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

Abstract

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.

High‐level gonosomal mosaicism for a pathogenic non‐coding CNV deletion of the lung‐specific FOXF1 enhancer in an unaffected mother of an infant with ACDMPV

“…Our results further confirm the notion that quantitative testing of parental DNA samples for the mosaicism for the causative apparent de novo variants is essential to accurately evaluate the recurrence risk (Zemet et al, 2022). They also demonstrate the need for more extensive genetic testing in patients with histopathologically diagnosed ACDMPV, or with high level of suspicion for this diagnosis, or even in the setting of severe refractory persistent pulmonary hypertension of the newborn when routine clinical rWGS, CMA, or other genetic studies are negative.…”

Impact of variation in practice in the prenatal reporting of variants of uncertain significance by commercial laboratories: Need for greater adherence to published guidelines

“…Although 17 of those 23 patients were caused by a de novo variant, in two cases, the fetus had inherited the causative variant (one P, one VUS) from a healthy parent with low‐grade mosaicism. Exome sequencing allows for the detection of low‐level mosaicism that was previously undetected by Sanger sequencing and allows more accurate counseling of recurrence risk in future pregnancies 15 . In one case of an isolated heart defect in mother and baby, an inherited VUS in GATA4 was detected and altered recurrence risk counseling.…”

Case report: A novel case of parental mosaicism in SMC1A gene causes inherited Cornelia de Lange syndrome

“…Clinical exome sequencing in patients and accompanied Sanger validation of parental blood-derived DNA are commonly used in routine clinical diagnostics in CdLS, but have limited sensitivity detecting low-frequency variants. During the last few years, the development of high-throughput genomic technologies such as quantitative polymerase chain reaction (qPCR), deep sequencing or droplet digital PCR (ddPCR) has enhanced our capabilities to assess low grade mosaicism ( Zemet et al, 2022 ). As stated above, in our study, a deep targeted panel (>1,000x) was applied allowing the identification of the causal variant with a very low AAF (9.34%) in the mother’s DNA.…”

“…Otherwise, the uncertainty about the representative tissues to precisely study mosaicism entails another limitation in its detection. Most genetic tests are performed on blood-derived DNA, but this may not be the best choice sample ( Zemet et al, 2022 ), especially in CdLS, in which great disparity in the distribution of mosaic variants across tissues has been already recognized ( Latorre-Pellicer et al, 2021 ). Thus, the analysis of additional samples besides blood with highly sensitive technologies should be recommended in CdLS co-segregation studies.…”

“…Therefore, although it has been already demonstrated that the level of somatic mosaicism correlates positively with the overall recurrence risk ( Rahbari et al, 2016 ; Jónsson et al, 2018 ), the difficulty of calculating the proportion of germinal mutated cells, especially in women, makes the recurrence risk estimation next to impossible. In this context, preimplantation genetic testing (PGT) could be a feasible option for couples who wish to have additional children to avoid intrafamilial recurrence ( Zemet et al, 2022 ).…”