Noninherited genetic mutations affecting the SCN1A gene may help explain almost 1% of Dravet syndrome cases of unknown cause, according to researchers from Japan.
Genetic disorders are commonly inherited from parents who are carriers of the abnormal gene variant that cause the disease. If the disease is recessive, it means the child received two copies — one from the mother and the other from the father — of the disease-associated gene variant.
If it is a dominant disorder, only one copy of the mutated gene is required for the child to develop the disease. In some situations, though, the inheritance pattern is not this straightforward.
Sometimes people have what is called somatic mosaic mutations. These are point genetic alterations that happen in some cells and are not inherited from the parents. Because they don’t follow the common rules of genetics, they are often difficult to identify. Still, they can be just as harmful as any other genetic mutation.
In the study “Somatic mosaic deletions involving SCN1A cause Dravet syndrome,” published in the American Journal of Medical Genetics, Japanese researchers evaluated the incidence of somatic mosaic mutations in children with Dravet syndrome.
They performed a genetic analysis in 237 patients with diagnosed Dravet syndrome who did not have mutations in the SCN1A or PCDH19 genes, which are recognized to cause about 70% of all Dravet cases.
“Our study indicates that the minimum prevalence of SCN1A mosaic deletion is estimated to be 0.9% of children who were negative for conventional SCN1A and PCDH19 mutation screening,” the researchers wrote.
Two children were found to have several microdeletions affecting the SCN1A gene. In both cases, they had healthy parents and symptom onset during early infancy. Additional analysis revealed that half of the childrens’ cells had SCN1A deletions.
The deletions were found to not only affect the SCN1A gene, but also adjacent genes. However, these did not have an impact on the health of patients, suggesting they were not sufficient to promote disease.
The results revealed that a level of genetic mosaicism of 35-39% in the SCN1A gene, or having approximately 75% of SCN1A gene dysfunction, is sufficient to promote the development of Dravet syndrome. This correlates with the hypothesis that the disease can be caused by somatic mosaic mutations of SCN1A.
The researchers suggest that “somatic deletions in SCN1A should, therefore, be considered in cases with Dravet syndrome when standard screenings for SCN1A mutations are apparently negative for mutations.”