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Pulmonary arterial hypertension (PAH) is a rare disease that can be caused by (likely) pathogenic germline genomic variants. In addition to the most prevalent disease gene, BMPR2 (bone morphogenetic protein receptor 2), several genes, some belonging to distinct functional classes, are also now known to predispose to the development of PAH. As a consequence, specialist and non-specialist clinicians and healthcare professionals are increasingly faced with a range of questions regarding the need for, approaches to and benefits/risks of genetic testing for PAH patients and/or related family members. We provide a consensus-based approach to recommendations for genetic counselling and assessment of current best practice for disease gene testing. We provide a framework and the type of information to be provided to patients and relatives through the process of genetic counselling, and describe the presently known disease causal genes to be analysed. Benefits of including molecular genetic testing within the management protocol of patients with PAH include the identification of individuals misclassified by other diagnostic approaches, the optimisation of phenotypic characterisation for aggregation of outcome data, including in clinical trials, and importantly through cascade screening, the detection of healthy causal variant carriers, to whom regular assessment should be offered., Competing Interests: Conflict of interest: C.A. Eichstaedt reports lecture fees from MSD, outside the submitted work; and has a patent “Gene panel specific for pulmonary hypertension and its uses” (European Patent ID: EP3507380) issued. C. Belge reports consulting fees, participation on advisory boards and lecture honoraria from Janssen and MSD/Bayer; travel support from MSD/Bayer, outside the submitted work. W.K. Chung reports scientific advisory board participation with Regeneron Genetics Center, outside the submitted work. E. Grünig reports grants from Actelion, Bayer, GSK, United Therapeutics, Novartis, Bellerophon, OMT, Pfizer and REATA; lecture fees and consultancy fees from Actelion, Bayer/MSD and GSK; travel support from Janssen; advisory board participation with MSD and Ferrer, outside the submitted work; has a patent “Gene panel specific for pulmonary hypertension and its uses” (European Patent ID: EP3507380) issued; and has also served in leadership roles for ADue and pH e.V., outside the submitted work. D. Montani reports grants from Acceleron, Janssen and Merck; consulting fees from Acceleron; lecture honoraria from Bayer, Janssen and Merck, outside the submitted work. R.C. Trembath reports lecture fees from Clinical Cases, outside the submitted work. N.W. Morrell reports employment and stock/stock options from Centessa Pharmaceuticals. All other authors have nothing to disclose., (Copyright ©The authors 2023.)

Background: The phenotype of pulmonary arterial hypertension (PAH) patients carrying SOX17 pathogenic variants remains mostly unknown., Methods: We report the genetic analysis findings, characteristics and outcomes of patients with heritable PAH carrying SOX17 variants from the French Pulmonary Hypertension Network., Results: 20 patients and eight unaffected relatives were identified. The median (range) age at diagnosis was 17 (2-53) years, with a female:male ratio of 1.5. At diagnosis, most of the patients (74%) were in New York Heart Association Functional Class III or IV with severe haemodynamic compromise, including a median pulmonary vascular resistance of 14.0 (4.2-31.5) WU. An associated congenital heart disease (CHD) was found in seven PAH patients (35%). Patients with CHD-associated PAH were significantly younger at diagnosis than PAH patients without CHD. Four patients (20%) suffered from recurrent haemoptysis requiring repeated arterial embolisations. 13 out of 16 patients (81%) for whom imaging was available displayed chest computed tomography abnormalities, including dilated, tortuous pulmonary vessels, ground-glass opacities as well as anomalies of the bronchial and nonbronchial arteries. After a median (range) follow-up of 47 (1-591) months, 10 patients underwent lung transplantation and one patient benefited from a heart-lung transplantation due to associated CHD. Histopathological analysis of lung explants showed a congested lung architecture with severe pulmonary arterial remodelling, subpleural vessel dilation and numerous haemorrhagic foci., Conclusions: PAH due to SOX17 pathogenic variants is a severe phenotype, frequently associated with CHD, haemoptysis and radiological abnormalities. Pathological assessment reveals severe pulmonary arterial remodelling and malformations affecting pulmonary vessels and thoracic systemic arteries., Competing Interests: Conflict of interest: D. Montani reports grants from Acceleron, Janssen and Merck; consulting fees from Acceleron; lecture honoraria from Bayer, Janssen and Merck; outside the submitted work. A. Boucly reports grants from Acceleron, Janssen and MSD; lecture honoraria from Janssen and Merck; travel support from Janssen; outside the submitted work. D. Bonnet reports grants and consulting fees from Janssen and Novartis; participation on an advisory board for Lupin; outside the submitted work. M. Humbert reports grants from Acceleron, Janssen and Merck; consulting fees from Acceleron, Janssen, Merck, Altavant, MorphogenIX and Bayer; lecture honoraria from Janssen and Merck; participation on advisory boards for Acceleron, Janssen, Merck and United Therapeutics; outside the submitted work. All other authors have nothing to disclose., (Copyright ©The authors 2022.)

Background: Inflammation and dysregulated immunity are important in the development of pulmonary arterial hypertension (PAH). Compelling preclinical data supports the therapeutic blockade of interleukin-6 (IL-6) signalling., Methods: We conducted a phase 2 open-label study of intravenous tocilizumab (8 mg·kg -1 ) over 6 months in patients with group 1 PAH. Co-primary end-points were safety, defined by incidence and severity of adverse events, and change in pulmonary vascular resistance. Separately, a mendelian randomisation study was undertaken on 11 744 individuals with European ancestry including 2085 patients with idiopathic/heritable disease for the IL-6 receptor ( IL6R ) variant (rs7529229), known to associate with circulating IL-6R levels., Results: We recruited 29 patients (male/female 10/19; mean±sd age 54.9±11.4 years). Of these, 19 had heritable/idiopathic PAH and 10 had connective tissue disease-associated PAH. Six were withdrawn prior to drug administration; 23 patients received at least one dose of tocilizumab. Tocilizumab was discontinued in four patients owing to serious adverse events. There were no deaths. Despite evidence of target engagement in plasma IL-6 and C-reactive protein levels, both intention-to-treat and modified intention-to-treat analyses demonstrated no change in pulmonary vascular resistance. Inflammatory markers did not predict treatment response. Mendelian randomisation did not support an effect of the lead IL6R variant on risk of PAH (OR 0.99, p=0.88)., Conclusion: Adverse events were consistent with the known safety profile of tocilizumab. Tocilizumab did not show any consistent treatment effect., Competing Interests: Conflict of interest: M. Toshner reports grants and personal fees from Bayer and Actelion, and personal fees from MSD and GSK, during the conduct of the study, and serves on the advisory board for MorphogenIX. Conflict of interest: C. Church has received travel grants and speaker fees from GSK, Actelion and Bayer. Conflict of interest: L. Harbaum has nothing to disclose. Conflict of interest: C. Rhodes reports personal fees for advisory board work from Actelion and United Therapeutics, outside the submitted work. Conflict of interest: S.S. Villar Moreschi has nothing to disclose. Conflict of interest: J. Liley has nothing to disclose. Conflict of interest: R. Jones has nothing to disclose. Conflict of interest: A. Arora has nothing to disclose. Conflict of interest: K. Batai has nothing to disclose. Conflict of interest: A.A. Desai has nothing to disclose. Conflict of interest: J.G. Coghlan reports research support, consultancy fees and speaker honoraria from Actelion. Conflict of interest: J.S.R. Gibbs reports personal fees from Acceleron, Arena, Bayer, Bellepheron, Complexa, Pfizer and United Therapeutics, grants and personal fees from Actelion, and personal fees and non-financial support from GSK, outside the submitted work. Conflict of interest: D. Gor was an employee of Roche, during the conduct of the study. Conflict of interest: S. Gräf has nothing to disclose. Conflict of interest: L. Harlow has nothing to disclose. Conflict of interest: J. Hernandez-Sanchez is an employee of Roche but was not at the time of trial conduct. Conflict of interest: L.S. Howard has received personal fees and institutional grants/research support from Bayer and personal fees from MSD, Daichii Sayo and Pfizer. Conflict of interest: M. Humbert has received personal fees from Actelion, Merck and United Therapeutics, and grants and personal fees from Bayer and GSK. Conflict of interest: J. Karnes has nothing to disclose. Conflict of interest: D.G. Kiely reports grants and personal fees from Bayer and Actelion, and personal fees from GSK and MSD, during the conduct of the study. Conflict of interest: R. Kittles has nothing to disclose. Conflict of interest: E. Knightbridge has nothing to disclose. Conflict of interest: B. Lam has nothing to disclose. Conflict of interest: K.A. Lutz has nothing to disclose. Conflict of interest: W.C. Nichols has nothing to disclose. Conflict of interest: M.W. Pauciulo has nothing to disclose. Conflict of interest: J. Pepke-Zaba has served on advisory boards of and received personal fees and institutional grant/research support from Actelion, Bayer, MSD and GSK. Conflict of interest: J. Suntharalingam has nothing to disclose. Conflict of interest: F. Soubrier has nothing to disclose. Conflict of interest: R.C. Trembath has nothing to disclose. Conflict of interest: T-H.L. Schwantes-An has nothing to disclose. Conflict of interest: S.J. Wort reports grants and personal fees from Actelion and Bayer, and personal fees from GSK and MSD, outside the submitted work. Conflict of interest: M.R. Wilkins has nothing to disclose. Conflict of interest: S. Gaine has received honoraria from Actelion and United Therapeutics; has received travel grants from Actelion, Novartis and Menerini; and has performed drug safety board monitoring for United Therapeutics, GSK and Novartis. Conflict of interest: N.W. Morrell reports personal fees from MorphogenIX, during the conduct of the study. Conflict of interest: P.A. Corris has served on speakers’ bureau and advisory boards of Actelion, Bayer and MSD, and received institutional grant/research support from Actelion and Bayer., (Copyright ©The authors 2022.)

Background: Heritable pulmonary arterial hypertension (PAH) is most commonly due to heterozygous mutations of the BMPR2 gene. Based on expert consensus, guidelines recommend annual screening echocardiography in asymptomatic BMPR2 mutation carriers. The main objectives of this study were to evaluate the characteristics of asymptomatic BMPR2 mutation carriers, assess their risk of occurrence of PAH and detect PAH at an early stage in this high-risk population., Methods: Asymptomatic BMPR2 mutation carriers underwent screening at baseline and annually for a minimum of 2 years (DELPHI-2 study; ClinicalTrials.gov: NCT01600898). Annual screening included clinical assessment, ECG, pulmonary function tests, 6-min walk distance, cardiopulmonary exercise testing, chest radiography, echocardiography and brain natriuretic peptide (BNP) or N-terminal (NT)-proBNP level. Right heart catheterisation (RHC) was performed based on predefined criteria. An optional RHC at rest and exercise was proposed at baseline., Results: 55 subjects (26 males; median age 37 years) were included. At baseline, no PAH was suspected based on echocardiography and NT-proBNP levels. All subjects accepted RHC at inclusion, which identified two mild PAH cases (3.6%) and 12 subjects with exercise pulmonary hypertension (21.8%). At long-term follow-up (118.8 patient-years of follow-up), three additional cases were diagnosed, yielding a PAH incidence of 2.3% per year (0.99% per year in males and 3.5% per year in females). All PAH cases remained at low-risk status on oral therapy at last follow-up., Conclusions: Asymptomatic BMPR2 mutation carriers have a significant risk of developing incident PAH. International multicentre studies are needed to confirm that refined multimodal screening programmes with regular follow-up allow early detection of PAH., Competing Interests: Conflict of interest: D. Montani reports grants and personal fees from Actelion and Bayer, personal fees from GlaxoSmithKline, Pfizer, Chiesi, Boehringer and Incyte Biosciences France, grants, personal fees and nonfinancial support from MSD, nonfinancial support from Acceleron, outside the submitted work. Conflict of interest: B. Girerd has nothing to disclose. Conflict of interest: X. Jaïs reports grants from Bayer, grants and personal fees from MSD, grants, personal fees and nonfinancial support from Actelion/Janssen, outside the submitted work. Conflict of interest: P. Laveneziana reports personal fees from Novartis France and Chiesi France, outside the submitted work. Conflict of interest: E.M.T. Lau reports grants and personal fees from Actelion and GlaxoSmithKline, outside the submitted work. Conflict of interest: A. Bouchachi has nothing to disclose. Conflict of interest: S. Hascoët reports grants and personal fees from Abbott, outside the submitted work. Conflict of interest: S. Gunther has nothing to disclose. Conflict of interest: L. Godinas has nothing to disclose. Conflict of interest: F. Parent has nothing to disclose. Conflict of interest: C. Guignabert has nothing to disclose. Conflict of interest: A. Beurnier has nothing to disclose. Conflict of interest: D. Chemla has nothing to disclose. Conflict of interest: P. Hervé has nothing to disclose. Conflict of interest: M. Eyries has nothing to disclose. Conflict of interest: F. Soubrier has nothing to disclose. Conflict of interest: G. Simonneau reports personal fees from Bayer and Acceleron, personal fees and nonfinancial support from MSD, outside the submitted work. Conflict of interest: O. Sitbon reports grants, personal fees and nonfinancial support from Actelion Pharmaceuticals, personal fees from Acceleron Pharmaceuticals, AOP Orphan, Ferrer and Gossamer Bio, grants and personal fees from Bayer HealthCare and MSD, grants from GlaxoSmithKline, outside the submitted work. Conflict of interest: L. Savale reports personal fees and nonfinancial support from Actelion and Bayer, grants, personal fees and nonfinancial support from GlaxoSmithKline, nonfinancial support from MSD, outside the submitted work. Conflict of interest: M. Humbert reports grants, personal fees and nonfinancial support from GlaxoSmithKline, personal fees from AstraZeneca, Novartis, Roche, Sanofi, Teva and Merck, grants and personal fees from Acceleron, Actelion and Bayer, outside the submitted work., (Copyright ©The authors 2021. For reproduction rights and permissions contact permissions@ersnet.org.)

Introduction: TBX4 mutation causes small patella syndrome (SPS) and/or pulmonary arterial hypertension (PAH). The characteristics and outcomes of PAH associated with TBX4 mutations are largely unknown., Methods: We report the clinical, functional, radiologic, histologic and haemodynamic characteristics and outcomes of heritable PAH patients carrying a TBX4 mutation from the French pulmonary hypertension (PH) network., Results: 20 patients were identified in 17 families. They were characterised by a median age at diagnosis of 29 years (0-76 years) and a female to male ratio of three. Most of the patients (70%) were in New York Heart Association (NYHA) functional class III or IV with a severe haemodynamic impairment (median pulmonary vascular resistance (PVR) of 13.6 (6.2-41.8) Wood units). Skeletal signs of SPS were present in 80% of cases. Half of the patients had mild restrictive or obstructive limitation and diffusing capacity of the lung for carbon monoxide ( D LCO ) was decreased in all patients. High-resolution computed tomography (HRCT) showed bronchial abnormalities, peri-bronchial cysts, mosaic distribution and mediastinal lymphadenopathies. PAH therapy was associated with significant clinical improvement. At follow-up (median 76 months), two patients had died and two had undergone lung transplantation. One-year, three-year and five-year event-free survival rates were 100%, 94% and 83%, respectively. Histologic examination of explanted lungs revealed alveolar growth abnormalities, major pulmonary vascular remodelling similar to that observed in idiopathic pulmonary arterial hypertension (IPAH) and accumulation of cholesterol crystals within the lung parenchyma., Conclusion: PAH due to TBX4 mutations may occur with or without skeletal abnormalities across a broad age range from birth to late adulthood. PAH is usually severe and associated with bronchial and parenchymal abnormalities., Competing Interests: Conflict of interest: P. Thoré has nothing to disclose. Conflict of interest: B. Girerd has nothing to disclose. Conflict of interest: X. Jaïs reports grants and personal fees from Actelion and MSD, and grants from Bayer, outside the submitted work. Conflict of interest: L. Savale reports grants, personal fees and non-financial support from Actelion, grants and personal fees from MSD, and non-financial support from GSK, outside the submitted work. Conflict of interest: M-R. Ghigna has nothing to disclose. Conflict of interest: M. Eyries has nothing to disclose. Conflict of interest: M. Levy has nothing to disclose. Conflict of interest: C. Ovaert has nothing to disclose. Conflict of interest: A. Servettaz has nothing to disclose. Conflict of interest: A. Guillaumot has nothing to disclose. Conflict of interest: C. Dauphin has nothing to disclose. Conflict of interest: C. Chabanne has nothing to disclose. Conflict of interest: E. Boiffard has nothing to disclose. Conflict of interest: V. Cottin reports personal fees for advisory board work and non-financial (travel) support from Actelion, grants and personal fees for advisory board work, lectures and steering committee work, as well as non-financial (travel) support from Boehringer Ingelheim, personal fees for advisory board work and data monitoring committee work from Bayer/MSD and Galapagos, personal fees for advisory board work from Gilead and Novartis, personal fees for advisory board work, lectures and steering committee work, as well as non-financial (travel) support from Roche SAS, personal fees for lectures and non-financial (travel) support from Sanofi, personal fees for steering committee work and data monitoring committee work from Promedior, and personal fees for data monitoring committee work from Celgene and Galecto, outside the submitted work. Conflict of interest: F.Perros has nothing to disclose. Conflict of interest: G. Simonneau reports grants, personal fees and non-financial support from Actelion, Bayer, GSK and Merck, outside the submitted work. Conflict of interest: O. Sitbon reports grants, personal fees and non-financial support from Actelion Pharmaceuticals, Bayer HealthCare and MSD, personal fees from Acceleron Pharmaceuticals, Ferrer, Gossamer Bio and United Therapeutics, and grants from GlaxoSmithKline, outside the submitted work. Conflict of interest: F. Soubrier has nothing to disclose. Conflict of interest: D. Bonnet reports personal fees for advisory board work and steering committee work from Actelion Pharmaceuticals, Eli Lilly and Novartis, outside the submitted work. Conflict of interest: M. Remy-Jardin has nothing to disclose. Conflict of interest: A. Chaouat has nothing to disclose. Conflict of interest: M. Humbert reports personal fees from Acceleron, Actelion, MSD and United Therapeutics, and grants and personal fees from Bayer and GSK, outside the submitted work. Conflict of interest: D. Montani reports grants and personal fees from Actelion and Bayer, and personal fees from GSK, Pfizer, MSD and Chiesi, outside the submitted work., (Copyright ©ERS 2020.)

Beyond the major gene BMPR2 , several new genes predisposing to PAH have been identified during the last decade. Recently, preliminary evidence of the involvement of the KDR gene was found in a large genetic association study.We prospectively analysed the KDR gene by targeted panel sequencing in a series of 311 PAH patients referred to a clinical molecular laboratory for genetic diagnosis of PAH.Two index cases with severe PAH from two different families were found to carry a loss-of-function mutation in the KDR gene. These two index cases were clinically characterised by low diffusing capacity for carbon monoxide adjusted for haemoglobin ( D LCO c) and interstitial lung disease. In one family, segregation analysis revealed that variant carriers are either presenting with PAH associated with low D LCO c, or have only decreased D LCO c, whereas non-carrier relatives have normal D LCO c. In the second family, a single affected carrier was alive. His carrier mother was unaffected with normal D LCO c.We provided genetic evidence for considering KDR as a newly identified PAH-causing gene by describing the segregation of KDR mutations with PAH in two families. In our study, KDR mutations are associated with a particular form of PAH characterised by low D LCO c and radiological evidence of parenchymal lung disease including interstitial lung disease and emphysema., Competing Interests: Conflict of interest: M. Eyries has nothing to disclose. D. Montani reports grants and personal fees from Actelion and Bayer, personal fees from GSK, Pfizer and MSD, outside the submitted work. Conflict of interest: B. Girerd has nothing to disclose. Conflict of interest: N. Favrolt has nothing to disclose. Conflict of interest: M. Riou has nothing to disclose. Conflict of interest: L. Faivre has nothing to disclose. Conflict of interest: G. Manaud has nothing to disclose. Conflict of interest: F. Perros has nothing to disclose. Conflict of interest: S. Gräf has nothing to disclose. Conflict of interest: M.W. Morrell is an employee of Morphogen-IX. Conflict of interest: M. Humbert reports personal fees from Acceleron, Actelion, Merck and United Therapeutics, grants and personal fees from Bayer and GSK, outside the submitted work. Conflict of interest: F. Soubrier has nothing to disclose., (Copyright ©ERS 2020.)

Pulmonary arterial hypertension (PAH) is a rare disease that leads to premature death from right heart failure. It is strongly associated with elevated red cell distribution width (RDW), a correlate of several iron status biomarkers. High RDW values can signal early-stage iron deficiency or iron deficiency anaemia. This study investigated whether elevated RDW is causally associated with PAH.A two-sample Mendelian randomisation (MR) approach was applied to investigate whether genetic predisposition to higher levels of RDW increases the odds of developing PAH. Primary and secondary MR analyses were performed using all available genome-wide significant RDW variants (n=179) and five genome-wide significant RDW variants that act via systemic iron status, respectively.We confirmed the observed association between RDW and PAH (OR 1.90, 95% CI 1.80-2.01) in a multicentre case-control study (cases n=642, disease controls n=15 889). The primary MR analysis was adequately powered to detect a causal effect (odds ratio) between 1.25 and 1.52 or greater based on estimates reported in the RDW genome-wide association study or from our own data. There was no evidence for a causal association between RDW and PAH in either the primary (OR causal 1.07, 95% CI 0.92-1.24) or the secondary (OR causal 1.09, 95% CI 0.77-1.54) MR analysis.The results suggest that at least some of the observed association of RDW with PAH is secondary to disease progression. Results of iron therapeutic trials in PAH should be interpreted with caution, as any improvements observed may not be mechanistically linked to the development of PAH., Competing Interests: Conflict of interest: A. Ulrich has nothing to disclose. Conflict of interest: J. Wharton has nothing to disclose. Conflict of interest: T.E. Thayer has nothing to disclose. Conflict of interest: E.M. Swietlik has nothing to disclose. Conflict of interest: T.R. Assad has nothing to disclose. Conflict of interest: A.A. Desai has nothing to disclose. Conflict of interest: S. Gräf has nothing to disclose. Conflict of interest: L. Harbaum has nothing to disclose. Conflict of interest: M. Humbert reports grants and personal fees from Bayer and GSK, personal fees from Actelion, Merck and from United Therapeutics, outside the submitted work. Conflict of interest: N.W. Morrell reports personal fees from Actelion and Morphogen-IX, outside the submitted work. Conflict of interest: W.C. Nichols has nothing to disclose. Conflict of interest: F. Soubrier has nothing to disclose. Conflict of interest: L. Southgate has nothing to disclose. Conflict of interest: D-A. Trégouët has nothing to disclose. Conflict of interest: R.C. Trembath reports personal fees for advisory board work from Ipsen Pharmaceuticals, personal fees for non-executive board membership from King's College Hospital NHS Foundation Trust, outside the submitted work. Conflict of interest: E.L. Brittain reports personal fees for advisory board work from Bayer, outside the submitted work. Conflict of interest: M.R. Wilkins reports grants from Vifor Pharma, outside the submitted work. Conflict of interest: I. Prokopenko has nothing to disclose. Conflict of interest: C.J. Rhodes reports personal fees from Actelion, outside the submitted work., (Copyright ©ERS 2020.)

Background: Heritable forms of pulmonary arterial hypertension (PAH) and pulmonary veno-occlusive disease/pulmonary capillary haemangiomatosis (PVOD/PCH) diverge by lung histopathological lesions, clinical and para-clinical presentation, their responsible genes, and mode of transmission. Since the identification of the BMPR2 gene in families affected by PAH, mutations in several other genes have been discovered for both forms. The mutation landscape in these new genes is not yet well known., Methods: We set up a next-generation sequencing-based targeted sequencing gene panel allowing known genes for PAH and PVOD/PCH to be analysed simultaneously . Genetic analysis was prospectively performed on 263 PAH and PVOD/PCH patients (adult and paediatric cases)., Results: Pathogenic mutations were identified in 19.5% of sporadic PAH patients (n=180), 54.5% of familial PAH patients and 13.3% of PVOD/PCH patients. BMPR2 was the most frequently mutated gene, followed by TBX4 in both paediatric and adult PAH. BMP9 mutations were identified in 1.2% of adult PAH cases. EIF2AK4 biallelic mutations were restricted to PVOD/PCH. A truncating mutation and a predicted loss-of-function variant were also identified in BMP10 in two severely affected sporadic PAH female patients., Conclusion: Our results confirm that mutations are found in genes beyond BMPR2 in heritable PAH, emphasise the role of TBX4 and BMP9 , and designate BMP10 as a new PAH gene., Competing Interests: Conflict of interest: M. Eyries reports personal fees from Roche Diagnostics France, during the conduct of the study. Conflict of interest: D. Montani reports personal fees from Actelion, GSK, MSD and Pfizer, outside the submitted work. Conflict of interest: S. Nadaud has nothing to disclose. Conflict of interest: B. Girerd has nothing to disclose. Conflict of interest: M. Levy has nothing to disclose. Conflict of interest: A. Bourdin reports grants, personal fees for speaking and nonfinancial support from GSK, grants, personal fees for speaking and advisory board work, and nonfinancial support from AstraZeneca and Boehringer Ingelheim, personal fees for speaking and advisory board work, and nonfinancial support from Novartis, grants from MSD, grants and personal fees for speaking from Actelion, and personal fees for speaking and nonfinancial support from Chiesi Farmaceuticals, outside the submitted work. Conflict of interest: R. Trésorier has nothing to disclose. Conflict of interest: A. Chaouat has nothing to disclose. Conflict of interest: V. Cottin reports personal fees for consultancy, lectures and travel to medical meetings from Actelion and Roche, personal fees for development of educational presentations, consultancy, lectures and travel to medical meetings from Boehringer Ingelheim, personal fees for consultancy from Bayer, personal fees for adjudication committee work from Gilead, personal fees for consultancy and travel to medical meetings from MSD, personal fees for consultancy and lectures from Novartis and Sanofi, institutional grants from Boehringer Ingelheim and Roche, personal fees for data and safety monitoring board work from Promedior and Celgene, and personal fees for consultancy and data and safety monitoring board work from Galapagos, outside the submitted work. Conflict of interest: C. Sanfiorenzo has nothing to disclose. Conflict of interest: G. Prevot has nothing to disclose. Conflict of interest: M. Reynaud-Gaubert has nothing to disclose. Conflict of interest: C. Dromer has nothing to disclose. Conflict of interest: A. Houeijeh has nothing to disclose. Conflict of interest: K. Nguyen has nothing to disclose. Conflict of interest: F. Coulet has nothing to disclose. Conflict of interest: D. Bonnet reports personal fees for advisory board work from Actelion Pharmaceuticals, Bayer Health Care and Novartis, outside the submitted work. Conflict of interest: M. Humbert reports personal fees from Actelion, Bayer, GSK, Johnson & Johnson, Merck and United Therapeutics, outside the submitted work. Conflict of interest: F. Soubrier has nothing to disclose., (Copyright ©ERS 2019.)

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., Competing Interests: Conflict of interest: N.W. Morrell reports grants and personal fees from Morphogen-IX, outside the submitted work. Conflict of interest: M.A. Aldred reports grants from the NIH, during the conduct of the study. Conflict of interest: W.K. Chung has nothing to disclose. Conflict of interest: C.G. Elliott reports personal fees for steering committee work from Bayer and Bellerophon, grants and personal fees for registry and data safety monitoring from Actelion, and was a consultant for end-point adjudication for Lung LLC, with fees paid to his employer (Intermountain Healthcare), outside the submitted work. Conflict of interest: W.C. Nichols has nothing to disclose. Conflict of interest: F. Soubrier has nothing to disclose. Conflict of interest: R.C. Trembath has nothing to disclose. Conflict of interest: J.E. Loyd has nothing to disclose., (Copyright ©ERS 2019.)

The impact of bone morphogenetic protein receptor 2 (BMPR2) gene mutations on vascular remodelling in pulmonary arterial hypertension (PAH) is unknown. We sought to identify a histological profile of BMPR2 mutation carriers.Clinical data and lung histology from 44 PAH patients were subjected to systematic analysis and morphometry.Bronchial artery hypertrophy/dilatation and bronchial angiogenesis, as well as muscular remodelling of septal veins were significantly increased in PAH lungs carrying BMPR2 mutations. We found that patients displaying increased bronchial artery remodelling and bronchial microvessel density, irrespective of the mutation status, were more likely to suffer from severe haemoptysis. History of substantial haemoptysis (>50 mL) was significantly more frequent in BMPR2 mutation carriers. 43.5% of BMPR2 mutation carriers, as opposed to 9.5% of noncarriers, displayed singular large fibrovascular lesions, which appear to be closely related to the systemic lung vasculature.Our analysis provides evidence for the involvement of the pulmonary systemic circulation in BMPR2 mutation-related PAH. We show that BMPR2 mutation carriers are more prone to haemoptysis and that haemoptysis is closely correlated to bronchial arterial remodelling and angiogenesis; in turn, pronounced changes in the systemic vasculature correlate with increased pulmonary venous remodelling, creating a distinctive profile in PAH patients harbouring a BMPR2 mutation., (Copyright ©ERS 2016.)

The prevalence of germline mutations in paediatric pulmonary hypertension (PH) is poorly documented. The objective of this study was to determine the mutation frequency in PH genes in a paediatric cohort and describe the clinical characteristics of mutation carriers.The study involved 66 index cases with PH: 35 children with idiopathic pulmonary arterial hypertension (IPAH); five children with familial PAH (FPAH); three children with pulmonary veno-occlusive disease (PVOD); and 23 children with PAH associated with congenital heart disease (APAH-CHD).No mutations were found in the 23 children with APAH-CHD. In the 40 children with IPAH or FPAH, 12 mutations were found: five on BMPR2; four on ACVRL1; and three on TBX4. In the three PVOD cases, two carried the EIF2AK4 mutation. Mutation carriers had a more severe disease at diagnosis and more aggressive first-line therapy was required. The three patients with PVOD had a very severe disease at diagnosis and required a lung transplantation.The genetic architecture of paediatric PAH is enriched in ACVRL1 and TBX4 mutations compared to adult PAH, but further studies are required to confirm these results. Childhood-onset PAH in children carrying a mutation in one of the genes tested has a more severe presentation at diagnosis but a similar outcome to that observed in non-carriers., (Copyright ©ERS 2016.)

Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension (PH) characterised by preferential remodelling of the pulmonary venules. In the current PH classification, PVOD and pulmonary capillary haemangiomatosis (PCH) are considered to be a common entity and represent varied expressions of the same disease. The recent discovery of biallelic mutations in the EIF2AK4 gene as the cause of heritable PVOD/PCH represents a major milestone in our understanding of the molecular pathogenesis of PVOD. Although PVOD and pulmonary arterial hypertension (PAH) share a similar clinical presentation, with features of severe precapillary PH, it is important to differentiate these two conditions as PVOD carries a worse prognosis and life-threatening pulmonary oedema may occur following the initiation of PAH therapy. An accurate diagnosis of PVOD based on noninvasive investigations is possible utilising oxygen parameters, low diffusing capacity for carbon monoxide and characteristic signs on high-resolution computed tomography of the chest. No evidence-based medical therapy exists for PVOD at present and lung transplantation remains the preferred definitive therapy for eligible patients., (Copyright ©ERS 2016.)

Genetic causes of pulmonary arterial hypertension (PAH) and pulmonary veno-occlusive disease (PVOD) have been identified, leading to a growing need for genetic counselling.Between 2003 and 2014, genetic counselling was offered to 529 PAH and 100 PVOD patients at the French Referral Centre for Pulmonary Hypertension.Mutations in PAH-predisposing genes were identified in 72 patients presenting as sporadic PAH (17% of cases; 62 mutations in BMPR2, nine in ACVRL1 (ALK1) and one in ENG) and in 94 patients with a PAH family history (89% of cases; 89 mutations in BMPR2, three in ACVRL1 (ALK1) and two in KCNK3). Bi-allelic mutations in EIF2AK4 were identified in all patients with a family history of PVOD (n=19) and in seven patients (8.6%) presenting as sporadic PVOD. Pre-symptomatic genetic diagnosis was offered to 272 relatives of heritable PAH patients, identifying mutations in 36.4% of them. A screening programme is now offered to asymptomatic mutation carriers to detect PAH in an early phase and to identify predictors of outcomes in asymptomatic BMPR2 mutation carriers. BMPR2 screening allowed us to offer pre-implantation diagnosis to two couples with a BMPR2 mutation.Genetic counselling can be implemented in pulmonary hypertension centres., (Copyright ©ERS 2016.)

Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension characterised by predominant remodelling of pulmonary venules. Bi-allelic mutations in the eukaryotic translation initiation factor 2α kinase 4 (EIF2AK4) gene were recently described as the major cause of heritable PVOD, but risk factors associated with PVOD remain poorly understood. Occupational exposures have been proposed as a potential risk factor for PVOD, but epidemiological studies are lacking.A case-control study was conducted in consecutive PVOD (cases, n=33) and pulmonary arterial hypertension patients (controls, n=65). Occupational exposure was evaluated via questionnaire interview with blinded assessments using an expert consensus approach and a job exposure matrix (JEM).Using the expert consensus approach, PVOD was significantly associated with occupational exposure to organic solvents (adjusted OR 12.8, 95% CI 2.7-60.8), with trichloroethylene being the main agent implicated (adjusted OR 8.2, 95% CI 1.4-49.4). JEM analysis independently confirmed the association between PVOD and trichloroethylene exposure. Absence of significant trichloroethylene exposure was associated with a younger age of disease (54.8±21.4 years, p=0.037) and a high prevalence of harbouring bi-allelic EIF2AK4 mutations (41.7% versus 0%, p=0.015).Occupational exposure to organic solvents may represent a novel risk factor for PVOD. Genetic background and environmental exposure appear to influence the phenotypic expression of the disease., (Copyright ©ERS 2015.)

Mutations of the bone morphogenetic protein type II receptor (BMPR2) gene predispose to pulmonary arterial hypertension (PAH). 290 idiopathic (I)PAH patients and 15 heritable (H)PAH were screened to determine the spectrum and rate of BMPR2 mutations in a large Chinese patient group. Gene sequencing and multiplex ligation-dependent probe amplification (MLPA®) were used to detect sequence mutations and large rearrangements (RGTs). Total mutation rate was 14.5% (n = 42 out of 290) in Chinese IPAH patients, and 53.3% (n = 8 out of 15) in HPAH patients. RGT mutation rate was 3.1% (n = 7 out of 229) and represented 14% (n = 7 out of 50) of all identified mutations. 25 BMPR2 mutations were newly identified. Patients in this study were younger than other reported PAH subjects. BMPR2 mutation carriers were ~6 yrs younger at diagnosis than noncarriers (p = 0.002), but this relationship was significant only in the female group, which was larger. The proportion of females carrying a BMPR2 mutation was half that of males (12.8% versus 25.3%; p = 0.008). Our results indicate that the overall genetics of Chinese PAH patients is similar to that of other populations, but the clinical picture differs by the precocity of the disease in the whole patient group, and the lower proportion of females found to carry a BMPR2 mutation.

The aim of the present study was to describe a large cohort of fenfluramine-associated pulmonary arterial hypertension (fen-PAH) and its possible prognostic markers. The records of all patients with a diagnosis of fen-PAH evaluated at the present authors' centre from 1986-2004 were retrospectively studied. Baseline clinical and haemodynamic data were collected, as well as survival times. The median duration of fenfluramine exposure was 6 months, with a median of 4.5 yrs between exposure and onset of symptoms. Nine (22.5%) out of 40 patients evaluated resulted positive for the presence of germline bone morphogenetic protein receptor (BMPR) type 2 mutations. In these patients, the duration of exposure to fenfluramine was significantly lower than in patients without mutation. The median survival was 6.4 yrs, without significant difference between fen-PAH and a control group of idiopathic and familial pulmonary arterial hypertension patients referred to the present authors' centre during the same time frame and treated identically. Duration of fenfluramine exposure showed no relation to survival, while cardiac index was the only independent predictor of multivariate analysis. Fenfluramine-associated pulmonary arterial hypertension shares clinical, functional, haemodynamic and genetic features with idiopathic pulmonary arterial hypertension, as well as overall survival rates. Therefore, the present authors conclude that fenfluramine exposure characterises a potent trigger for pulmonary arterial hypertension without influencing its clinical course.