Large-scale analysis of de novo mutations identifies risk genes for female infertility characterized by oocyte and early embryo defects

Qun Li; Lin Zhao; Yang Zeng; Yanping Kuang; Yichun Guan; Biaobang Chen; Shiru Xu; Bin Tang; Ling Wu; Xiaoyan Mao; Xiaoxi Sun; Juanzi Shi; Peng Xu; Feiyang Diao; Songguo Xue; Shihua Bao; Qingxia Meng; Ping Yuan; Wenjun Wang; Ning Ma; Di Song; Bei Xu; Jie Dong; Jian Mu; Zhihua Zhang; Huizhen Fan; Hao Gu; Qiaoli Li; Lin He; Li Jin; Lei Wang; Qing Sang

doi:10.1186/s13059-023-02894-0

Large-scale analysis of de novo mutations identifies risk genes for female infertility characterized by oocyte and early embryo defects

Genome Biol. 2023 Apr 6;24(1):68. doi: 10.1186/s13059-023-02894-0.

Authors

Qun Li^#^{1

2}, Lin Zhao^#¹, Yang Zeng^#¹, Yanping Kuang^#³, Yichun Guan^#⁴, Biaobang Chen^#⁵, Shiru Xu⁶, Bin Tang⁷, Ling Wu³, Xiaoyan Mao³, Xiaoxi Sun⁸, Juanzi Shi⁹, Peng Xu¹⁰, Feiyang Diao¹¹, Songguo Xue¹², Shihua Bao¹³, Qingxia Meng¹⁴, Ping Yuan¹⁵, Wenjun Wang¹⁵, Ning Ma¹⁶, Di Song¹⁷, Bei Xu¹⁸, Jie Dong¹, Jian Mu¹, Zhihua Zhang¹, Huizhen Fan¹, Hao Gu¹, Qiaoli Li¹, Lin He¹⁹, Li Jin²⁰, Lei Wang²¹, Qing Sang²²

Affiliations

¹ Institute of Pediatrics, Children's Hospital of Fudan University, the Shanghai Key Laboratory of Medical Epigenetics, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China.
² Human Phenome Institute, Fudan University, Shanghai, 200438, China.
³ Reproductive Medicine Center, Shanghai Ninth Hospital, Shanghai Jiao Tong University, Shanghai, 200011, China.
⁴ Department of Reproductive Medicine, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
⁵ NHC Key Lab of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), Fudan University, Shanghai, 200032, China.
⁶ Fertility Center, Shenzhen Zhongshan Urology Hospital, Shenzhen, 518001, Guangdong, China.
⁷ Reproductive Medicine Center, The First People's Hospital of Changde City, Changde, 415000, China.
⁸ Shanghai Ji Ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China.
⁹ Reproductive Medicine Center, Northwest Women's and Children's Hospital, Xi'an, 710000, China.
¹⁰ Hainan Jinghua Hejing Hospital for Reproductive Medicine, Haikou, 570125, China.
¹¹ Reproductive Medicine Center, Jiangsu Province Hospital, Nanjing, 210036, China.
¹² Reproductive Medicine Center, School of Medicine, Shanghai East Hospital, Tongji University, Shanghai, China.
¹³ Department of Reproductive Immunology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 201204, China.
¹⁴ Center for Reproduction and Genetics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, 215000, China.
¹⁵ IVF Center, Department of Obstetrics and Gynecology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
¹⁶ Reproductive Medical Center, Maternal and Child Health Care Hospital of Hainan Province, Haikou, 570206, Hainan Province, China.
¹⁷ Naval Medical University, Changhai Hospital, Shanghai, China.
¹⁸ Reproductive Medicine Centre, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030, China.
¹⁹ Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, 200030, China.
²⁰ State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, 200438, China.
²¹ Institute of Pediatrics, Children's Hospital of Fudan University, the Shanghai Key Laboratory of Medical Epigenetics, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China. wangleiwanglei@fudan.edu.cn.
²² Institute of Pediatrics, Children's Hospital of Fudan University, the Shanghai Key Laboratory of Medical Epigenetics, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China. sangqing@fudan.edu.cn.

^# Contributed equally.

Abstract

Background: Oocyte maturation arrest and early embryonic arrest are important reproductive phenotypes resulting in female infertility and cause the recurrent failure of assisted reproductive technology (ART). However, the genetic etiologies of these female infertility-related phenotypes are poorly understood. Previous studies have mainly focused on inherited mutations based on large pedigrees or consanguineous patients. However, the role of de novo mutations (DNMs) in these phenotypes remains to be elucidated.

Results: To decipher the role of DNMs in ART failure and female infertility with oocyte and embryo defects, we explore the landscape of DNMs in 473 infertile parent-child trios and identify a set of 481 confident DNMs distributed in 474 genes. Gene ontology analysis reveals that the identified genes with DNMs are enriched in signaling pathways associated with female reproductive processes such as meiosis, embryonic development, and reproductive structure development. We perform functional assays on the effects of DNMs in a representative gene Tubulin Alpha 4a (TUBA4A), which shows the most significant enrichment of DNMs in the infertile parent-child trios. DNMs in TUBA4A disrupt the normal assembly of the microtubule network in HeLa cells, and microinjection of DNM TUBA4A cRNAs causes abnormalities in mouse oocyte maturation or embryo development, suggesting the pathogenic role of these DNMs in TUBA4A.

Conclusions: Our findings suggest novel genetic insights that DNMs contribute to female infertility with oocyte and embryo defects. This study also provides potential genetic markers and facilitates the genetic diagnosis of recurrent ART failure and female infertility.

Keywords: De novo mutations; Female infertility; Microtubule stability; Reproductive pathways; TUBA4A.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Female
HeLa Cells
Humans
Infertility, Female* / diagnosis
Infertility, Female* / genetics
Infertility, Female* / metabolism
Mice
Mutation
Oocytes / metabolism
Phenotype
Pregnancy