Detecting genomic mosaicism in “de novo” genetic epilepsy by amplicon-based deep sequencing

Aim To investigate the occurrence of mosaicism in epilepsy probands and their parents using amplicon-based deep sequencing (ADS). Methods Patients were recruited from the outpatient of Peking University First Hospital. Two hundred and sixty-four probands with pathogenic variants tested by next-generation sequencing (NGS) were enrolled. Results Mosaic variants were detected in seventeen disease-associated genes from 20 probands, 5 paternal, and 6 maternal parents. The frequency of mosaicism was 11.74% (31/264). Mosaicism in 11 genes was identified from 20 probands with the mutant allelic fractions (MAFs) of 12.95–38.00% in autosomal dominant genes. Five paternal mosaicisms were identified in genes with a MAF of 6.30–20.99%, and six maternal mosaic individuals with a MAF of 2.07–21.90%. Only four mosaic parents had milder seizure history. The affected sibling had the same phenotype consistent with that of the proband, who inherited the variant of SLC1A2 or STXBP1 from their unaffected mosaic mothers, respectively. Interpretation Mosaic phenomenon is not rare in families with epilepsy. Phenotypes of mosaic parents were milder or normal. Mosaicism detection is helpful to identify the mutation origin and it provides a theoretical basis for prenatal diagnosis of family reproduction. ADS is a reliable way of mosaicism detection for clinical application.