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.

Keywords: De novo mutation; mosaicism; prenatal diagnosis; recurrence risk; variants.

Figure 1.. An overview of the possible origin of de novo variants.

A) Father has a constitutional heterozygous mutation in all cells and transmits it to his child, who is also heterozygous in all cells. B) Father has gonosomal mosaicism that affects both the germline and somatic cells. Child is heterozygous in all cells. C) Father has germline (gonadal) mosaicism, and child is heterozygous in all cells. The mutation occurs shortly after the primordial germ cell specification. Child is heterozygous in all cells. D) DNM occurs prezygotically, during final sperm cell division, and is present in a single sperm cell. Father transmits this mutation to his child, who is heterozygous in all cells. E) DNM occurs in the zygote, before the first embryonic cell division, and the child is heterozygous in all cells. F) DNM occurs postzygotically, and the child has a mosaic somatic mutation in a fraction of cells. Paternal inheritance is depicted for simplification and because of a higher rate of paternal origin of DNM that arise prezygotically. However, parental gonosomal mosaicism that can lead to “apparent” DNMs in offspring is equally frequently of maternal or paternal origin. DNM = de novo mutation

Figure 2.. Timing of de novo mutations and reproductive recurrence risk.

A) Postzygotic de novo mutation in the child is not present in any parental cells and is mosaic in the child. The recurrence risk in this form of mosaicism is the same as the population risk. B) DNM that occurs in the parental gametes is inherited in the child as a constitutive mutation. The recurrence risk varies and is higher for mutations that arise earlier after primordial germ cell specification, affecting all gametes that arise from this mutant cell through subsequent cell divisions, than for mutations that arise during later sperm cell division. C) A postzygotic DNM in the parent results in gonosomal mosaicism across multiple parental tissues, including the germline. When a gamete carrying this mutation is fertilized, it results in a constitutively inherited variant in the child. The recurrence risk correlates with the percentage of affected gametes.

Figure 3.

Factors affecting the recurrence risk of apparent de novo variants.