Abstracts

Rationale: Dravet syndrome is caused in approximately 80% of cases by mutations in the voltage-gated sodium channel subunit gene SCN1A, with most mutations being de novo. De novo mutations of SCN1A are also seen in other epileptic encephalopathies. The proportion of paternal to maternal origin of de novo mutations varies widely between genes responsible for a range of disorders in clinical genetics. Methods: To determine the parent of origin we studied lymphocyte derived genomic DNA from 69 patients with de novo SCN1A mutations and their parents. Single-nucleotide polymorphisms (SNPs) in the region surrounding the mutation were genotyped by sequencing or by restriction enzyme assay. Allele-specific PCR based on the informative SNPs was used to tag, amplify and sequence the paternal and maternal alleles to determine in which parental chromosome the mutation arose. Results: We established the parental origin of de novo SCN1A mutations in 42 patients with Dravet syndrome and related disorders. The mutations were of paternal origin in 35 cases (83%) and of maternal origin in the remaining 7 cases. Conclusions: De novo mutation of SCN1A most commonly arises on the paternal allele. These data are similar to those observed for Rett syndrome; but interestingly, parental origin is not always paternal as has been observed in several other disorders. The greater frequency of paternally derived mutations is likely to be associated with the increased number of mitoses which occur during spermatogenesis compared with oogenesis.