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De-novo mutation burden in ART-conceived offspring: no overall increase but subgroup differences by fertilization and
Yingming Zheng1, Chuanping Lin2, Qijing Wang1
1Department of Reproductive Endocrinology, Key Laboratory of Reproductive Genetics of National Ministry of Education, Women's Reproductive Health Laboratory of Zhejiang Province, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, PR China.
Research Question:
Does assisted reproductive technology (ART), particularly specific procedures such as IVF, intracytoplasmic sperm injection (ICSI), and frozen embryo transfer (FET), affect the number of de-novo mutations (DNM) in offspring compared with natural conception?
Design:
Initially, 312 families with ART-conceived children and 157 families with naturally conceived children were enrolled in this prospective cohort study. After excluding those with low-quality DNA or kinship discrepancies, the final cohort comprised 454 families with 545 offspring, including 189 IVF (73 fresh, 116 frozen), 117 ICSI (50 fresh, 67 frozen), and 148 natural conception families. All subjects underwent whole-genome sequencing at an average depth of >30 × . DNM were identified and validated using a standardized pipeline. The number of DNM was compared between conception methods. A linear mixed model (LMM) was used to assess independent effects and interactions of ART parameters.
Results:
No significant increase in DNM count was observed in ART-conceived offspring compared with naturally conceived offspring. In exploratory subgroup analyses, offspring conceived via FET following ICSI had significantly fewer DNM than those conceived via fresh embryo transfer following ICSI (mean DNM 51.63 versus 61.59, adjusted mean difference = 10.878, 95% CI 2.452-19.304; P = 0.003, Bonferroni-corrected). The ICSI-FET group did not differ significantly from the natural conception group. LMM analysis restricted to ART cycles identified FET (B = -6.13; P = 0.015) and paternal age (B = 0.74; P = 0.034) as independent factors influencing DNM count.
Conclusions:
Children conceived via ART procedures do not show an overall increase in DNM burden compared with naturally conceived children. Exploratory subgroup differences by fertilization and transfer strategy were observed; however, these findings require independent replication and should be interpreted with caution. Further studies are warranted to confirm these observations and to investigate potential mechanisms.