Parental mosaicism for apparent de novo genetic variants: Scope, detection, and counseling challenges

The disease burden of de novo mutations (DNMs) has been evidenced only recently when the common application of next‐generation sequencing technologies enabled their reliable and affordable detection through family‐based clinical exome or genome sequencing. Implementation of exome sequencing into prenatal diagnostics revealed that up to 63% of pathogenic or likely pathogenic variants associated with fetal structural anomalies are apparently de novo, primarily for autosomal dominant disorders. Apparent DNMs have been considered to primarily occur as germline or zygotic events, with consequently negligible recurrence risks. However, there is now evidence that a considerable proportion of them are in fact inherited from a parent mosaic for the variant. Here, the study review the burden of DNMs in prenatal diagnostics and the influence of parental mosaicism on the interpretation of apparent DNMs and discuss the challenges with detecting and quantifying parental mosaicism and its effect on recurrence risk. The present study also describes new bioinformatic and technological tools developed to assess mosaicism and discusses how they improve reproductive risk counselling accuracy when parental mosaicism is detected.