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

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.

Keywords: Congenital heart disease; Genetic; Pediatric cardiology; Pulmonary arterial hypertension.