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Evaluating the monogenic contribution and genotype–phenotype correlation in patients with isolated thoracic aortic aneurysm

European Journal of Human Genetics volume 29, pages 1129–1138 (2021)Cite this article

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Abstract

Thoracic aortic aneurysm with or without dissection (TAAD) can be broadly categorized as syndromic TAAD (sTAAD) and isolated TAAD (iTAAD). sTAAD and is highly correlated with genetics. However, although the incidence of iTAAD is much higher, its monogenic contribution is not yet clear. Here, we sequenced 15 known TAAD genes for 578 iTAAD cases from four cardiac centers in China and found that 10.6% patients with a pathogenic/likely pathogenic (P/LP) variant. Other 7.27% of patients carried variants of uncertain significance in these target genes. We further investigated the correlations among genetics, clinical features, and long-term outcomes. Genetic patients showed younger onset ages (P = 1.31E-13) and larger aortic diameter (P = 1.00E-6), with the youngest age in patients with FBN1 P/LP variants. Monogenic variants were also associated with more aortic segments involved (P = 0.043) and complicated with initial dissection (P = 4.50E-5), especially for genetic patients with non-FBN1 P/LP variants. MACEs occurred in 14.9% patients during follow-up of median 55 months. Genetic status (P = 0.001) and initial dissection (P = 3.00E-6) were two major risk factors for poor prognosis. Early onset age was associated with MACEs in non-genetic cases without initial dissection (P = 0.005). Our study revealed the monogenic contribution in known TAAD genes to iTAAD patients. The genotype–phenotype correlations may complement the risk stratification of iTAAD patients and identification of higher risk subgroups, as well as assist the development of tailored precision medicine in iTAAD.

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Fig. 1: Matrix of suspected functional variants in individual gene and patient.
Fig. 2: Distribution of onset ages of patients with different genetic status.
Fig. 3: Predictors for the risk of MACEs.

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Acknowledgements

We thank all the patients for their participation in this study.

Funding

This study was supported by grants from the National Key Research and Development Program of China (2016YFC0903000), the National Science Foundation of China (81800218 and 81930014), the Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education of China (PXM2014-014226-000012), International Cooperation Project from the Ministry of Science and Technology of China (2015DFA31070), and the Beijing Collaborative Innovative Research Center for Cardiovascular Diseases.

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Authors and Affiliations

  1. Beijing Anzhen Hospital, Capital Medical University, Beijing, China

    Yang Li, Yu Kong, Jinsheng Xie, Junming Zhu, Lizhong Sun, Yulin Li & Jie Du

  2. Beijing Institute of Heart, Lung & Blood Vessel Disease, Beijing, China

    Yang Li, Yu Kong, Jinsheng Xie, Junming Zhu, Lizhong Sun, Yulin Li & Jie Du

  3. The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing, China

    Yang Li, Yu Kong, Yulin Li & Jie Du

  4. Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China

    Weixun Duan, Shiqiang Yu & Dinghua Yi

  5. Depatment of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, Changsha, China

    Xinmin Zhou & Yerong Hu

  6. Division of Cardiac Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

    Jing-Song Ou

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Correspondence to Yulin Li or Jie Du.

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Li, Y., Kong, Y., Duan, W. et al. Evaluating the monogenic contribution and genotype–phenotype correlation in patients with isolated thoracic aortic aneurysm. Eur J Hum Genet 29, 1129–1138 (2021). https://doi.org/10.1038/s41431-021-00857-2

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