15q11.2 deletion is enriched in patients with total anomalous pulmonary venous connection
15q11.2 deletion is enriched in patients with total anomalous pulmonary venous connection
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完全肺静脉连接异常患者中 15q11.2 缺失较多
DOI：
10.1136/jmedgenet-2019-106608
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发表时间：
2021-02-01
影响因子：
4
通讯作者：
Wang, Bo
中科院分区：
文献类型：
--
作者：
Li, Xiaoliang;Shi, Guocheng;Wang, Bo
前言CNV是先天性心脏病（CHD）的重要致病因素。然而，很少有关于完全性肺静脉异位引流（TAPVC）的CNV报道，TAPVC是一种罕见的CHD形式。通过病例对照研究，我们确定了与TAPVC相关的15q11.2缺失。然后，我们使用TAPVC三人组作为模型，以揭示可能的15q11.2微缺失的分子基础。方法应用CNVplex和染色体微阵列技术对上海市儿童医学中心231例TAPVC患者和200例健康对照者的外周血标本进行CNVs检测。在体外心肌细胞分化诱导多能干细胞从外周血单核细胞的TAPVC三人与父系遗传15q11.2缺失进行，以验证删除心肌细胞分化和基因表达的影响。结果15q11.2微缺失在TAPVC患者中显著富集，与健康对照相比（患者13/231 vs对照0/200，p=5.872×10−2，Bonferroni校正）。先证者的诱导多能干细胞不能分化为正常心肌细胞。转录组学分析确定了一些差异表达的基因在15q11.2缺失携带者的家庭。TAPVC致病基因PITX 2、NKX 2 -5和ANKRD 1在先证者中的表达显著高于其健康母亲。TUBGCP 5的敲低可导致心肌细胞分化异常。结论15q11.2缺失与TAPVC的发生密切相关。使用细胞实验表征了可能由TAPVC家族的15q11.2缺失引起的基因表达谱。
Introduction CNV is a vital pathogenic factor of congenital heart disease (CHD). However, few CNVs have been reported for total anomalous pulmonary venous connection (TAPVC), which is a rare form of CHD. Using case-control study, we identified 15q11.2 deletion associated with TAPVC. We then used a TAPVC trio as model to reveal possible molecular basis of 15q11.2 microdeletion. Methods CNVplex and Chromosomal Microarray were used to identify and validate CNVs in samples from 231 TAPVC cases and 200 healthy controls from Shanghai Children’s Medical Center. In vitro cardiomyocyte differentiation of induced pluripotent stem cells from peripheral blood mononuclear cells for a TAPVC trio with paternal inherited 15q11.2 deletion was performed to characterise the effect of the deletion on cardiomyocyte differentiation and gene expression. Results The 15q11.2 microdeletion was significantly enriched in patients with TAPVC compared with healthy control (13/231 in patients vs 0/200 in controls, p=5.872×10−2, Bonferroni adjusted) using Fisher’s exact test. Induced pluripotent stem cells from the proband could not differentiate into normal cardiomyocyte. Transcriptomic analysis identified a number of differentially expressed genes in the 15q11.2 deletion carriers of the family. TAPVC disease-causing genes such as PITX2, NKX2-5 and ANKRD1 showed significantly higher expression in the proband compared with her healthy mother. Knockdown of TUBGCP5 could lead to abnormal cardiomyocyte differentiation. Conclusion We discovered that the 15q11.2 deletion is significantly associated with TAPVC. Gene expression profile that might arise from 15q11.2 deletion for a TAPVC family was characterised using cell experiments.