Mosaicism and incomplete penetrance of mutations.

BACKGROUND

Mutations in the gene have mainly been reported in female patients with epilepsy. To date, mutations have been reported in hundreds of females and only in 10 mosaic male epileptic patients with mosaicism.

OBJECTIVE

We aimed to investigate the occurrence of mosaic mutations in 42 families comprising at least one patient with -related epilepsy.

METHODS

Two male patients with mosaic variants were identified using targeted next-generation sequencing. Forty female patients with variants were identified by Sanger sequencing and Multiple Ligation Probe Amplification (MLPA). Microdroplet digital PCR was used to quantify the mutant allelic fractions (MAFs) in 20 families with variants.

RESULTS

Five mosaic individuals, four males and one female, were identified in total. Mosaic variant was confirmed in multiple somatic tissues from one male patient and in blood from the other male patient. Among 22 female patients harbouring a newly occurred variant identified by Sanger sequencing and MLPA, Sanger sequencing revealed two mosaic fathers (9%, 2/22), one with two affected daughters and the other with an affected child. Two asymptomatic mosaic fathers were confirmed as gonosomal mosaicism, with MAFs ranging from 4.16% to 37.38% and from 1.27% to 19.13%, respectively. In 11 families with apparent de novo variants, 1 female patient was identified as a mosaic with a blood MAF of 26.72%.

CONCLUSION

Our study provides new insights into phenotype-genotype correlations in related epilepsy and the finding of high-frequency mosaicism has important implications for genetic counselling.