Shared Segment Analysis and Next-Generation Sequencing Implicates the Retinoic Acid Signaling Pathway in Total Anomalous Pulmonary Venous Return (TAPVR).
Shared Segment Analysis and Next-Generation Sequencing Implicates the Retinoic Acid Signaling Pathway in Total Anomalous Pulmonary Venous Return (TAPVR).
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DOI：
10.1371/journal.pone.0131514
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Bleyl SB
中科院分区：
文献类型：
--
作者：
Nash D;Arrington CB;Kennedy BJ;Yandell M;Wu W;Zhang W;Ware S;Jorde LB;Gruber PJ;Yost HJ;Bowles NE;Bleyl SB
大多数孤立的先天性心脏缺陷被认为是散发性的，通常被归因于多因素机制，但对遗传学了解很少。完全性肺静脉异常返流(TAPVR)发生在15,000名活产婴儿中就有1名，要么是孤立发生的，要么是左右发育异常的综合征的一部分。此前，我们报道了TAVPR和PDGFRA基因之间的因果联系。TAPVR还与ANKRD1/CARP基因相关联。然而，这些基因只解释了这种疾病的遗传性的一小部分。通过对5例远亲TAPVR患者的阶段性单核苷酸多态基因数据的分析，我们发现其中3例患者及其专职携带者父母在12号染色体短臂上有一个共同的25 cM、相同的下降基因组片段。全基因组序列(WGS)分析发现视黄醇结合蛋白5(RBP5)基因共有片段中存在一个非同义变异。RBP5变异体被预测是有害的，在TAPVR人群中被过度表达。斑马鱼同源基因rbp7的基因表达和功能分析支持rbp5是TAPVR易感基因的观点。额外的序列分析也发现了与视黄酸信号相关的基因的有害变异，包括节点和视黄醇脱氢酶10。这些数据表明，视黄酸信号通路的遗传变异在一定程度上增加了对TAPVR的易感性。
Most isolated congenital heart defects are thought to be sporadic and are often ascribed to multifactorial mechanisms with poorly understood genetics. Total Anomalous Pulmonary Venous Return (TAPVR) occurs in 1 in 15,000 live-born infants and occurs either in isolation or as part of a syndrome involving aberrant left-right development. Previously, we reported causative links between TAVPR and the PDGFRA gene. TAPVR has also been linked to the ANKRD1/CARP genes. However, these genes only explain a small fraction of the heritability of the condition. By examination of phased single nucleotide polymorphism genotype data from 5 distantly related TAPVR patients we identified a single 25 cM shared, Identical by Descent genomic segment on the short arm of chromosome 12 shared by 3 of the patients and their obligate-carrier parents. Whole genome sequence (WGS) analysis identified a non-synonymous variant within the shared segment in the retinol binding protein 5 (RBP5) gene. The RBP5 variant is predicted to be deleterious and is overrepresented in the TAPVR population. Gene expression and functional analysis of the zebrafish orthologue, rbp7, supports the notion that RBP5 is a TAPVR susceptibility gene. Additional sequence analysis also uncovered deleterious variants in genes associated with retinoic acid signaling, including NODAL and retinol dehydrogenase 10. These data indicate that genetic variation in the retinoic acid signaling pathway confers, in part, susceptibility to TAPVR.
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