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Novel mutations of AXIN2 identified in a Chinese Congenital Heart Disease Cohort

Journal of Human Geneticsvolume 64pages427435 (2019) | Download Citation



Congenital heart defects (CHDs), the most common congenital human birth anomalies, involves complex genetic factors. Wnt/β-catenin pathway is critical for cardiogenesis and proved to be associated with numerous congenital heart abnormities. AXIN2 has a unique role in Wnt/β-catenin pathway, as it is not only an important inhibitor but also a direct target of Wnt/β-catenin pathway. However, whether AXIN2 is associated with human CHDs has not been reported. In our present study, we found a differential expression of Axin2 mRNA during the development of mouse heart, indicating its importance in mouse cardiac development. Then using targeted next-generation sequencing, we found two novel case-specific rare mutations [c.28 C > T (p.L10F), c.395 A > G (p.K132R)] in the sequencing region of AXIN2. In vitro functional analysis suggested that L10F might be a loss-of-function mutation and K132R is a gain-of-function mutation. Both mutations disrupted Wnt/β-catenin pathway and failed to rescue CHD phenotype caused by Axin2 knockdown in zebrafish model. Collectively, our study indicates that rare mutations in AXIN2 might contribute to the risk of human CHDs and a balanced canonical Wnt pathway is critical for cardiac development process. To our knowledge, it is the first study of AXIN2 mutations associated with human CHDs, providing new insights into CHD etiology.

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We appreciate the patient family for their collaboration in this study. We thank Professor Tao Zhong for his plasmid that was used in this study. This study was funded by grants from the National Natural Science Foundation of China (81670973, 31601029, and 81601298) and China Postdoctoral Science Foundation (BX20180069 and 2018M641918).

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Author notes

  1. These authors contributed equally: Meng-Jiao Zhu, Xiao-Yun Ma


  1. Department of Orthodontics, School and Hospital of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, 200072, China

    • Meng-Jiao Zhu
    • , Xiao-Yun Ma
    •  & Feng-Shan Chen
  2. Department of Cardiothoracic Surgery, Children’s Hospital of Nanjing Medical University, Nanjing, 210008, China

    • Pei-Cheng Ding
  3. Department of Vascular Surgery, Institute of Vascular Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    • Han-Fei Tang
  4. Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics & Development at School of Life Sciences of Fudan University, 20043, Shanghai, China

    • Rui Peng
    • , Lei Lu
    • , Yu-Fang Zheng
    • , Hong-Yan Wang
    •  & Yun-Qian Gao
  5. Institute of Genetics, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, China

    • Pei-Qiang Li
  6. Institute of Cardiovascular Disease, General Hospital of Jinan Military Region, Jinan, 250022, China

    • Bin Qiao
  7. State Key Laboratory of Genetic Engineering at School of Life Sciences of Fudan University, 20043, Shanghai, China

    • Xue-Yan Yang
  8. Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China

    • Hong-Yan Wang
    •  & Yun-Qian Gao


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The authors declare that they have no conflict of interest.

Corresponding authors

Correspondence to Yun-Qian Gao or Feng-Shan Chen.

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