Heritable pulmonary hypertension: from bench to bedside

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.

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Genetic counselling in pre-capillary pulmonary hypertension

ESC CardioMed ◽

10.1093/med/9780198784906.003.0602 ◽

2018 ◽

pp. 2558-2560

Author(s):

Barbara Girerd ◽

David Montani ◽

Marc Humbert

Keyword(s):

Pulmonary Hypertension ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Genetic Counselling ◽

Autosomal Dominant ◽

Autosomal Dominant Disease ◽

Pulmonary Capillary ◽

Dominant Disease ◽

Pulmonary Arterial ◽

Biallelic Mutations

Pre-capillary pulmonary hypertension can be heritable in the context of pulmonary arterial hypertension (an autosomal dominant disease mainly due to mutations in BMPR2), and pulmonary veno-occlusive disease or pulmonary capillary haemangiomatosis (an autosomal recessive disease due to biallelic mutations in the EIF2AK4 gene). Genetic counselling can be implemented in referral centres for pulmonary hypertension as outlined in this chapter.

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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).

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Genetic counselling in pre-capillary pulmonary hypertension

ESC CardioMed ◽

10.1093/med/9780198784906.003.0602_update_001 ◽

2018 ◽

pp. 2558-2560

Author(s):

Barbara Girerd ◽

David Montani ◽

Marc Humbert

Keyword(s):

Pulmonary Hypertension ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Genetic Counselling ◽

Autosomal Dominant ◽

Autosomal Dominant Disease ◽

Pulmonary Capillary ◽

Dominant Disease ◽

Pulmonary Arterial ◽

Biallelic Mutations

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Pulmonary arterial hypertension in systemic sclerosis: Diagnosis and treatment according to the European Society of Cardiology and European Respiratory Society 2015 guidelines

Journal of Scleroderma and Related Disorders ◽

10.1177/2397198318808998 ◽

2018 ◽

Vol 4 (1) ◽

pp. 35-42 ◽

Cited By ~ 4

Author(s):

Nicola Giordano ◽

Claudio Corallo ◽

Chiara Chirico ◽

Angelica Brazzi ◽

Adriana Marinetti ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Systemic Sclerosis ◽

Pulmonary Arterial Hypertension ◽

Endothelial Dysfunction ◽

Arterial Hypertension ◽

Correct Diagnosis ◽

European Respiratory Society ◽

Long Term Outcome ◽

Screening Programs ◽

Pulmonary Arterial

Scleroderma (systemic sclerosis) is an autoimmune connective tissue disease which presents endothelial dysfunction and fibroblast dysregulation, resulting in vascular and fibrotic disorders. Pulmonary hypertension is frequent in patients with systemic sclerosis: the natural evolution of the disease can induce the development of different forms of pulmonary hypertension, representing one of the main causes of death. Among the different forms of pulmonary hypertension in systemic sclerosis, pulmonary arterial hypertension is the most frequent one (rate of occurrence is estimated between 7% and 12%). This pulmonary vascular complication should be treated with a combination of drugs that is able to counteract endothelial dysfunction, antagonizing the endothelin-1 system and replacing prostaglandin I2 and nitric oxide activity. A correct diagnosis is mandatory, because it is possible only for pulmonary arterial hypertension to use specific drugs that are able to control the symptomatic condition and the evolution of the disease. According to the most recent guidelines, for the patients with systemic sclerosis, also without pulmonary hypertension symptoms, echocardiography screening for the detection of pulmonary hypertension is recommended. Pulmonary arterial hypertension screening programs in systemic sclerosis patients is able to identify milder forms of the disease, allowing earlier management and better long-term outcome.

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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.

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The Recent Prognosis and Treatment of Idiopathic and Heritable Pulmonary Arterial Hypertension; The Report from Single Pulmonary Hypertension Center in Japan

The Journal of Heart and Lung Transplantation ◽

10.1016/j.healun.2017.01.1022 ◽

2017 ◽

Vol 36 (4) ◽

pp. S362-S363

Author(s):

H. Maki ◽

M. Hatano ◽

S. Minatsuki ◽

I. Komuro

Keyword(s):

Pulmonary Hypertension ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Pulmonary Arterial ◽

Heritable Pulmonary Arterial Hypertension

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Pregnancy in pulmonary arterial hypertension

European Respiratory Review ◽

10.1183/16000617.0079-2016 ◽

2016 ◽

Vol 25 (142) ◽

pp. 431-437 ◽

Cited By ~ 25

Author(s):

Karen M. Olsson ◽

Richard Channick

Keyword(s):

Pulmonary Hypertension ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Post Partum ◽

Early Termination ◽

European Respiratory Society ◽

Advanced Therapies ◽

Pulmonary Arterial ◽

European Society Of Cardiology ◽

In Pregnancy

Despite advanced therapies, maternal mortality in women with pulmonary arterial hypertension (PAH) remains high in pregnancy and is especially high during the post-partum period. However, recent data indicates that morbidity and mortality during pregnancy and after birth have improved for PAH patients. The current European Society of Cardiology/European Respiratory Society guidelines recommend that women with PAH should not become pregnant. Therefore, the risks associated with pregnancy must be emphasised and counselling offered to women at the time of PAH diagnosis and to women with PAH who become pregnant. Early termination should be discussed. Women who choose to continue with their pregnancy should be treated at specialised pulmonary hypertension centres with experience in managing PAH during and after pregnancy.

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

Cells ◽

10.3390/cells10113178 ◽

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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