Patent Ductus Arteriosus 1
Description
Persistent patency of the ductus arteriosus, or patent ductus arteriosus (PDA), is the second most common congenital heart disease, affecting approximately 1 in 1,600 to 5,000 live births in the U.S. (Mitchell et al., 1971). In fetal life, the ductus arteriosus, a muscular artery, shunts blood from the pulmonary artery to the aorta, bypassing the lungs. Its abrupt closure at birth establishes the mature circulatory pattern and represents a dramatic example of vascular remodeling. Failure of this normal process results in persistent PDA, which left untreated can result in pulmonary hypertension and heart failure. Closure of the ductus is a complex process. Aspects of this process are regulated by oxygen tension and a decrease in levels of hormones such as prostaglandin E2. PDA occurring in preterm infants often closes spontaneously or in response to inhibitors of prostaglandin biosynthesis (Ramsay et al., 1987). Term PDA typically has not been regarded as a genetic disorder, because it most often occurs sporadically. Nonetheless, term PDA recurs among 5% of sibs of PDA cases (Polani and Campbell, 1960; Lamy et al., 1957), suggesting a genetic component to disease pathogenesis that has typically been presumed to be multifactorial. That single genes can influence this trait has been demonstrated by a mouse model of PDA resulting from disruption of the prostaglandin E2 receptor (Nguyen et al., 1997) and by rare syndromic forms of PDA such as Char syndrome (169100), an autosomal dominant disorder caused by mutations in the transcription factor TFAP2B (601601) (Mani et al., 2002).
Genetic Heterogeneity of Patent Ductus Arteriosus
Autosomal dominant forms of patent ductus arteriosus include PDA2 (617035), caused by mutation in the TFAP2B gene (601601) on chromosome 6p12, and PDA3 (617039), caused by mutation in the PRDM6 gene (616982) on chromosome 5q23.
Hajj and Dagle (2012) reviewed the genetics of patent ductus arteriosus in both term and preterm infants, and discussed possible environmental risk factors as well as animal models of PDA.
Population GeneticsA possible explanation for the genetics of many sporadic diseases is the contribution of recessive loci with reduced penetrance. Mani et al. (2002) first searched for diseases with higher prevalence in populations with high rates of consanguinity, then determined whether disease cases are more commonly the product of consanguineous union than controls in such populations, followed by analysis of genetic linkage in consanguineous cases. They demonstrated the utility of this approach by investigation of congenital heart disease in Iran. They found that PDA accounts for a higher fraction of congenital heart disease in Iran (15%) than in the U.S. (2 to 7%). Moreover, Iranian PDA cases demonstrated a marked increase of parental consanguinity (63%) compared with the general Iranian population (25%) or control cases with tetralogy of Fallot (30%). The recurrence of PDA among sibs was 5%.
MappingBy a genomewide analysis of linkage in 21 unrelated consanguineous Iranian PDA cases, Mani et al. (2002) demonstrated a multipoint lod score of 6.27 in favor of linkage of PDA to a 3-cM interval of chromosome 12q24, with 53% of kindreds linked. The authors concluded that their findings established a recessive component to PDA and indicated that a single locus, which they designated PDA1, is responsible for at least one-third of all PDA cases in Iran and presumably has a role in PDA worldwide.