Parental mosaicism in de novo neurodevelopmental diseases

Neurodevelopmental diseases are increasingly recognized to be caused by “de novo” variants with the expanding use of next‐generation sequencing. The apparent de novo variants may actually be low‐level hereditary parental mosaic variants, which could increase the recurrence risk of disease by >50% and is thought to be an underappreciated cause of neurodevelopmental diseases. Our study aimed to investigate the frequency of parental mosaicism in “de novo” neurodevelopmental diseases. A total of 237 patients (and parents) with neurodevelopmental diseases carrying apparent de novo pathogenic or likely pathogenic variants were recruited consecutively. Deep next‐generation sequencing was performed on parental samples to identify parental mosaicism. Fourteen parental disease‐causing mosaicism variants (3.0%) in 11 genes were detected with alternate allele frequency (AAF) 0.22%–34%. Three parents showed milder clinical phenotypes than their offspring with relatively high AAF (23.33%, 25%, 34% separately). One recurrent variant was identified prenatally. A review of cohort study on parental mosaicism in neurodevelopmental diseases was performed. Our study highlights that identifying the parental mosaic disease‐causing variants especially the low‐level mosaicism will contribute to improving the accuracy of genetic counseling and prenatal diagnosis for reproductive risks.