Abstract
As a rare type of Congenital Heart Defects (CHD), the genetic mechanism of Total Anomalous Pulmonary Venous Return (TAPVR) remains unknown, although previous studies have revealed potential disease-driving regions/genes. Blood samples collected from the 6 sporadic TAPVR cases and 81 non-TAPVR controls were subjected to whole exome sequencing. All detected variations were confirmed by direct Sanger sequencing. Here, we identified 2 non-synonymous missense mutations: c.C652T, p.R218W in activin A receptor type II-like 1 (ACVRL1), c.C717G, p.D239E in sarcoglycan delta (SGCD). Our results offered the landscape of mutations for TAPVR in Chinese population firstly and are valuable in the mutation-based pre- and post-natal screening and genetic diagnosis for TAPVR.
Highlights
Total Anomalous Pulmonary Venous Return (TAPVR) (OMIM:%106700) is one type of cyanotic Congenital Heart Defects (CHD), in which none of the pulmonary veins connect to the left atrium and are malpositioned to the systemic venous circulation [1] (Figure 1A, 1B)
After filtered through Public and in-house database, genes were classified referring to American College of Medical Genetics (ACMG) standards and guidelines [9] as follows: Category I genes were 15 TAPVR Pathogenic or likely Pathogenic Genes. (Supplementary Table 3); Category II genes were TAPVR associated Genes containing 221 human cardiac development related genes from gene ontology (GO) (Supplementary Table 4); Category III genes were unknown genes have not been reported previously
Part III variants were not located in Category I genes and low frequency in the 1000 Genomes, Exome Sequencing Project (ESP) and the Exome Aggregation Consortium (ExAC, version 0.3)
Summary
Total Anomalous Pulmonary Venous Return (TAPVR) (OMIM:%106700) is one type of cyanotic Congenital Heart Defects (CHD), in which none of the pulmonary veins connect to the left atrium and are malpositioned to the systemic venous circulation [1] (Figure 1A, 1B). Bleyl et al established a locus for TAPVR at 4p13-q12 [6] and found the PDGFRA as a driver gene in the further detailed research [7]. A non-synonymous variant in retinol binding protein 5 (RBP5) by Whole genome sequence (WGS) was analysised in 2 TAPVR patients recently [8]. The contribution of known genes above was still limited to investigate the genetic cause. We applied WES to the investigation of the genetic cause in 6 sporadic TAPVR cases and 81 non-TAPVR controls. We performed independent replication on additional 12 TAPVR patients by Sanger sequencing to identify the possible genetic variants
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