Rare variant analysis of 4,241 pulmonary arterial hypertension cases from an international consortium implicateFBLN2,PDGFDand rarede novovariants in PAH

Abstract

Background -Group 1 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. Recent highthroughput sequencing studies have identified additional PAH risk genes and suggested differences in genetic causes by age of onset. However, known risk genes explain only 15-20% of non-familial idiopathic PAH cases. Methods-To identify new risk genes, we utilized an international consortium of 4,241 PAH cases with 4,175 sequenced exomes (n=2,572 National Biological Sample and Data Repository for PAH; n=469 Columbia University Irving Medical Center, enriched for pediatric trios) and 1,134 sequenced genomes (UK NIHR Bioresource -Rare Diseases Study). Most of the cases were adult-onset disease (93%), and 55% idiopathic (IPAH) and 35% associated with other diseases (APAH). We identified protein-coding variants and performed rare variant association analyses in unrelated participants of European ancestry, including 2,789 cases and 18,819 controls (11,101unaffected parents from the Simons Powering Autism Research for Knowledge study and 7,718 gnomAD individuals). We analyzed de novo variants in 124 pediatric trios.Results -Seven genes with rare deleterious variants were significantly associated (false discovery rate <0.1) with IPAH, including three known genes (BMPR2, GDF2, and TBX4), two recently identified candidate genes (SOX17, KDR), and two new candidate genes (FBLN2, fibulin 2; PDGFD, platelet-derived growth factor D). The candidate genes exhibit expression patterns in lung and heart similar to that of known PAH risk genes, and most of the variants occur in conserved protein domains. Variants in known PAH gene, ACVRL1, showed association with APAH. Predicted deleterious de novo variants in pediatric cases exhibited a significant burden compared to the background mutation rate (2.5x, p=7.0E-6). At least eight novel candidate genes carrying de novo variants have plausible roles in lung/heart development.Conclusions -Rare variant analysis of a large international consortium identifies two new candidate genes -FBLN2 and PDGFD. The new genes have known functions in vasculogenesis and remodeling but have not been previously implicated in PAH. Trio analysis predicts that ~15% of pediatric IPAH may be explained by de novo variants.

Genetics and Genomics of Pediatric Pulmonary Arterial Hypertension

“…An NRF2 activator is currently being investigated in a phase 2 clinical trial for PAH (ichgcp.net/clinical-trials-registry/NCT02036970). Finally, one third of all of the de novo variants identified in the trio analysis are in causal genes for developmental syndromes, consistent with the enrichment of developmental phenotypes among the variant carriers [ 10 ]. The genes identified in this study require replication in a larger pediatric cohort.…”

“…Emerging data from genetic studies of pediatric-onset PAH indicate that the genetic basis in children is different from that of adults [ 10 , 11 , 13 ]. There is a greater genetic burden in children, with rare genetic factors contributing to ~42% of pediatric-onset PAH compared to ~12.5% of adult-onset PAH ( Figure 1 ).…”

“…There is a greater genetic burden in children, with rare genetic factors contributing to ~42% of pediatric-onset PAH compared to ~12.5% of adult-onset PAH ( Figure 1 ). De novo variants are frequent in children, likely contributing to ~15% of pediatric PAH [ 10 , 13 ]. Among rare inherited variants, variants in BMPR2 are causal in ~6.5–7% of both pediatric- and adult-onset PAH; most of the cases are FPAH or idiopathic PAH (IPAH), rarely PAH associated with other diseases (APAH) [ 11 , 22 ], and no occurrences in PPHN have been reported to date [ 23 ].…”

“…De novo variants have emerged as an important class of genetic factors underlying rare diseases, especially early-onset severe conditions [ 15 , 33 , 48 , 49 , 50 ], due to strong negative selection decreasing reproductive fitness [ 51 ]. We recently assessed the role of rare deleterious de novo variants in pediatric PAH using a cohort of 124 parent-child trios (56% IPAH, 38% APAH-CHD, 6% other PAH) [ 10 ]. We observed a 2.5-fold enrichment of de novo variants among all PAH cases compared to the expected rate, almost entirely due to genes that are highly expressed in developing lung or heart ( Table 3 ).…”

“…The frequency of PAH is ~3–4-fold higher in females relative to males for adult-onset disease. However, data from the National Biological Sample and Data Repository for PAH (aka PAH Biobank, Table 1 ) [ 10 , 11 ] and other studies [ 12 , 13 ] indicate that the frequency of pediatric-onset PAH is similar for females and males, suggesting less dependence on sex-specific factors in children. Children present with increased severity of disease, e.g., elevated mean pulmonary artery pressure (mPAP), decreased cardiac output, and increased pulmonary vascular resistance, compared to adults at diagnosis ( Table 1 ) [ 10 , 11 ].…”