Parental Age and Assisted Reproductive Technology Shape the Genomic Landscape of De Novo Mutations in Offspring
Background
De novo mutations (DNMs), which are newly arising mutations in offspring that are not present in their parents, are a source of human genetic diversity and also contribute to the etiology of some rare diseases and developmental disorders. Given that sperm precursor cells undergo continuous division throughout a male's lifetime, paternal age is a known major factor increasing the number of DNMs in offspring. Maternal age has also been suggested to be associated with DNMs, potentially due to oocyte aging, chromosomal segregation errors, and specific types of point mutations.
Assisted reproductive technology (ART), including in vitro fertilization and intracytoplasmic sperm injection, is increasingly utilized. However, it is unclear whether the processes involved in ART, such as gamete handling, embryo culture, and fertilization methods, introduce new mutations into the offspring's genome. ART users tend to have a higher average age at conception and may have underlying biological factors related to infertility, making it difficult to distinguish the effects of the procedure from those of parental age and baseline reproductive capacity. Previous studies have been limited by small sample sizes or a focus on specific chromosomal abnormalities and epigenetic changes, hindering a comprehensive assessment of the spectrum of rare DNMs.
Key Findings
The researchers analyzed whole-genome sequencing (WGS) data from 7,851 parent-offspring families. They identified variants present in the offspring but not in the parents and conducted a large-scale, family-based study to analyze the association between parental age, ART use, and the number and types of DNMs. Unlike exome sequencing, which only analyzes a portion of the genome, WGS captures variants across the entire genome, including non-coding regions.
The analysis revealed that parental age was associated with the overall burden of DNMs in offspring, and the effect of age extended beyond simply the number of variants. Differences were also observed in the types of variants that occurred. ART was also identified as a factor that leaves a distinct trace on the number and spectrum of DNMs. This provides clues to track the biological processes in which mutations arise, going beyond the approach of simply comparing the average number of variants in naturally conceived and ART-conceived offspring.
However, the published abstract does not provide the number of additional variants per year of parental age, the effect size and confidence interval for specific ART procedures. The abstract also does not provide sufficient evidence to conclude that a specific procedure directly causes a specific mutation. The study results should be interpreted as demonstrating an association between parental age and ART and the patterns of genetic variation in offspring.
Significance and Implications
The strength of this study lies in its large sample size of 7,851 families and the combination of parental and offspring WGS data. Rare DNMs may not show statistically significant signals in small cohorts, but analyzing thousands of families allows for a more robust identification of subtle differences in mutation spectra associated with parental age and reproductive procedures. In the future, this may serve as a basis for estimating risk by mutation type in genetic counseling, going beyond simply explaining average age-related risks.
However, this does not imply an immediate warning about the safety of ART. Even if the number or proportion of DNMs increases, most of them do not affect health, and the actual risk of disease varies greatly depending on the location and function of the mutation and its presence in the embryo. Other confounding factors, such as the cause of infertility, parental lifestyle, whether gametes are donated, and culture conditions, also need to be considered.
The next steps are replication studies of specific ART procedures and long-term clinical follow-up. If an increase in mutations is confirmed in a specific process, there is room to reduce the risk by adjusting the culture period, temperature, oxidative stress, and gamete handling methods. It is also necessary to verify whether the same signals are observed in different populations and medical institutions, and whether the observed mutations are associated with the actual incidence of childhood diseases, before they can be reflected in clinical guidelines.
Nature Medicine, Published online: 07 August 2026; doi:10.1038/s41591-026-04585-2This whole-genome sequencing study based on 7,851 parent−offspring families shows that parental age and assisted reproductive technologies influence the number and types of de novo mutations, highlighting potential health impacts and the need to optimize reproductive practices.
Reproductive medicine clinics can link ART type, culture conditions, parental age, and offspring genomic data to design quality control indicators. For example, if a specific DNM type repeatedly increases under specific culture conditions, this could lead to a prospective safety study comparing culture medium composition or processing times. In genetic counseling, results should be translated into absolute risks for older parents or ART users, and guidelines should be established to avoid increasing anxiety based on association alone. In the long term, this could be used to evaluate the genomic safety of specific procedures and improve standard processes in the embryo lab, but the clinical utility, cost, and privacy implications should be considered before recommending routine additional genomic testing.