Rare variant analysis of 4241 pulmonary arterial hypertension cases from an international consortium implicates FBLN2, PDGFD, and rare de novo variants in PAH

Regeneron Genetics Center, PAH Biobank Enrolling Centers’ Investigators, NIHR BioResource for Translational Research - Rare Diseases, National Cohort Study of Idiopathic and Heritable PAH

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14 Scopus citations


Background: Pulmonary arterial hypertension (PAH) is a lethal vasculopathy characterized by pathogenic remodeling of pulmonary arterioles leading to increased pulmonary pressures, right ventricular hypertrophy, and heart failure. PAH can be associated with other diseases (APAH: connective tissue diseases, congenital heart disease, and others) but often the etiology is idiopathic (IPAH). Mutations in bone morphogenetic protein receptor 2 (BMPR2) are the cause of most heritable cases but the vast majority of other cases are genetically undefined. Methods: To identify new risk genes, we utilized an international consortium of 4241 PAH cases with exome or genome sequencing data from the National Biological Sample and Data Repository for PAH, Columbia University Irving Medical Center, and the UK NIHR BioResource – Rare Diseases Study. The strength of this combined cohort is a doubling of the number of IPAH cases compared to either national cohort alone. We identified protein-coding variants and performed rare variant association analyses in unrelated participants of European ancestry, including 1647 IPAH cases and 18,819 controls. We also analyzed de novo variants in 124 pediatric trios enriched for IPAH and APAH-CHD. Results: Seven genes with rare deleterious variants were associated with IPAH with false discovery rate smaller than 0.1: three known genes (BMPR2, GDF2, and TBX4), two recently identified candidate genes (SOX17, KDR), and two new candidate genes (fibulin 2, FBLN2; platelet-derived growth factor D, PDGFD). The new genes were identified based solely on rare deleterious missense variants, a variant type that could not be adequately assessed in either cohort alone. The candidate genes exhibit expression patterns in lung and heart similar to that of known PAH risk genes, and most variants occur in conserved protein domains. For pediatric PAH, predicted deleterious de novo variants exhibited a significant burden compared to the background mutation rate (2.45×, p = 2.5e−5). At least eight novel pediatric candidate genes carrying de novo variants have plausible roles in lung/heart development. Conclusions: Rare variant analysis of a large international consortium identified two new candidate genes—FBLN2 and PDGFD. The new genes have known functions in vasculogenesis and remodeling. Trio analysis predicted that ~ 15% of pediatric IPAH may be explained by de novo variants.

Original languageEnglish (US)
Article number80
JournalGenome medicine
Issue number1
StatePublished - Dec 2021

Bibliographical note

Funding Information:
Samples and/or data from the National Biological Sample and Data Repository for PAH (aka PAH Biobank) were used in this study. We thank contributors, including the Pulmonary Hypertension Centers who collected samples used in this study, as well as patients and their families, whose help and participation made this work possible. We appreciate the contribution of the research coordinators across the clinical sites and Patricia Lanzano for coordinating the Columbia biorepository. Exome sequencing and genotyping data were generated by the Regeneron Genetics Center.

Funding Information:
This study was funded in part by NIH grants R24HL105333 (WCN, MWP), RO1HL060056 (WKC), UO1HL125218 (WKC, ER), and RO1GM1200609 (YS). The UK National Cohort of Idiopathic and Heritable PAH is supported by the NIHR Cambridge Biomedical Research Centre (BRC) and Cambridge University Hospitals NHS Foundation Trust (CUH) (BRC 2012-2017), the British Heart Foundation (BHF) (SP/12/12/29836 and SP/18/10/33975), the BHF Cambridge Centre of Cardiovascular Research Excellence (CRE), the UK Medical Research Council (MR/K020919/1), and the Dinosaur Trust, BHF Programme grants to RCT (RG/08/006/25302) and NWM (RG/13/4/30107). NWM is a BHF Professor and NIHR Senior Investigator. AL is supported by a BHF Senior Basic Science Research Fellowship (FS/13/48/30453). All research at Great Ormond Street Hospital NHS Foundation Trust and UCL Great Ormond Street Institute of Child Health is made possible by the NIHR Great Ormond Street Hospital Biomedical Research Centre.

Funding Information:
We thank the research nurses and coordinators at the specialist pulmonary hypertension centers involved in this study. We acknowledge the support of the Imperial NIHR Clinical Research Facility, the Netherlands CardioVascular Research Initiative, the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Sciences. We thank all the patients and their families who contributed to this research and the Pulmonary Hypertension Association (UK) for their support.

Publisher Copyright:
© 2021, The Author(s).


  • Case-control association testing
  • De novo variant analysis
  • Exome sequencing
  • Genetics
  • Genome sequencing
  • Pulmonary arterial hypertension


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