scholarly journals Rare variant analysis of 4,241 pulmonary arterial hypertension cases from an international consortium implicate FBLN2, PDGFD and rare de novo variants in PAH

2020 ◽  
Author(s):  
Na Zhu ◽  
Emilia M. Swietlik ◽  
Carrie L. Welch ◽  
Michael W. Pauciulo ◽  
Jacob J. Hagen ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Candidate Genes ◽  
Rare Variant ◽  
De Novo ◽  
Risk Genes ◽  
International Consortium ◽  
Rare Variant Analysis ◽  
Pulmonary Arterial ◽  
Variant Analysis

AbstractBackgroundGroup 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 high-throughput 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.MethodsTo 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 (11,101 unaffected parents from the Simons Powering Autism Research for Knowledge study and 7,718 gnomAD individuals). We analyzed de novo variants in 124 pediatric trios.ResultsSeven 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.ConclusionsRare 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.

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

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Na Zhu ◽  
◽  
Emilia M. Swietlik ◽  
Carrie L. Welch ◽  
Michael W. Pauciulo ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Candidate Genes ◽  
Rare Variant ◽  
De Novo ◽  
Risk Genes ◽  
International Consortium ◽  
Rare Variant Analysis ◽  
New Genes ◽  
Pulmonary Arterial ◽  
Variant Analysis

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.

scholarly journals EXPRESS: Genetic basis of pulmonary arterial hypertension: A prospective study from a highly inbred population

2021 ◽  
pp. 204589402110320
Author(s):  
Abdullah Aldalaan ◽  
Khushnooda Ramzan ◽  
Sarfraz Saleemi ◽  
Ihab Weheba ◽  
Laila Alquait ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Genetic Basis ◽  
Genetic Diagnosis ◽  
Saudi Arabian ◽  
High Rate ◽  
Risk Genes ◽  
Entire Cohort ◽  
Pulmonary Arterial ◽  
A Prospective Study

Pulmonary arterial hypertension (PAH), whether idiopathic PAH (IPAH), heritable PAH, or associated with other conditions, is a rare and potentially lethal disease characterized by progressive vascular changes. To date, there is limited data on the genetic basis of PAH in the Arab region, and none from Saudi Arabian patients. This study aims to identify genetic variations and to evaluate the frequency of risk genes associated to PAH, in Saudi Arabian patients. Adult PAH patients, diagnosed with IPAH and pulmonary veno-occlusive disease (PVOD), of Saudi Arabian origin, were enrolled in this study. Forty-eight patients were subjected to whole exome sequencing (WES), with screening of 26 genes suggested to be associated with the disease. The median age at diagnosis was 29.5 years of age, with females accounting for 89.5% of our cohort population. Overall, we identified variations in 9 genes previously associated with PAH, in 16 patients. Fourteen of these variants have not been described before. Plausible deleterious variants in risk genes were identified in 33.3% (n=16/48) of our entire cohort and 25% of these cases carried variants in BMPR2 (n=4/16). Our results highlight the genetic etiology of PAH in Saudi Arabia patients and provides new insights for the genetic diagnosis of familial and IPAH, as well as for the identification of the biological pathways of the disease. This will enable the development of new target therapeutic strategies, for a disease with a high rate of morbidity and mortality.

scholarly journals Where the congenital heart disease meets the pulmonary arterial hypertension, FLNA matters: a case report and literature review

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Xiaoxian Deng ◽  
Shanshan Li ◽  
Qiu Qiu ◽  
Bowen Jin ◽  
Menghuan Yan ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Congenital Heart ◽  
Pediatric Patients ◽  
De Novo ◽  
Wide Spectrum ◽  
Heart Defects ◽  
Pulmonary Arterial

Abstract Background Pediatric patients with genetic disorders have a higher incidence of pulmonary arterial hypertension (PAH) regardless of their heart defects. Filamin A (FLNA) mutation is recently recognized to be associated with pediatric pulmonary disorders, however, the clinical courses of PAH related to the mutation were reported in limited cases. Here, we presented a case and pooled data for better understanding of the correlation between FLNA mutation and pediatric PAH. Case presentation The patient was a 8-month-old female with repeated episodes of pneumonia. Physical examination revealed cleft lip, cleft palate and developmental retardation. Imaging examination showed a small atrial septal defect (ASD), central pulmonary artery enlargement, left upper lobe of lung atelectasis, and pulmonary infiltration. Genetic test showed she carried a de novo pathogenic variant of FLNA gene (c.5417-1G > A, p.-). Oral medications didn’t slow the progression of PAH in the patient, and she died two years later. Conclusions FLNA mutation causes rare but progressive PAH in addition to a wide spectrum of congenital heart disease and other comorbidities in pediatric patients. We highly recommend genetic testing for pediatric patients when suspected with PAH. Given the high mortality in this group, lung transplantation may offer a better outcome.

Alemtuzumab and de novo pulmonary arterial hypertension: A potential association?

2017 ◽  
Vol 36 (3) ◽  
pp. 370-371 ◽  
Author(s):  
Laura Beaumier ◽  
Sébastien Chanoine ◽  
Boubou Camara ◽  
Christophe Pison ◽  
Pierrick Bedouch
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
De Novo ◽  
Potential Association ◽  
Pulmonary Arterial

scholarly journals TGFβ receptor gene variants in systemic sclerosis-related pulmonary arterial hypertension: results from a multicentre EUSTAR study of European Caucasian patients

2012 ◽  
Vol 71 (11) ◽  
pp. 1900-1903 ◽  
Author(s):  
Eugénie Koumakis ◽  
Julien Wipff ◽  
Philippe Dieudé ◽  
Barbara Ruiz ◽  
Matthieu Bouaziz ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Candidate Genes ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Direct Sequencing ◽  
Receptor Gene ◽  
Tgfβ Receptor ◽  
Pulmonary Arterial

IntroductionSystemic sclerosis (SSc)-related pulmonary arterial hypertension (PAH) has emerged as a major mortality prognostic factor. Mutations of transforming growth factor beta (TGFβ) receptor genes strongly contribute to idiopathic and familial PAH.ObjectiveTo explore the genetic bases of SSc–PAH, we combined direct sequencing and genotyping of candidate genes encoding TGFβ receptor family members.Materials and methodsTGFβ receptor genes, BMPR2, ALK1, TGFR2 and ENG, were sequenced in 10 SSc–PAH patients, nine SSc and seven controls. In addition, 22 single-nucleotide polymorphisms (SNP) of these four candidate genes were tested for association in a first set of 824 French Caucasian SSc patients (including 54 SSc–PAH) and 939 controls. The replication set consisted of 1516 European SSc (including 219 SSc–PAH) and 3129 controls from the European League Against Rheumatism Scleroderma Trials and Research group network.ResultsNo mutation was identified by direct sequencing. However, two repertoried SNP, ENG rs35400405 and ALK1 rs2277382, were found in SSc–PAH patients only. The genotyping of 22 SNP including the latter showed that only rs2277382 was associated with SSc–PAH (p=0.0066, OR 2.13, 95% CI 1.24 to 3.65). Nevertheless, this was not replicated with the following result in combined analysis: p=0.123, OR 0.79, 95% CI 0.59 to 1.07.ConclusionsThis study demonstrates the lack of association between these TGFβ receptor gene polymorphisms and SSc–PAH using both sequencing and genotyping methods.

scholarly journals A Bayesian method for rare variant analysis using functional annotations and its application to Autism

2019 ◽  
Author(s):  
Shengtong Han ◽  
Nicholas Knoblauch ◽  
Gao Wang ◽  
Siming Zhao ◽  
Yuwen Liu ◽  
...  
Keyword(s):  
Rare Variant ◽  
Bayesian Method ◽  
Rare Variants ◽  
External Information ◽  
Risk Genes ◽  
Prior Probabilities ◽  
Functional Connections ◽  
Rare Variant Analysis ◽  
Risk Variants ◽  
Variant Analysis

AbstractRare genetic variants make significant contributions to human diseases. Compared to common variants, rare variants have larger effect sizes and are generally free of linkage disequilibrium (LD), which makes it easier to identify causal variants. Numerous methods have been developed to analyze rare variants in a gene or region in association studies, with the goal of finding risk genes by aggregating information of all variants of a gene. These methods, however, often make unrealistic assumptions, e.g. all rare variants in a risk gene would have non-zero effects. In practice, current methods for gene-based analysis often fail to show any advantage over simple single-variant analysis. In this work, we develop a Bayesian method: MIxture model based Rare variant Analysis on GEnes (MIRAGE). MIRAGE captures the heterogeneity of variant effects by treating all variants of a gene as a mixture of risk and non-risk variants, and models the prior probabilities of being risk variants as function of external information of variants, such as allele frequencies and predicted deleterious effects. MIRAGE uses an empirical Bayes approach to estimate these prior probabilities by combining information across genes. We demonstrate in both simulations and analysis of an exome-sequencing dataset of Autism, that MIRAGE significantly outperforms current methods for rare variant analysis. In particular, the top genes identified by MIRAGE are highly enriched with known or plausible Autism risk genes. Our results highlight several novel Autism genes with high Bayesian posterior probabilities and functional connections with Autism. MIRAGE is available at https://xinhe-lab.github.io/mirage.

Sign in / Sign up

Export Citation Format

Share Document