Large-scale whole-genome sequencing reveals the landscape and health implications of de novo mutations.

De novo mutations, arising in the parental germline or after fertilisation, are an important source of congenital disease; their number and spectrum vary with parental age and with the assisted reproduction procedure used.

Delayed parenthood and increasing use of assisted reproductive technology make it essential to clarify how these factors influence de novo mutations and whether those mutations affect offspring health. The authors performed whole-genome sequencing of 24,030 individuals from 7,851 parent-offspring families and identified 390,924 de novo single-nucleotide variants. Paternal and maternal ageing produced distinct mutational patterns, with maternal accumulation accelerating at advanced ages, and increased paternal de novo variants partly accounted for the association between advanced parental age and shorter gestational duration. Assisted reproduction showed age-independent, procedure-specific effects: intracytoplasmic sperm injection and ovarian stimulation were associated with increased paternal and maternal de novo variants respectively, and ICSI-associated paternal variants partly accounted for the association between ICSI and shorter gestational duration. In vitro embryo manipulation was associated with increased early post-zygotic mosaic mutations, particularly C > A substitutions, themselves linked to delayed neurocognitive development at 1 year.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The strength here is the separation of procedure effects from age effects, which only a cohort of this size makes possible: ICSI and ovarian stimulation do not act on the same parent, which moves preconception counselling beyond paternal age alone. The associations nevertheless remain statistical and only partly mediated, not causal, and one year of follow-up is short for a neurocognitive endpoint: nothing here justifies alarming a couple undergoing assisted reproduction. The point to carry into clinic is the acceleration of maternal accumulation at advanced ages, long considered negligible next to the paternal effect.

Analysis by Dr Thibaut Benquey