Abstract
Pulmonary arterial hypertension (PAH) is a rare, progressive vasculopathy with significant cardiopulmonary morbidity and mortality. The underlying pathogenetic mechanisms are heterogeneous and current therapies aim to decrease pulmonary vascular resistance but no curative treatments are available. Causal genetic variants can be identified in ~13% of adults and 43% of children with PAH. Knowledge of genetic diagnoses can inform clinical management of PAH, including multimodal medical treatment, surgical intervention and transplantation decisions, and screening for associated conditions, as well as risk stratification for family members. Roles for rare variants in three channelopathy genes—ABCC8, ATP13A3, and KCNK3—have been validated in multiple PAH cohorts, and in aggregate explain ~2.7% of PAH cases. Complete or partial loss of function has been demonstrated for PAH-associated variants in ABCC8 and KCNK3. Channels can be excellent targets for drugs, and knowledge of mechanisms for channel mutations may provide an opportunity for the development of PAH biomarkers and novel therapeutics for patients with hereditary PAH but also potentially more broadly for all patients with PAH.
Highlights
Pulmonary arterial hypertension (PAH) is a rare, progressive and often lethal disease characterized by distinctive changes in pulmonary arteries that lead to increased pulmonary vascular resistance [1,2,3]
ABCC8, and rare or novel missense variants were identified in seven unrelated patients with idiopathic PAH (IPAH), HPAH or APAH-congenital heart disease (APAH-CHD)
PAH cases compared to two independent European population control groups (n > 33,000 individuals each), indicated a 3-fold enrichment rate of ABCC8 variants among PAH cases with no significant difference in the frequency of predicted benign synonymous variants between cases and controls
Summary
Pulmonary arterial hypertension (PAH) is a rare, progressive and often lethal disease characterized by distinctive changes in pulmonary arteries that lead to increased pulmonary vascular resistance [1,2,3]. The entire PAH cohort was screened for genetic variants in ABCC8, and rare or novel missense variants were identified in seven unrelated patients with IPAH, HPAH or APAH-congenital heart disease (APAH-CHD). Of the 45 rare, predicted deleterious ABCC8 variants identified in 49 unrelated PAH cases, 41 are missense variants. In the PAH Biobank, seven unique variants (three frameshift, one stopgain, and three missense) were identified in seven unrelated cases (five HPAH/IPAH, one APAH-CTD, and one APAH-CHD) [6] In each of these studies, the cases were adult-onset disease, with the exception of one child, and all were heterozygous. KCNK3 was first identified as a PAH causal gene by rare variant analysis of exome sequencing data in a family with five affected members [17]. 2085 PAH cases [52]
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