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

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.

Download Full-text

Genetics and genomics of pulmonary arterial hypertension

European Respiratory Journal ◽

10.1183/13993003.01899-2018 ◽

2019 ◽

Vol 53 (1) ◽

pp. 1801899 ◽

Cited By ~ 72

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.

Download Full-text

Customized Massive Parallel Sequencing Panel for Diagnosis of Pulmonary Arterial Hypertension

Genes ◽

10.3390/genes11101158 ◽

2020 ◽

Vol 11 (10) ◽

pp. 1158

Author(s):

Jair Antonio Tenorio Castaño ◽

Ignacio Hernández-Gonzalez ◽

Natalia Gallego ◽

Carmen Pérez-Olivares ◽

Nuria Ochoa Parra ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Massive Parallel Sequencing ◽

Presumptive Diagnosis ◽

Parallel Sequencing ◽

Variants Of Unknown Significance ◽

Pathogenic Variants ◽

Custom Script ◽

Pulmonary Arterial ◽

Custom Panel

Pulmonary arterial hypertension is a very infrequent disease, with a variable etiology and clinical expressivity, making sometimes the clinical diagnosis a challenge. Current classification based on clinical features does not reflect the underlying molecular profiling of these groups. The advance in massive parallel sequencing in PAH has allowed for the describing of several new causative and susceptibility genes related to PAH, improving overall patient diagnosis. In order to address the molecular diagnosis of patients with PAH we designed, validated, and routinely applied a custom panel including 21 genes. Three hundred patients from the National Spanish PAH Registry (REHAP) were included in the analysis. A custom script was developed to annotate and filter the variants. Variant classification was performed according to the ACMG guidelines. Pathogenic and likely pathogenic variants have been found in 15% of the patients with 12% of variants of unknown significance (VUS). We have found variants in patients with connective tissue disease (CTD) and congenital heart disease (CHD). In addition, in a small proportion of patients (1.75%), we observed a possible digenic mode of inheritance. These results stand out the importance of the genetic testing of patients with associated forms of PAH (i.e., CHD and CTD) additionally to the classical IPAH and HPAH forms. Molecular confirmation of the clinical presumptive diagnosis is required in cases with a high clinical overlapping to carry out proper management and follow up of the individuals with the disease.

Download Full-text

Heritable pulmonary hypertension: from bench to bedside

European Respiratory Review ◽

10.1183/16000617.0037-2017 ◽

2017 ◽

Vol 26 (145) ◽

pp. 170037 ◽

Cited By ~ 8

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.

Download Full-text

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

Pulmonary Circulation ◽

10.1177/20458940211032057 ◽

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.

Download Full-text

Pulmonary hypertension genes as major diagnostic tools

ESC CardioMed ◽

10.1093/med/9780198784906.003.0577 ◽

2018 ◽

pp. 2490-2493

Author(s):

Mélanie Eyries ◽

Barbara Girerd ◽

David Montani ◽

David-Alexandre Tregouët ◽

Marc Humbert ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Gene Mutations ◽

Diagnostic Tools ◽

Genetic Mutations ◽

Incomplete Penetrance ◽

Hereditary Haemorrhagic Telangiectasia ◽

Sporadic Cases ◽

Pulmonary Arterial

A few genes have been shown to be major predisposing factors for pulmonary hypertension and are responsible for heritable forms of the disease. However, for nearly all genes described, not all mutation carriers develop the disease (autosomal transmission with incomplete penetrance) explaining the presence of genetic mutations in apparently sporadic cases. Beside mutations in major genes (BMPR2 for pulmonary arterial hypertension and EIF2AK4 for recessive heritable pulmonary veno-occlusive disease), other genes have been involved in a very limited number of cases (KCNK3, CAV1, and Smad8). Gene mutations are also been found as part of syndromic diseases (ACVRL1 mutations in hereditary haemorrhagic telangiectasia and TBX4 in small patella syndrome).

Download Full-text

Molecular Genetic Diagnosis of Pulmonary Arterial Hypertension: An Increased Complexity

Revista Española de Cardiología (English Edition) ◽

10.1016/j.rec.2016.05.026 ◽

2016 ◽

Vol 69 (11) ◽

pp. 1003-1004

Author(s):

Mélanie Eyries ◽

Florent Soubrier

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Molecular Genetic ◽

Genetic Diagnosis ◽

Molecular Genetic Diagnosis ◽

Pulmonary Arterial

Download Full-text

Mutually reinforcing effects of genetic variants and interferon-β 1a therapy for pulmonary arterial hypertension development in multiple sclerosis patients

Pulmonary Circulation ◽

10.1177/2045894019872192 ◽

2019 ◽

Vol 9 (3) ◽

pp. 204589401987219 ◽

Cited By ~ 2

Author(s):

Marianne Lerche ◽

Christina A. Eichstaedt ◽

Katrin Hinderhofer ◽

Ekkehard Grünig ◽

Kristin Tausche ◽

...

Keyword(s):

Multiple Sclerosis ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Missense Variant ◽

Right Heart Catheterization ◽

Heart Catheterization ◽

Sequence Variant ◽

Pulmonary Arterial ◽

Multiple Sclerosis Patients ◽

Pah Gene

Based on a small number of cases, interferon beta (IFN-β) has been added to the list of drugs that might induce pulmonary arterial hypertension (PAH) in the current European guidelines for the diagnosis and treatment of pulmonary hypertension. Here, we propose that multiple sclerosis patients who are genetically predisposed to PAH may be at higher risk to develop disease when treated with IFN-β. We included two patients with multiple sclerosis who developed a manifest PAH after five amd eight years on IFN-β 1a therapy, respectively (without confirmed right heart catheterization). In both patients, PAH markedly improved after discontinuation of IFN-β 1a and initiation of targeted PAH therapy. For genetic analysis, we used a PAH-gene panel based on next-generation sequencing of 16 PAH and 38 candidate genes. In one of the two patients, we could identify a nonsense variant in the PAH gene ATP13A3. The second patient showed a missense variant of the CYP1B1 gene, which might be linked to PAH predisposition. The results of this study support the hypothesis that multiple sclerosis patients who receive IFN-β 1a therapy might be at higher risk for the development of manifest PAH, if they carry a pathogenic variant or sequence variant genetically predisposing to the disease. However, further studies are necessary to systematically investigate the presence of predisposing PAH gene variants in these patients.

Download Full-text

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

Molecular Genetics & Genomic Medicine ◽

10.1002/mgg3.147 ◽

2015 ◽

Vol 3 (4) ◽

pp. 354-362 ◽

Cited By ~ 5

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

Download Full-text

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

Journal of Medical Genetics ◽

10.1136/jmedgenet-2021-107831 ◽

2021 ◽

pp. jmedgenet-2021-107831

Author(s):

Rajiv Machado ◽

Carrie L Welch ◽

Matthias Haimel ◽

Marta Bleda ◽

Elizabeth Colglazier ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Autosomal Recessive ◽

Disease Onset ◽

Compound Heterozygous ◽

Childhood Onset ◽

Catalytic Phosphorylation ◽

Childhood All ◽

Pulmonary Arterial ◽

Dose Dependent

BackgroundThe molecular genetic basis of pulmonary arterial hypertension (PAH) is heterogeneous, with at least 26 genes displaying putative evidence for disease causality. Heterozygous variants in the ATP13A3 gene were recently identified as a new cause of adult-onset PAH. However, the contribution of ATP13A3 risk alleles to child-onset PAH remains largely unexplored.Methods and resultsWe report three families with a novel, autosomal recessive form of childhood-onset PAH due to biallelic ATP13A3 variants. Disease onset ranged from birth to 2.5 years and was characterised by high mortality. Using genome sequencing of parent–offspring trios, we identified a homozygous missense variant in one case, which was subsequently confirmed to cosegregate with disease in an affected sibling. Independently, compound heterozygous variants in ATP13A3 were identified in two affected siblings and in an unrelated third family. The variants included three loss of function variants (two frameshift, one nonsense) and two highly conserved missense substitutions located in the catalytic phosphorylation domain. The children were largely refractory to treatment and four died in early childhood. All parents were heterozygous for the variants and asymptomatic.ConclusionOur findings support biallelic predicted deleterious ATP13A3 variants in autosomal recessive, childhood-onset PAH, indicating likely semidominant dose-dependent inheritance for this gene.

Download Full-text