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

Abstract

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.

Biallelic variants of ATP13A3 cause dose-dependent childhood-onset pulmonary arterial hypertension characterised by extreme morbidity and mortality

“…1 2 However, approximately 80% of IPAH cases remain genetically undiagnosed. Recent sequencing studies have accelerated the identification of additional risk genes, [3][4][5] including monoallelic ATP13A3 variants associated with adult-onset IPAH across genetic ancestries. 3 4 6 7 ATP13A3 encodes a P-type ATPase, a cation transporter with a documented role in the polyamine transport system.…”

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

“…It was highlighted that the original article [ 1 ] contained an error in the name of Claudia Gonzaga-Jauregui. It was incorrectly captured as Gonzaga-Juaregui.…”

Rare and de novo variants in 827 congenital diaphragmatic hernia probands implicate LONP1 and ALYREF as new candidate risk genes

“…Exome and WGS data of cases and controls were processed using a pipeline implementing GATK Best Practice v4.0 as previously described 9,22 . Specifically, reads of exome cases were mapped to human genome GRCh37 reference using BWA-MEM 23 , while reads of WGS cases, SPARK and WHICAP controls were mapped to GRCh38; duplicated reads were marked using Picard 24 ; variants were called using GATK 25 (v4.0) HaplotypeCaller to generate gVCF files for joint genotyping.…”

“…To reduce batch effects in combined datasets from different sources 30 in analysis of rare variants, for non-Latinx population we targeted ultra-rare variants located in xGen-captured protein coding regions and for Latinx population in regions targeted by xGen and SeqCap EZ v3.0. We used the following criteria to minimize technical artifacts and select ultra-rare variants 22 : cohort AF <0.5% and population cohort <1×10 −5 across all genomes in gnomAD v3.0; mappability=1; >90% target region with depth ≥10; overlapped with segmental duplication regions <95%; genotype quality >30, allele balance >20% and depth >10 in cases.…”

“…To identify CDH risk genes, we tested the burden of ultra-rare deleterious variants (AF <1×10 −5 across all gnomAD v3.0 genomes, LGD or D-Mis) in each protein-coding gene in cases compared to controls. To improve statistical power, we searched for a gene-specific CADD 33 score threshold for defining D-Mis that maximized the burden of ultra-rare deleterious variants in cases compared to controls and used permutations to calculate statistical significance with the variable threshold test 22,45 . For the binomial tests in each permutation, we used binom.test function in R to calculate p values.…”