Genetic Variants Associated with Persistent Pulmonary Hypertension of Newborn: A Systematic Review

Persistent pulmonary hypertension of newborn (PPHN) occurs due to the impairment in the expected fall in pulmonary vascular resistance during the fetal to neonatal circulatory transition, with a prevalence of 1.9 per 1,000 live births and a significant mortality rate of 4-33%. We aimed to systematically review the genetic variants associated with PPHN in term and late preterm infants without a known genetic syndrome.

In February 2025, the MEDLINE Ovid, Scopus, and Cochrane databases were searched for eligible studies without publication date restriction. Our review included cohort studies, case-control studies, and case series that examined the association of PPHN and genetic variants in term and late preterm infants. We extracted data regarding the methodology, participant characteristics, and outcome measures.

We included nine studies (7 case-control studies and 2 cohort studies) that enrolled 1,494 participants. The risk of bias assessment using the Quality of Genetic Association Studies tool showed that 100% of the studies were of moderate or good quality. Our review found reports of positive associations between specific genetic variants in genes such as CPS1, CRHR1, NOTCH3, EDN1, EPAS1, WWC2, ABCA3, RFX3, EP300, GNA11, PKLR, SLC2A1, BMPR2, and EGLN1. One study reported no association between an ACE gene variant and PPHN.

Studies of common genetic variants associated with an increased risk of PPHN in term and late preterm infants are limited, based on small cohorts and frequently focused on small sets of candidate genes, yielding inconsistent results across studies.