The Role of Genetics in Congenital Heart Disease-Associated Pulmonary Arterial Hypertension

TL;DR

This study explores how genetic variants contribute to pulmonary arterial hypertension in patients with congenital heart disease.

Contribution

The study identifies 12 novel genetic variants that may help explain the genetic basis of APAH-CHD.

Findings

21 distinct variants across 11 genes were detected in 17 out of 42 APAH-CHD patients.

The most common congenital heart defect in patients with detected variants was ventricular septal defect (VSD).

Genetic variants were found in both children and adults with APAH-CHD.

Abstract

Pulmonary arterial hypertension associated with congenital heart disease (APAH-CHD) is a severely progressive condition with complex pathogenesis. The aim of this study was to evaluate the contribution of genetic variants to the development of PAH in patients with APAH-CHD. Fifteen children and twenty-seven adults diagnosed with APAH-CHD were enrolled. Targeted next-generation sequencing was performed on PAH-associated genes (ABCC8, ACVRL1, AQP1, ATP13A3, BMPR2, CAV1, GDF2, GGCX, EIF2AK4, ENG, KCNK3, KDR, KLK1, SMAD1, SMAD4, SMAD9, SOX17, TBX4, TET2). A total of 21 distinct variants across 11 different genes were detected in 17 of the 42 patients. (ABCC8 = 2, ACVRL1 = 1, ATP13A3 = 2, BMPR2 = 4, GGCX = 1, EIF2AK4 = 2, ENG = 1, KDR = 3, SMAD1 = 1, SMAD9 = 1, TET2 = 3). Five of the patients with the mutation were under the age of 18, and 12 patients were adults. The most common CHD in patients with detected variants was VSD. PAH-related genetic variants were not uncommon in APAH-CHD patients. Our study identified 12 novel variants that may help to understand the genetic basis of APAH-CHD. Trial Registration The study has been registered on ClinicalTrials.gov with the identification number NCT05550389.

The online version contains supplementary material available at 10.1007/s00246-025-03847-z.

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