Volume 31, No 8, Aug 2021

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 31 Issue 8, August 2021: 919-928

ORIGINAL ARTICLES

Association of assisted reproductive technology, germline de novo mutations and congenital heart defects in a prospective birth cohort study

Cheng Wang^1,2,3 , Hong Lv^1,2,4 , Xiufeng Ling^1,5 , Hong L^1,6 , Feiyang Diao^1,7 , Juncheng Dai1^1,2 , Jiangbo Du^1,2 , Ting Chen⁸ , Qi Xi⁹ , Yang Zhao^1,2 , Kun Zhou^1,2 , Bo Xu^1,2 , Xiumei Han^1,2 , Xiaoyu Liu^1,2 , Meijuan Peng^1,2 , Congcong Chen^1,2 , Shiyao Tao^1,2 , Lei Huang^1,2 , Cong Liu^1,2 , Mingyang Wen^1,2 , Yangqian Jiang^1,2 , Tao Jiang^1,2 , Chuncheng Lu^1,10 , Wei Wu^1,10 , Di Wu^1,10 , Minjian Chen^1,10 , Yuan Lin^1,4,11 , Xuejiang Guo¹ , Ran Huo¹ , Jiayin Liu^1,4,7 , Hongxia Ma^1,2 , Guangfu Jin^1,2 , Yankai Xia^1,10 , Jiahao Sha¹ , Hongbing Shen^1,2,4,* , Zhibin Hu^1,2,4,*

¹State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
²Department of Epidemiology and Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
³Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, Jiangsu, China
⁴State Key Laboratory of Reproductive Medicine (Suzhou Centre), The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, China
⁵Department of Reproduction, Women’s Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Hospital, Nanjing, Jiangsu, China
⁶Reproductive Genetic Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, China
⁷Clinical Center of Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu, China
⁸Scientific Education Section, Women’s Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Hospital, Nanjing, Jiangsu, China
⁹Department of Obstetrics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, China
¹⁰Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
¹¹Department of Maternal, Child and Adolescent Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
These authors contributed equally: Cheng Wang, Hong Lv, Xiufeng Ling, Hong Li, Feiyang Diao Correspondence: Hongbing Shen(hbshen@njmu.edu.cn)Zhibin Hu(zhibin_hu@njmu.edu.cn)

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.

https://doi.org/10.1038/s41422-021-00521-w

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