2. Academic Validation
  3. Loss-of-function variants in ciliary genes confer high risk for tetralogy of Fallot

Loss-of-function variants in ciliary genes confer high risk for tetralogy of Fallot

  • Sci Adv. 2025 Oct 10;11(41):eadt0836. doi: 10.1126/sciadv.adt0836.
Yan Zhou 1 2,  Tao Jiang 1 2,  Jimiao Gao 1 2,  Jie Zang 1 2,  Xuming Mo 3,  Shen Yue 4,  Yiqiang Cui 1,  Qiuye Wang 1 2,  Min Da 3,  Jing Xu 5,  Qingguo Li 6,  Bin Shen 1,  Juncheng Dai 1 2 7,  Hongxia Ma 1 2,  Guangfu Jin 1 2,  Hongbing Shen 1 2,  Cheng Wang 1 2,  Yayun Gu 1 2 7,  Yuan Lin 1 2,  Zhibin Hu 1 2 7 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, Jiangsu 211100, China.
  • 2 School of Public Health, Center for Global Health, Nanjing Medical University, Nanjing, Jiangsu 211100, China.
  • 3 Department of Cardiothoracic Surgery, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu 210008, China.
  • 4 Department of Developmental Genetics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 211100, China.
  • 5 Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.
  • 6 Department of Cardiovascular Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210003, China.
  • 7 State Key Laboratory of Reproductive Medicine and Offspring Health (Suzhou Centre), The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou 215002, China.
  • 8 Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, Jiangsu 210000, China.
PMID: 41071877 DOI: 10.1126/sciadv.adt0836
Abstract

Tetralogy of Fallot (TOF), the most common severe cyanotic congenital heart disease, has unclear genetic causes. Through next-generation Sequencing in 131 patients with nonsyndromic TOF, we identified an increased burden of rare deleterious variants in ciliary genes and cilium pathway and observed a multigenic inheritance pattern, with an odds ratio (OR) of 1.672 [95% confidence interval (CI), 1.120 to 2.547; P = 0.0104] for more than two deleterious variants and a cumulative OR of 3.158 (95% CI, 1.381 to 6.371; P = 0.0038) for six variants. Functional validation in single- and double-heterozygous mouse models carrying these variants recapitulated TOF-like phenotypes and impaired normal cilia structure and function, particularly disrupting Hedgehog signaling in cardiomyocytes, and down-regulating key transcription factors Gata4 and Nkx2-5. Together, our study provides compelling evidence linking ciliary gene variants to a heightened risk of TOF in Han Chinese, offering valuable genetic insights into the etiology and pathogenesis of nonsyndromic TOF and supporting a multigenic inheritance model for the disease.

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