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.