Unrevealing parental mosaicism : the hidden answer to the recurrence of apparent de novo variants

Abstract

Mosaicism refers to the presence of two or more genetically distinct cell populations within an individual. According to the literature, the percentage of parental mosaicism ranges from 0.33% to 25.9%. In this study, we recruited parents whose children had previously been diagnosed with developmental disorders with an apparent de novo variant identified using peripheral blood by trio sequencing. Peripheral blood and buccal swabs from both parents, and semen samples from the father were collected to detect potential parental mosaicism by droplet digital PCR, and blocker displacement amplification. In total 21 families were included in the analysis. Here, we report four families with parental mosaicism caused by a pathogenic/likely pathogenic variant (4/21, 19%). Two families had maternal gonosomal mosaicism (EYA1 and EBF3) and one family had paternal gonadal mosaicism (CHD7), which was undetectable in blood and buccal mucosa. The last family had gonadal mosaicism inferred from the family history (ALT1). One family had a variant of uncertain significance with paternal gonosomal mosaic missense variant in FLNC with high potential clinical significance. The detectable variant allele frequencies in our cohort ranged from 8.7%-35.9%, limit of detection 0.08%-0.16%. We found a higher level of mosaicism in semen than in blood in both families with paternal mosaicism. Our results highlight the clinical significance of utilizing appropriate sample type and sensitive detection methods to identify parental mosaicism compared with those used in routine clinical diagnostics. Carrying a hidden variant in the germ cells will have an impact on reproductive risk, which is important for family planning. Robust detection of parental mosaicism not only allows the accurate assessment of recurrence risk during genetic counselling of families to make early informed decisions about future pregnancies, but also facilitates prenatal medical teams to make proper pregnancy and delivery plans.