Patent Ductus Arteriosus 3

A number sign (#) is used with this entry because of evidence that patent ductus arteriosus-3 (PDA3) is caused by heterozygous mutation in the PRDM6 gene (616982) on chromosome 5q23.

Description

The ductus arteriosus is a vital in utero vascular connection between the aorta and pulmonary artery that allows right ventricular output to bypass the nonventilated fetal lungs. Postnatal closure of the ductus arteriosus is an important step in normal cardiopulmonary transition. Failure of ductal closure results in patent ductus arteriosus (PDA), which occurs in approximately 2 to 8 per 10,000 term infants and constitutes 5% to 7% of all congenital heart defects (summary by Hajj and Dagle, 2012).

For a discussion of genetic heterogeneity of isolated PDA, see PDA1 (607411).

Clinical Features

Lynch et al. (1965) reported 2 families segregating autosomal dominant nonsyndromic patent ductus arteriosus, with intraoperative confirmation of the diagnosis in 3 individuals over 2 generations in both families. The first was a large African American family (family A) in which the proband was a 17-year-old woman with PDA who presented during pregnancy with a loud machinery-like murmur at the base of the precordial area. Her female infant was born with PDA, and the proband also had an affected brother and sister and an affected half-sister. In the second family (family B), 2 sisters, their mother, and their maternal great-aunt were affected. Li et al. (2016) restudied family A of Lynch et al. (1965) and noted that the proband also had a sib who died in the neonatal period of congestive heart failure; autopsy showed hypoplastic left heart, ventricular septal defect, mild pulmonary artery stenosis, and a large and severely dilated PDA. In addition, the affected half-sister had a son with PDA, and an affected male cousin also had a son with PDA.

Mapping

In a large African American family segregating autosomal dominant nonsyndromic PDA, originally reported by Lynch et al. (1965), Li et al. (2016) performed linkage analysis and obtained positive lod scores for a cluster of markers in chromosome region 5q23. Multipoint linkage analysis confirmed the locus, yielding a maximum lod score of 3.12 at rs2081914 (theta = 0). No other interval in the genome yielded a lod score greater than 1.0.

Nomenclature

Li et al. (2016) designated the PDA locus on 5q23 'PDA1,' but that symbol had already been used for an autosomal recessive PDA locus on 12q24 (607411).

Molecular Genetics

In a large African American family segregating autosomal dominant nonsyndromic PDA mapping to chromosome 5q23, originally reported by Lynch et al. (1965), Li et al. (2016) performed exome sequencing and identified a heterozygous missense mutation in the PRDM6 gene (R549Q; 616982.0001) that segregated completely with disease. Analysis of exome data from 34 additional probands with isolated PDA revealed 2 more missense mutations: C263S (616982.0002) in a woman whose deceased mother and maternal grandfather had also been affected, and Q462R (616982.0003) in an affected mother and daughter. None of the mutations were found in public variant databases.