MosaicSCN1Amutations in familial partial epilepsy with antecedent febrile seizures

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Abstract

SCN1Ais the most relevant epilepsy gene. Mutations ofSCN1Agenerate phenotypes ranging from the extremely severe form of Dravet syndrome (DS) to a mild form of generalized epilepsy with febrile seizures plus (GEFS+). MosaicSCN1Amutations have been identified in rare familial DS. It is suspected that mosaic mutations ofSCN1Amay cause other types of familial epilepsies with febrile seizures (FS), which are more common clinically. Thus, we screenedSCN1Amutations in 13 families with partial epilepsy with antecedent febrile seizures (PEFS+) using denaturing high-performance liquid chromatography and sequencing. The level of mosaicism was further quantified by pyrosequencing. Two missenseSCN1Amutations with mosaic origin were identified in two unrelated families, accounting for 15.4% (2/13) of the PEFS+ families tested. One of the mosaic carriers with ˜25.0% mutation of c.5768A>G/p.Q1923R had experienced simple FS; another with ˜12.5% mutation of c.4847T>C/p.I1616T was asymptomatic. Their heterozygous children had PEFS+. Recurrent transmission occurred in both families, as noted in most of the families with germline mosaicism reported previously. The two mosaic mutations identified in this study are less destructive missense, compared with the more destructive truncating and splice-site mutations identified in the majority of previous studies. This is the first report of mosaicSCN1Amutations in families with probands that do not exhibit DS, but manifest only a milder phenotype. Therefore, such families with mild cases should be approached with caution in genetic counseling and the possibility of mosaicism origin associated with high recurrence risk should be excluded.

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