Rare Variants in Novel Candidate Genes Associated With Nonsyndromic Patent Ductus Arteriosus Identified With Whole-Exome Sequencing

Abstract

Background: Patent ductus arteriosus (PDA) is one of the most common congenital heart defects causing pulmonary hypertension, infective endocarditis, and even death. The important role of genetics in determining spontaneous ductal closure has been well-established. However, as many of the identified variants are rare, thorough identification of the associated genetic factors is necessary to further explore the genetic etiology of PDA.Methods: We performed whole-exome sequencing (WES) on 39 isolated nonsyndromic PDA patients and 100 healthy controls. Rare variants and novel genes were identified through bioinformatic filtering strategies. The expression patterns of candidate genes were explored in human embryo heart samples.Results: Eighteen rare damaging variants of six novel PDA-associated genes (SOX8, NES, CDH2, ANK3, EIF4G1, and HIPK1) were newly identified, which were highly expressed in human embryo hearts.Conclusions: WES is an efficient diagnostic tool for exploring the genetic pathogenesis of PDA. These findings contribute new insights into the molecular basis of PDA and may inform further studies on genetic risk factors for congenital heart defects.

Solitary patent ductus arteriosus in a Japanese macaque (Macaca fuscata): a case report and genetic investigation

“…Of the 6,227 identi ed variants, we applied a lter based on the annotation of variants, resulting in 1,133 variants for further analysis. We ltered the candidate SNVs using publicly available databases, including OMIM, MalaCards, ClinVar, STRING, the Gene Ontology database, and relevant literature, to assess their potential relevance to PDA and cardiovascular development (Gao et al 2022). This process resulted in a nal list of 32 potentially relevant variants.…”

“…Studies of patients with syndromic PDA, including Char (TFAP2B), Mowat-Wilson (ZEB2), Noonan (PTPN11), and Holt-Oram (TBX5) syndromes (Hajj and Dagle 2012), have shed light on the genetic mechanisms underlying PDA. The development of whole-exome sequencing (WES) has allowed researchers to actively explore the genetic causes of non-syndromic PDA, with recent studies uncovering rare damaging variants in six candidate genes (SOX8, NES, CDH2, ANK3, EIF4G1, and HIPK1) as potential causes of PDA (Gao et al 2022).…”

Whole‐exome sequencing analysis of patent ductus arteriosus in a Japanese macaque (Macaca fuscata)

“…We identified a total of 6227 variants and filtered them based on the annotation, resulting in 1133 variants. Candidate SNVs were filtered using public databases, including OMIM, MalaCards, ClinVar, STRING, the Gene Ontology (GO) database, and relevant literature, to assess their potential relevance to PDA and cardiovascular development, 5,7,8 resulting in a final list of 32 potentially relevant variants (Figure 1). We used the nucleotide BLAST program from NCBI to compare the 32 potentially relevant SNVs with sequences from five reference species (M. fuscata, M. mulatta, M. fascicularis, Papio anubis, and Homo sapiens) to assess the conservation level across species and identify the potential functional consequences of these variants.…”

“…Studies on patients with syndromic PDA, including Char ( TFAP2B ), Mowat–Wilson ( ZEB2 ), Noonan ( PTPN11 ), and Holt–Oram ( TBX5 ) syndromes, have highlighted the genetic mechanisms underlying PDA 4 . The development of whole‐exome sequencing (WES) has enabled the active investigation of the genetic causes of nonsyndromic PDA, and recent studies have uncovered rare damaging variants in six candidate genes ( SOX8 , NES , CDH2 , ANK3 , EIF4G1 , and HIPK1 ) 5 …”

“…4 The development of whole-exome sequencing (WES) has enabled the active investigation of the genetic causes of nonsyndromic PDA, and recent studies have uncovered rare damaging variants in six candidate genes (SOX8, NES, CDH2, ANK3, EIF4G1, and HIPK1). 5 Despite evident potential in human studies, WES encounters significant limitations in non-human primates (NHPs), primarily due to the absence of exome capture kits specifically designed for NHPs, 6 creating a bottleneck in veterinary medicine, particularly in the diagnosis of genetic diseases. Owing to WES, the availability of genetic data on congenital cardiovascular diseases in humans has rapidly increased; however, a striking disparity exists due to the absence of a comparable database for NHPs.…”