• Na Zhu, Emilia M Swietlik, Carrie L Welch, Michael W Pauciulo, Jacob J Hagen, Xueya Zhou, Yicheng Guo, Johannes Karten, Divya Pandya, Tobias Tilly, Katie A Lutz, Jennifer M Martin, Carmen M Treacy, Erika B Rosenzweig, Usha Krishnan, Anna W Coleman, Claudia Gonzaga-Jauregui, Allan Lawrie, Richard C Trembath, Martin R Wilkins, Regeneron Genetics Center, PAH Biobank Enrolling Centers’ Investigators, NIHR BioResource for Translational Research - Rare Diseases, National Cohort Study of Idiopathic and Heritable PAH, Nicholas W Morrell, Yufeng Shen, Stefan Gräf, William C Nichols, and Wendy K Chung.
• Department of Pediatrics, Columbia University Irving Medical Center, 1150 St. Nicholas Avenue, Room 620, New York, NY, 10032, USA.
• Genome Med. 2021 May 10; 13 (1): 80.

BackgroundPulmonary 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.MethodsTo 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.ResultsSeven 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.ConclusionsRare 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.

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