Defining the Clinical Validity of Genes Reported to Cause Pulmonary Arterial Hypertension

Overview

Journal Genet Med

Publisher Elsevier

Specialty Genetics

Date 2023 Jul 9

PMID 37422716

Authors

Carrie L Welch

Micheala A Aldred

Srimmitha Balachandar

Dennis Dooijes

Christina A Eichstaedt

Stefan Graf

Arjan C Houweling

Rajiv D Machado

Divya Pandya

Matina Prapa

Memoona Shaukat

Laura Southgate

Jair Tenorio-Castano

Wendy K Chung

Affiliations

Soon will be listed here.

Abstract

Purpose: Pulmonary arterial hypertension (PAH) is a rare, progressive vasculopathy with significant cardiopulmonary morbidity and mortality. Genetic testing is currently recommended for adults diagnosed with heritable, idiopathic, anorexigen-, hereditary hemorrhagic telangiectasia-, and congenital heart disease-associated PAH, PAH with overt features of venous/capillary involvement, and all children diagnosed with PAH. Variants in at least 27 genes have putative evidence for PAH causality. Rigorous assessment of the evidence is needed to inform genetic testing.

Methods: An international panel of experts in PAH applied a semi-quantitative scoring system developed by the NIH Clinical Genome Resource to classify the relative strength of evidence supporting PAH gene-disease relationships based on genetic and experimental evidence.

Results: Twelve genes (BMPR2, ACVRL1, ATP13A3, CAV1, EIF2AK4, ENG, GDF2, KCNK3, KDR, SMAD9, SOX17, and TBX4) were classified as having definitive evidence and 3 genes (ABCC8, GGCX, and TET2) with moderate evidence. Six genes (AQP1, BMP10, FBLN2, KLF2, KLK1, and PDGFD) were classified as having limited evidence for causal effects of variants. TOPBP1 was classified as having no known PAH relationship. Five genes (BMPR1A, BMPR1B, NOTCH3, SMAD1, and SMAD4) were disputed because of a paucity of genetic evidence over time.

Conclusion: We recommend that genetic testing includes all genes with definitive evidence and that caution be taken in the interpretation of variants identified in genes with moderate or limited evidence. Genes with no known evidence for PAH or disputed genes should not be included in genetic testing.

Citing Articles

Pulmonary Hypertension: Molecular Mechanisms and Clinical Studies.

Adu-Amankwaah J, You Q, Liu X, Jiang J, Yang D, Liu K MedComm (2020). 2025; 6(3):e70134.

PMID: 40066229 PMC: 11892029. DOI: 10.1002/mco2.70134.

Introducing Historical Vignettes in .

Palevsky H, Butrous G, Elliott C Pulm Circ. 2025; 15(1):e70061.

PMID: 39980709 PMC: 11839388. DOI: 10.1002/pul2.70061.

Ineffectiveness of Sotatercept Therapy in a Patient With Heritable Pulmonary Arterial Hypertension Associated With a Previously Unreported Missense Variant in GDF2, the Gene for Bone Morphogenic Protein-9.

Langleben D, Lesenko L, Fox B, Eintracht S, Foulkes W, Rosenblatt D Chest. 2025; 167(2):e37-e39.

PMID: 39939060 PMC: 11867889. DOI: 10.1016/j.chest.2024.09.002.

Genetic evidence for the causal effect of clonal hematopoiesis on pulmonary arterial hypertension.

Qiu J, Huang S, Liu C, Ding D, Xu Y, Mao Y BMC Cardiovasc Disord. 2025; 25(1):38.

PMID: 39849426 PMC: 11755826. DOI: 10.1186/s12872-025-04475-4.

Precision Medicine for Pulmonary Vascular Disease: The Future Is Now (2023 Grover Conference Series).

Forbes L, Bauer N, Bhadra A, Bogaard H, Choudhary G, Goss K Pulm Circ. 2025; 15(1):e70027.

PMID: 39749110 PMC: 11693987. DOI: 10.1002/pul2.70027.

References

Malhotra R, Paskin-Flerlage S, Zamanian R, Zimmerman P, Schmidt J, Deng D . Circulating angiogenic modulatory factors predict survival and functional class in pulmonary arterial hypertension. Pulm Circ. 2013; 3(2):369-80. PMC: 3757832. DOI: 10.4103/2045-8932.110445. View

Eichstaedt C, Sassmannshausen Z, Shaukat M, Cao D, Xanthouli P, Gall H . Gene panel diagnostics reveals new pathogenic variants in pulmonary arterial hypertension. Respir Res. 2022; 23(1):74. PMC: 8962083. DOI: 10.1186/s12931-022-01987-x. View

Jerkic M, Kabir M, Davies A, Yu L, McIntyre B, Husain N . Pulmonary hypertension in adult Alk1 heterozygous mice due to oxidative stress. Cardiovasc Res. 2011; 92(3):375-84. DOI: 10.1093/cvr/cvr232. View

Waite K, Eng C . From developmental disorder to heritable cancer: it's all in the BMP/TGF-beta family. Nat Rev Genet. 2003; 4(10):763-73. DOI: 10.1038/nrg1178. View

Eichstaedt C, Song J, Viales R, Pan Z, Benjamin N, Fischer C . First identification of mutation in heritable pulmonary arterial hypertension. Clin Sci (Lond). 2017; 131(8):689-698. DOI: 10.1042/CS20160930. View

Atkins G, Jain M . Role of Krüppel-like transcription factors in endothelial biology. Circ Res. 2007; 100(12):1686-95. DOI: 10.1161/01.RES.0000267856.00713.0a. View

Hong K, Lee Y, Lee E, Park S, Han C, Beppu H . Genetic ablation of the BMPR2 gene in pulmonary endothelium is sufficient to predispose to pulmonary arterial hypertension. Circulation. 2008; 118(7):722-30. PMC: 3920834. DOI: 10.1161/CIRCULATIONAHA.107.736801. View

Zhu N, Gonzaga-Jauregui C, Welch C, Ma L, Qi H, King A . Exome Sequencing in Children With Pulmonary Arterial Hypertension Demonstrates Differences Compared With Adults. Circ Genom Precis Med. 2018; 11(4):e001887. PMC: 5896781. DOI: 10.1161/CIRCGEN.117.001887. View

Wani M, Conkright M, Jeffries S, Hughes M, Lingrel J . cDNA isolation, genomic structure, regulation, and chromosomal localization of human lung Kruppel-like factor. Genomics. 1999; 60(1):78-86. DOI: 10.1006/geno.1999.5888. View

10.

Gore B, Izikki M, Mercier O, Dewachter L, Fadel E, Humbert M . Key role of the endothelial TGF-β/ALK1/endoglin signaling pathway in humans and rodents pulmonary hypertension. PLoS One. 2014; 9(6):e100310. PMC: 4067299. DOI: 10.1371/journal.pone.0100310. View

11.

Zhu N, Swietlik E, Welch C, Pauciulo M, Hagen J, Zhou X . Rare variant analysis of 4241 pulmonary arterial hypertension cases from an international consortium implicates FBLN2, PDGFD, and rare de novo variants in PAH. Genome Med. 2021; 13(1):80. PMC: 8112021. DOI: 10.1186/s13073-021-00891-1. View

12.

Rhodes C, Ghataorhe P, Wharton J, Rue-Albrecht K, Hadinnapola C, Watson G . Plasma Metabolomics Implicates Modified Transfer RNAs and Altered Bioenergetics in the Outcomes of Pulmonary Arterial Hypertension. Circulation. 2016; 135(5):460-475. PMC: 5287439. DOI: 10.1161/CIRCULATIONAHA.116.024602. View

13.

Attisano L, Carcamo J, Ventura F, Weis F, Massague J, Wrana J . Identification of human activin and TGF beta type I receptors that form heteromeric kinase complexes with type II receptors. Cell. 1993; 75(4):671-80. DOI: 10.1016/0092-8674(93)90488-c. View

14.

Genovese G, Kahler A, Handsaker R, Lindberg J, Rose S, Bakhoum S . Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014; 371(26):2477-87. PMC: 4290021. DOI: 10.1056/NEJMoa1409405. View

15.

Renard M, Francis C, Ghosh R, Scott A, Witmer P, Ades L . Clinical Validity of Genes for Heritable Thoracic Aortic Aneurysm and Dissection. J Am Coll Cardiol. 2018; 72(6):605-615. PMC: 6378369. DOI: 10.1016/j.jacc.2018.04.089. View

16.

Khetarpal S, Qamar A, Bick A, Fuster J, Kathiresan S, Jaiswal S . Clonal Hematopoiesis of Indeterminate Potential Reshapes Age-Related CVD: JACC Review Topic of the Week. J Am Coll Cardiol. 2019; 74(4):578-586. PMC: 6662618. DOI: 10.1016/j.jacc.2019.05.045. View

17.

Liu F, Ventura F, Doody J, Massague J . Human type II receptor for bone morphogenic proteins (BMPs): extension of the two-kinase receptor model to the BMPs. Mol Cell Biol. 1995; 15(7):3479-86. PMC: 230584. DOI: 10.1128/MCB.15.7.3479. View

18.

Seki T, Yun J, Oh S . Arterial endothelium-specific activin receptor-like kinase 1 expression suggests its role in arterialization and vascular remodeling. Circ Res. 2003; 93(7):682-9. DOI: 10.1161/01.RES.0000095246.40391.3B. View

19.

Zhu N, Pauciulo M, Welch C, Lutz K, Coleman A, Gonzaga-Jauregui C . Novel risk genes and mechanisms implicated by exome sequencing of 2572 individuals with pulmonary arterial hypertension. Genome Med. 2019; 11(1):69. PMC: 6857288. DOI: 10.1186/s13073-019-0685-z. View

20.

Stone O, Richer C, Emanueli C, van Weel V, Quax P, Katare R . Critical role of tissue kallikrein in vessel formation and maturation: implications for therapeutic revascularization. Arterioscler Thromb Vasc Biol. 2009; 29(5):657-64. PMC: 2827862. DOI: 10.1161/ATVBAHA.108.182139. View