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 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 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

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.

scholarly journals Heritable pulmonary hypertension: from bench to bedside

2017 ◽  
Vol 26 (145) ◽  
pp. 170037 ◽  
Author(s):  
Barbara Girerd ◽  
Jason Weatherald ◽  
David Montani ◽  
Marc Humbert
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Genetic Diagnosis ◽  
Predictive Testing ◽  
Incomplete Penetrance ◽  
European Respiratory Society ◽  
Dominant Disease ◽  
Pulmonary Arterial ◽  
Heritable Pulmonary Arterial Hypertension

Mutations in the BMPR2 gene, and more rarely in ACVRL1, endoglin, caveolin-1, KCNK3 and TBX4 genes predispose to heritable pulmonary arterial hypertension, an autosomal dominant disease with incomplete penetrance. Bi-allelic mutations in the EIF2AK4 gene predispose to heritable pulmonary veno-occlusive disease/pulmonary capillary haemangiomatosis, an autosomal recessive disease with an unknown penetrance.In France, the national pulmonary hypertension referral centre offers genetic counselling and testing to adults and children. Predictive testing is also proposed to adult relatives at risk of carrying a predisposing mutation. In that context, we offer all asymptomatic BMPR2 mutation carriers a programme to detect pulmonary arterial hypertension at an early phase, as recommended by the 2015 European Society Society of Cardiology/European Respiratory Society pulmonary hypertension guidelines. Finally, pre-implantation genetic diagnosis has been conducted on five embryos from two couples in which the fathers were carriers of a pathogenic BMPR2 mutation.

scholarly journals Case Report: BMPR2-Targeted MinION Sequencing as a Tool for Genetic Analysis in Patients With Pulmonary Arterial Hypertension

2021 ◽  
Vol 8 ◽  
Author(s):  
Tomoya Takashima ◽  
Sophie Brisset ◽  
Asuka Furukawa ◽  
Hirohisa Taniguchi ◽  
Rika Takeyasu ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Genetic Analysis ◽  
Arterial Hypertension ◽  
Genetic Diagnosis ◽  
Variant Calling ◽  
Read Length ◽  
Sequencing Analysis ◽  
Bioinformatics Pipeline ◽  
Pulmonary Arterial ◽  
Nanopore Sequencer

Background: Mutations in the bone morphogenetic protein receptor type 2 gene (BMPR2) represent a major genetic cause of pulmonary arterial hypertension (PAH). Identification of BMPR2 mutations is crucial for the genetic diagnosis of PAH. MinION nanopore sequencer is a portable third-generation technology that enables long-read sequencing at a low-cost. This nanopore technology-based device has not been used previously for PAH diagnosis. This study aimed to determine the feasibility of using MinION nanopore sequencing for the genetic analysis of PAH patients, focused on BMPR2.Methods: We developed a protocol for the custom bioinformatics pipeline analysis of long reads generated by long-PCR. To evaluate the potential of using MinION sequencing in PAH, we analyzed five samples, including those of two idiopathic PAH patients and a family of three members with one affected patient. Sanger sequencing analysis was performed to validate the variants.Results: The median read length was around 3.4 kb and a good mean quality score of approximately 19 was obtained. The total number of reads generated was uniform among the cases and ranged from 2,268,263 to 3,126,719. The coverage was consistent across flow cells in which the average number of reads per base ranged from 80,375 to 135,603. We identified two polymorphic variants and three mutations in four out of five patients. Certain indel variant calling-related errors were observed, mostly outside coding sequences.Conclusion: We have shown the ability of this portable nanopore sequencer to detect BMPR2 mutations in patients with PAH. The MinION nanopore sequencer is a promising tool for screening BMPR2 mutations, especially in small laboratories and research groups.

scholarly journals Expanding the Evidence of a Semi-Dominant Inheritance in GDF2 Associated with Pulmonary Arterial Hypertension

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3178
Author(s):  
Natalia Gallego ◽  
Alejandro Cruz-Utrilla ◽  
Inmaculada Guillén ◽  
Amparo Moya Bonora ◽  
Nuria Ochoa ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Genetic Diagnosis ◽  
Missense Variant ◽  
Compound Heterozygous ◽  
Incomplete Penetrance ◽  
Presumptive Diagnosis ◽  
Pathogenic Variants ◽  
Pulmonary Arterial ◽  
Next Generation Sequencing Ngs

Pulmonary arterial hypertension (PAH) sometimes co-exists with hereditary hemorrhagic telangiectasia (HHT). Despite being clinically diagnosable according to Curaçao criteria, HHT can be difficult to diagnose due to its clinically heterogenicity and highly overlapping with PAH. Genetic analysis of the associated genes ACVRL1, ENG, SMAD4 and GDF2 can help to confirm or discard the presumptive diagnosis. As part of the clinical routine and to establish a genetic diagnosis, we have analyzed a cohort of patients with PAH and overlapping HHT features through a customized Next Generation Sequencing (NGS) panel of 21 genes, designed and validated in-house. We detected a homozygous missense variant in GDF2 in a pediatric patient diagnosed with PAH associated with HHT and a missense variant along with a heterozygous deletion in another idiopathic PAH patient (compound heterozygous inheritance). In order to establish variant segregation, we analyzed all available family members. In both cases, parents were carriers for the variants, but neither was affected. Our results expand the clinical spectrum and the inheritance pattern associated with GDF2 pathogenic variants suggesting incomplete penetrance and/or variability of expressivity with a semi-dominant pattern of inheritance.

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