Abstract
Emerging evidence suggests that children conceived through assisted reproductive technology (ART) have a higher risk of congenital heart defects (CHDs) even when there is no family history. De novo mutation (DNM) is a well-known cause of sporadic congenital diseases; however, whether ART procedures increase the number of germline DNM (gDNM) has not yet been well studied. Here, we performed whole-genome sequencing of 1137 individuals from 160 families conceived through ART and 205 families conceived spontaneously. Children conceived via ART carried 4.59 more gDNMs than children conceived spontaneously, including 3.32 paternal and 1.26 maternal DNMs, after correcting for parental age at conception, cigarette smoking, alcohol drinking, and exercise behaviors. Paternal DNMs in offspring conceived via ART are characterized by C>T substitutions at CpG sites, which potentially affect protein-coding genes and are significantly associated with the increased risk of CHD. In addition, the accumulation of non-coding functional mutations was independently associated with CHD and 87.9% of the mutations were originated from the father. Among ART offspring, infertility of the father was associated with elevated paternal DNMs; usage of both recombinant and urinary follicle-stimulating hormone and high-dosage human chorionic gonadotropin trigger was associated with an increase of maternal DNMs. In sum, the increased gDNMs in offspring conceived by ART were primarily originated from fathers, indicating that ART itself may not be a major reason for the accumulation of gDNMs. Our findings emphasize the importance of evaluating the germline status of the fathers in families with the use of ART.
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Acknowledgements
This work was funded by the National Key R&D Program of China (2018YFC1004200, 2016YFC1000200), and the National Natural Science Foundation of China (81830100). We are grateful to all the families participating in this study, and the whole CNBC cohort team. We thank the Nanjing Jiangbei New Area Biopharmaceutical Public Service Platform Co., Ltd, National Health & Medical Big Data Center (Nanjing), and National Human Genetic Resources Sharing Service Platform Jiangsu Innovation Center (YCZYPT[2018]05).
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Z.H. and H.S. initiated, conceived, and supervised the study. Z.H. and C.W. performed bioinformatics/statistical analysis and prepared the manuscript with C.C. H. Lv, X. Ling, H. Li, and J. Du were involved in study design, the conduct of the CNBC cohort study, long-term follow-up with T.C., Q.X., Y.Z., K.Z., B.X., X.H., X. Liu, M.P., S.T., L.H., C. Liu, M.W., C. Lu, W.W., D.W., M.C., and Y. L. H. Lv, F.D., J. Du, Y.Z., M.P., S.T., Y.J., and T.J. organized clinical information. J. Dai conducted the sequencing experiments with K.Z., B.X., X.H., X. Liu, L.H., C. Liu, and M.W. X.G., R.H., J.L., H.M., G.J., Y.X., and J.S. proofread the manuscript.
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Wang, C., Lv, H., Ling, X. et al. Association of assisted reproductive technology, germline de novo mutations and congenital heart defects in a prospective birth cohort study. Cell Res 31, 919–928 (2021). https://doi.org/10.1038/s41422-021-00521-w
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DOI: https://doi.org/10.1038/s41422-021-00521-w
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