From the State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (Xuanyu Liu, W.C., W.L., Y.F., B.M., B.H., Xuewen Liu, S.H., Z.Z.).
Beijing Key Laboratory for Molecular Diagnostics of Cardiovascular Diseases, Center of Laboratory Medicine, China (Xuanyu Liu, W.C., W.L., Y.F., Z.Z.).
Circ Res. 2020 Mar 27;126(7):811-821. doi: 10.1161/CIRCRESAHA.119.315821. Epub 2020 Feb 11.
Transposition of the great arteries (TGA) is one of the most severe types of congenital heart diseases. Understanding the clinical characteristics and pathogenesis of TGA is, therefore, urgently needed for patient management of this severe disease. However, the clinical characteristics and genetic cause underlying TGA remain largely unexplored.
We sought to systematically examine the clinical characteristics and genetic cause for isolated nonsyndromic TGA.
We recruited 249 patients with TGA (66 family trios) and performed whole-exome sequencing. The incidence of patent ductus arteriosus in dextro-TGA (52.7%) and dextrocardia/mesocardia in congenitally corrected TGA (32.8%) were significantly higher than that in other subtypes. A high prevalence of bicuspid pulmonic valve (9.6%) was observed in patients with TGA. Similar results were observed in a replication group of TGA (n=132). Through a series of bioinformatics filtering steps, we obtained 82 candidate genes harboring potentially damaging de novo, loss of function, compound heterozygous, or X-linked recessive variants. Established congenital heart disease-causing genes, such as , were found among the list of candidate genes. A total of 19 ciliary genes harboring rare potentially damaging variants were also found; for example, with a de novo putatively damaging variant. The enrichment of ciliary genes supports the roles of cilia in the pathogenesis of TGA. In total, 33% of the TGA probands had >1 candidate gene hit by putatively deleterious variants, suggesting that a portion of the TGA cases were probably affected by oligogenic or polygenic inheritance.
The findings of clinical characteristic analyses have important implications for TGA patient stratification. The results of genetic analyses highlight the pathogenic role of ciliary genes and a complex genetic architecture underlying TGA.
大动脉转位（TGA）是最严重的先天性心脏病之一。因此，了解 TGA 的临床特征和发病机制对于这种严重疾病的患者管理至关重要。然而，TGA 的临床特征和遗传原因在很大程度上仍未得到探索。
我们旨在系统研究孤立性非综合征型 TGA 的临床特征和遗传原因。
我们招募了 249 名 TGA 患者（66 个家系）并进行了全外显子组测序。右旋 TGA 患者中动脉导管未闭（52.7%）和右位心/中隔心的发生率明显高于其他亚型。TGA 患者中存在较高比例的二叶式肺动脉瓣（9.6%）。在 TGA 的复制组（n=132）中也观察到了类似的结果。通过一系列生物信息学过滤步骤，我们获得了 82 个候选基因，这些基因携带潜在的新生、功能丧失、复合杂合或 X 连锁隐性变异。已确立的先天性心脏病致病基因，如，在候选基因列表中被发现。总共还发现了 19 个携带罕见潜在破坏性变异的纤毛基因；例如，携带新生潜在破坏性变异的。纤毛基因的富集支持纤毛在 TGA 发病机制中的作用。总共，33%的 TGA 先证者有 >1 个候选基因被推定有害变异击中，这表明一部分 TGA 病例可能受到寡基因或多基因遗传的影响。
临床特征分析的结果对 TGA 患者分层具有重要意义。遗传分析的结果强调了纤毛基因在 TGA 中的致病作用和复杂的遗传结构。
