagnosis,” the researchers wrote.

“Gene-panel sequencing is helpful for reducing the time and cost, guiding early treatment, and estimating the recurrence risks,” they concluded.