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 Accurate genetic diagnosis of Finnish pulmonary arterial hypertension patients using oligonucleotide-selective sequencing

2015 ◽  
Vol 3 (4) ◽  
pp. 354-362 ◽  
Author(s):  
Sanna Vattulainen ◽  
Joonas Aho ◽  
Pertteli Salmenperä ◽  
Siina Bruce ◽  
Jonna Tallila ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Genetic Diagnosis ◽  
Pulmonary Arterial ◽  
Selective Sequencing

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.

Contraceptive Options for the Patient with Pulmonary Arterial Hypertension

2011 ◽  
Vol 10 (3) ◽  
pp. 167-172 ◽  
Author(s):  
Patricia Santiago-Munoz
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Maternal Mortality ◽  
Pregnancy Outcomes ◽  
High Rate ◽  
World Health ◽  
Main Concern ◽  
Care Providers ◽  
Unintended Pregnancies ◽  
Pulmonary Arterial

The World Health Organization describes contraception as desirable for many reasons. It allows families to make informed choices about their reproductive years. It allows family planning, with spacing of children, leading to better bonding between mother and child, higher exclusive breastfeeding rates, and improved health of the mother for a future pregnancy.1 Unintended pregnancies continue to occur at an astronomically high rate in the US, as high as 35% by most recent data,2 and of course, since women with pulmonary arterial hypertension (PAH) are not exempt from this statistic, it is imperative that as care providers, we help our patients to plan ahead. In their case, maternal health is our main concern. Weiss and colleagues, reporting on pregnancy outcomes with PAH between 1978 and 1996, found a maternal mortality of 36% in Eisenmenger syndrome, 30% in idiopathic PAH, and 56% in secondary PAH.3 A more recent systematic review reported slightly more optimistic pregnancy outcomes from 1997 to 2007. Still, maternal mortality ranged from 17% to 33%, depending on the exact etiology of pulmonary hypertension.4 It is therefore very clear that in the setting of PAH, contraception is important and potentially lifesaving.

scholarly journals Pre-implantation genetic diagnosis in pulmonary arterial hypertension due toBMPR2mutation: Figure 1–

2012 ◽  
Vol 39 (6) ◽  
pp. 1534-1535 ◽  
Author(s):  
Nelly Frydman ◽  
Julie Steffann ◽  
Barbara Girerd ◽  
René Frydman ◽  
Arnold Munnich ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Genetic Diagnosis ◽  
Pulmonary Arterial

Hyperthyroidism as a Cause of Pulmonary Arterial Hypertension: A Prospective Study

Angiology ◽  
2006 ◽  
Vol 57 (5) ◽  
pp. 600-606 ◽  
Author(s):  
Michela Armigliato ◽  
Rossella Paolini ◽  
Silvio Aggio ◽  
Sergio Zamboni ◽  
Maria Paola Galasso ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Prospective Study ◽  
Pulmonary Arterial ◽  
A Prospective Study

scholarly journals Genetics and genomics of pulmonary arterial hypertension

2019 ◽  
Vol 53 (1) ◽  
pp. 1801899 ◽  
Author(s):  
Nicholas W. Morrell ◽  
Micheala A. Aldred ◽  
Wendy K. Chung ◽  
C. Gregory Elliott ◽  
William C. Nichols ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Genetic Diagnosis ◽  
Molecular Classification ◽  
Incomplete Penetrance ◽  
Therapeutic Approaches ◽  
Genomic Studies ◽  
Pulmonary Arterial ◽  
The Impact

Since 2000 there have been major advances in our understanding of the genetic and genomics of pulmonary arterial hypertension (PAH), although there remains much to discover. Based on existing knowledge, around 25–30% of patients diagnosed with idiopathic PAH have an underlying Mendelian genetic cause for their condition and should be classified as heritable PAH (HPAH). Here, we summarise the known genetic and genomic drivers of PAH, the insights these provide into pathobiology, and the opportunities afforded for development of novel therapeutic approaches. In addition, factors determining the incomplete penetrance observed in HPAH are discussed. The currently available approaches to genetic testing and counselling, and the impact of a genetic diagnosis on clinical management of the patient with PAH, are presented. Advances in DNA sequencing technology are rapidly expanding our ability to undertake genomic studies at scale in large cohorts. In the future, such studies will provide a more complete picture of the genetic contribution to PAH and, potentially, a molecular classification of this disease.

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