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

• Published in: Prenatal diagnosis Vol. 42; no. 7; pp. 811 - 821
• Main Authors: Zemet, Roni, Veyver, Ignatia B., Stankiewicz, Paweł
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01-06-2022
• Subjects: Anomalies; Counseling; De novo mutation; Female; Fetuses; Gene sequencing; Genetic diversity; Genetic variance; Genomes; Humans; Medical diagnosis; Mosaicism; Mutation; Parents; Pregnancy; Pregnancy Trimester, First; prenatal diagnosis; recurrence risk; Ultrasonography, Prenatal; variants; variants; prenatal diagnosis; De novo mutation; recurrence risk; mosaicism
• ISSN: 0197-3851; 1097-0223
• DOI: 10.1002/pd.6144

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, we 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. We also describe new bioinformatic and technological tools developed to assess mosaicism and discuss how they improve the accuracy of reproductive risk counseling when parental mosaicism is detected.
Key points
What's already known about this topic?
More than 50% of prenatally diagnosed disease‐causing variants are apparently de novo.
Until recently, the theoretical recurrence risk for apparent de novo variants was thought to be exceedingly low.
What does this review add?
Parental mosaicism as the etiology of apparent de novo variants significantly increases their recurrence risk.
Implementation of more sensitive and precise molecular and computational methods enables robust screening for low‐level parental mosaicism.
Determination of the parental origin of de novo variants and testing multiple tissues improves the reproductive risk assessment.