Identification of Rare Copy Number Variants Associated With Pulmonary Atresia With Ventricular Septal Defect

Abstract

Copy number variants (CNVs) are major variations contributing to the gene heterogeneity of congenital heart diseases (CHD). pulmonary atresia with ventricular septal defect (PA-VSD) is a rare form of cyanotic CHD characterized by complex manifestations and the genetic determinants underlying PA-VSD are still largely unknown. We investigated rare CNVs in a recruited cohort of 100 unrelated patients with PA-VSD, PA-IVS, or TOF and a population-matched control cohort of 100 healthy children using whole-exome sequencing. Comparing rare CNVs in PA-VSD cases and that in PA-IVS or TOF positive controls, we observed twenty-two rare CNVs only in PA-VSD, five rare CNVs only in PA-VSD and TOF as well as thirteen rare CNVs only in PA-VSD and PA-IVS. Six of these CNVs were considered pathogenic or potentially pathogenic to PA-VSD: 16p11.2 del (PPP4C and TBX6), 5q35.3 del (FLT4), 5p13.1 del (RICTOR), 6p21.33 dup (TNXB), 7p15.2 del (HNRNPA2B1), and 19p13.3 dup (FGF22). The gene networks showed that four putative candidate genes for PA-VSD, PPP4C, FLT4, RICTOR, and FGF22 had strong interaction with well-known cardiac genes relevant to heart or blood vessel development. Meanwhile, the analysis of transcriptome array revealed that PPP4C and RICTOR were also significantly expressed in human embryonic heart. In conclusion, three rare novel CNVs were identified only in PA-VSD: 16p11.2 del (PPP4C), 5q35.3 del (FLT4) and 5p13.1 del (RICTOR), implicating novel candidate genes of interest for PA-VSD. Our study provided new insights into understanding for the pathogenesis of PA-VSD and helped elucidate critical genes for PA-VSD.

Mutations in fibroblast growth factor (FGF8) and FGF10 identified in patients with conotruncal defects

“…The total RNA was extracted using the TissueLyser II (Qiagen) and RNeasy MinElute Cleanup Kit (Qiagen). Then, we performed transcriptome array analysis [ 24 ] to detect gene expression levels at different developmental stages. Raw data was normalized by Affymetrix Transcriptome Analysis Console (TAC) software, and the normalized signal value was the signal value calculated by log2 transformation.…”

A Chromosomal Inversion of 46XX, inv (6) (p21.3p23) Connects to Congenital Heart Defects

“…Interestingly, several genes that reside in the proximal regions of these breakpoints, including TNXB ( 20 ) and CDKN1A ( 21 ) at around 6p21.3 and TFAP2A ( 22 ), EDN1 ( 23 ), and JARID2 ( 24 ) at around 6p23, were reported to be involved in the pathogenesis of VSD. Furthermore, duplication of the TNXB locus was considered as pathogenic to pulmonary atresia with ventricular septal defect in the human patient ( 25 ). In the future, the coverage of this genetic mutation in VSD and the major linked gene(s) in this chromosomal inversion need to be further determined in detail.…”

A loss‐of‐function mutation p.T256M in NDRG4 is implicated in the pathogenesis of pulmonary atresia with ventricular septal defect (PA/VSD) and tetralogy of Fallot (TOF)

“…The prevalence of PA/VSD is about 0.2% of live births and roughly 2% in CHDs. In addition, PA/VSD is also considered as one of the most complex and unmanageable CHD [2,30].…”

“…The difference is the severity of obstruction of right ventricle outflow tract. Therefore, it is moderately accepted that PA/VSD is the most severe type of TOF [6,22,30].…”