Defining the clinical validity of genes reported to cause pulmonary arterial hypertension

Carrie L Welch; Micheala A Aldred; Srimmitha Balachandar; Dennis Dooijes; Christina A Eichstaedt; Stefan Gräf; Arjan C Houweling; Rajiv D Machado; Divya Pandya; Matina Prapa; Memoona Shaukat; Laura Southgate; Jair Tenorio-Castano; ClinGen PH VCEP; Wendy K Chung; International Consortium for Genetic Studies in Pulmonary Arterial Hypertension (PAH-ICON) at the Pulmonary Vascular Research Institute (PVRI)

doi:10.1016/j.gim.2023.100925

Defining the clinical validity of genes reported to cause pulmonary arterial hypertension

Genet Med. 2023 Nov;25(11):100925. doi: 10.1016/j.gim.2023.100925. Epub 2023 Jul 5.

Authors

Carrie L Welch¹, Micheala A Aldred², Srimmitha Balachandar², Dennis Dooijes³, Christina A Eichstaedt⁴, Stefan Gräf⁵, Arjan C Houweling⁶, Rajiv D Machado⁷, Divya Pandya⁸, Matina Prapa⁹, Memoona Shaukat⁴, Laura Southgate⁷, Jair Tenorio-Castano¹⁰; ClinGen PH VCEP; Wendy K Chung¹¹; International Consortium for Genetic Studies in Pulmonary Arterial Hypertension (PAH-ICON) at the Pulmonary Vascular Research Institute (PVRI)

Collaborators

Emily P Callejo¹², Kristina M Day¹³, Daniela Macaya¹⁴, Gabriel Maldonado-Velez¹³, Stephen L Archer¹⁵, Kathryn Auckland¹⁶, Eric D Austin¹⁷, Roberto Badagliacca¹⁸, Joan-Albert Barberà¹⁹, Catharina Belge²⁰, Harm Jan Bogaard²¹, Sébastien Bonnet²², Karin A Boomars²³, Olivier Boucherat²⁴, Murali M Chakinala²⁵, Robin Condliffe²⁶, Rachel Lynn Damico²⁷, Marion Delcroix²⁸, Ankit A Desai²⁹, Anna Doboszynska³⁰, C Greg Elliott³¹, Melanie Eyries³², Maria Pilar Escribano Subías³³, Henning Gall³⁴, Stefano Ghio³⁵, Ardeschir-Hossein Ghofrani³⁶, Ekkehard Grünig³⁷, Rizwan Hamid³⁸, Lars Harbaum³⁹, Paul M Hassoun²⁷, Anna R Hemnes⁴⁰, Katrin Hinderhofer⁴¹, Luke S Howard³⁹, Marc Humbert⁴², David G Kiely⁴³, David Langleben⁴⁴, Allan Lawrie⁴⁵, Jim E Loyd⁴⁶, Shahin Moledina⁴⁷, David Montani⁴⁸, Nichols W Morrell⁴⁹, William C Nichols⁵⁰, Andrea Olschewski⁵¹, Horst Olschewski⁵², Silvia Papa¹⁸, Mike W Pauciulo⁵⁰, Steve Provencher²⁴, Rozenn Quarck²⁰, Christopher J Rhodes³⁹, Laura Scelsi⁵³, Werner Seeger³⁵, Duncan J Stewart⁵¹, Andrew Sweatt⁵⁴, Emilia M Swietlik⁵⁵, Carmen Treacy¹⁶, Richard C Trembath⁵⁶, Olga Tura-Ceide⁵⁷, Carmine Dario Vizza¹⁸, Anton Vonk Noordegraaf⁵⁸, Martin R Wilkins³⁹, Roham T Zamanian⁵⁹, Dmitry Zateyshchikov⁶⁰

Affiliations

¹ Department of Pediatrics, Columbia University Irving Medical Center, New York, NY.
² Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Indiana University School of Medicine, IN.
³ Department of Genetics, University Medical Centre Utrecht, Utrecht University, Utrecht, the Netherlands.
⁴ Center for Pulmonary Hypertension, Thoraxklinik-Heidelberg gGmbH, at Heidelberg University Hospital and Translational Lung Research Center, German Center for Lung Research, Heidelberg, Germany; Laboratory for Molecular Genetic Diagnostics, Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
⁵ NIHR BioResource for Translational Research - Rare Diseases, Department of Haemotology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom; Department of Medicine, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.
⁶ Department of Human Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
⁷ Molecular and Clinical Sciences Research Institute, St George's University of London, London, United Kingdom.
⁸ Department of Medicine, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.
⁹ Department of Medicine, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom; St. George's University Hospitals NHS Foundation Trust, London, United Kingdom.
¹⁰ Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, IDiPAZ, Universidad Autonoma de Madrid, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain; ITHACA, European Reference Network, Brussels, Belgium.
¹¹ Department of Pediatrics, Columbia University Irving Medical Center, New York, NY; Department of Medicine, Columbia University Irving Medical Center, New York, NY. Electronic address: Wendy.Chung@childrens.harvard.edu.
¹² Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA.
¹³ Indiana University School of Medicine, Indianapolis, IN, USA.
¹⁴ GeneDx, Gaithersburg, MD, USA.
¹⁵ Department of Medicine, Queen's University, Kingston, Ontario, Canada.
¹⁶ Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
¹⁷ Vanderbilt University Department of Pediatrics, Division of Allergy, Immunology, and Pulmonary Medicine, Nashville, TN, USA.
¹⁸ Pulmonary Hypertension Unit, Department of Cardiovascular and Respiratory Sciences, Sapienza University of Rome, Italy.
¹⁹ Department of Pulmonary Medicine, Hospital Clinic-IDIBAPS, University of Barcelona, Barcelona and Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Spain.
²⁰ Laboratory of Respiratory Diseases & Thoracic Surgery (BREATHE), Department of Chronic Diseases & Metabolism (CHROMETA), Clinical Department of Respiratory Diseases, University Hospitals, University of Leuven, 3000 Leuven, Belgium.
²¹ Department of Lung Disease, Amsterdam UMC (location VUmc), Amsterdam, the Netherlands.
²² Pulmonary Hypertension Research Group, Centre de Recherche de l'Institut de Cardiologie et de Pneumologie de Quebec, Quebec City, QC, Canada; Department of Medicine, Université Laval, Quebec City, Quebec, Canada.
²³ Department of Pulmonary Medicine, Erasmus MC, University Medical Center Rotterdam, the Netherlands.
²⁴ Department of Medicine, Université Laval, Quebec City, Quebec, Canada; Pulmonary Hypertension and Vascular Biology Research Group, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Department of Medicine, Université Laval, Quebec City, Quebec, Canada.
²⁵ Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
²⁶ Department of Infection, Immunity & Cardiovascular Disease, University of Sheffield, UK; Royal Hallamshire Hospital, Sheffield, UK.
²⁷ Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
²⁸ Department of Pneumology, University Hospital Leuven, Leuven, Belgium.
²⁹ Indiana University, Indianapolis, IN, USA.
³⁰ Department of Pulmonology, Faculty of Medicine, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland.
³¹ Pulmonary and Critical Care Divisions, Intermountain Medical Center, Murray, UT, USA.
³² Département de Génétique, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France; INSERM UMRS 1166, Sorbonne Université and Institute for Cardiometabolism and Nutrition (ICAN), Paris, France.
³³ Department of Cardiology, Hospital Universitario 12 de Octubre, Madrid, Spain; Ciber-CV, Centro de investigación Biomédica en Red de Enfermedades Cardiovasculares, Madrid, Spain; Centro de Referencia Nacional de Hipertensión Pulmonar Compleja and ERN-Lung-Pulmonary Hypertension Referal Center, Madrid, Spain; Instituto de Investigación Sanitaria del Hospital Universitario 12 de Octubre (Imas12), Red SAMID, Madrid, Spain.
³⁴ Justus-Liebig University, Excellence Cluster Cardio-Pulmonary Institute (CPI) and Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.
³⁵ Division of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
³⁶ Justus-Liebig University, Excellence Cluster Cardio-Pulmonary Institute (CPI) and Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany; Department of Medicine, Imperial College London, London, UK.
³⁷ Center for Pulmonary Hypertension, Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital, Heidelberg, Germany and Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany.
³⁸ Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, USA.
³⁹ National Heart and Lung Institute, Imperial College London, London, UK.
⁴⁰ Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
⁴¹ Laboratory of Molecular Genetic Diagnostics, Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
⁴² Faculté de Médecine, Université Paris-Sud and Université Paris-Saclay, Le Kremlin-Bicêtre, France; INSERM UMR_S 999, Hôpital Marie Lannelongue, Le Plessis-Robinson, France; AP-HP, Service de Pneumologie, Centre de Référence de l'Hypertension Pulmonaire Sévère, Département Hospitalo-Universitaire (DHU) Thorax Innovation (TORINO), Hôpital de Bicêtre, Le Kremlin-Bicêtre, France.
⁴³ Sheffield Pulmonary Vascular Disease Unit, Royal Hallamshire Hospital, Sheffield, UK.
⁴⁴ Center for Pulmonary Vascular Disease, Cardiology Division, Jewish General Hospital and McGill University, Montreal, QC, Canada.
⁴⁵ Department of Infection, Immunity & Cardiovascular Disease, University of Sheffield, UK.
⁴⁶ Vanderbilt University Medical Center, Nashville, TN, USA.
⁴⁷ Great Ormond Street Hospital, London, UK.
⁴⁸ INSERM UMR_S 999, Hôpital Marie Lannelongue, Le Plessis-Robinson, France; Université Paris-Saclay, AP-HP, French Referral Center for Pulmonary Hypertension, Pulmonary Department, Hôpital de Bicêtre, Le Kremlin-Bicêtre, France.
⁴⁹ Department of Medicine, University of Cambridge, UK; Department of Haematology, University of Cambridge, Cambridge, UK.
⁵⁰ Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
⁵¹ Ludwig Boltzmann Institute for Lung Vascular research, Graz, Austria.
⁵² Ludwig Boltzmann Institute for Lung Vascular research, Graz, Austria; Medical University of Graz, Graz, Austria.
⁵³ Department of Medicine, Imperial College London, London, UK.
⁵⁴ Medical University of Graz, Graz, Austria.
⁵⁵ Department of Medicine, University of Cambridge, UK.
⁵⁶ Ottawa Hospital Research Institute, Sinclair Centre for Regenerative Medicine and the University of Ottawa, Ontario, Canada.
⁵⁷ Department of Pulmonary, Allergy and Critical Care Medicine, Stanford University, Stanford, CA, USA; Department of Medical and Molecular Genetics, King's College London, London, UK; Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Spain.
⁵⁸ Biomedical Research Networking center on Respiratory diseases (CIBERES), 28029 Madrid, Spain.
⁵⁹ Department of Pulmonary Medicine, Dr. Josep Trueta University Hospital de Girona, Santa Caterina Hospital de Salt and the Girona Biomedical Research Institute (IDIBGI), Girona, Catalonia, Spain.
⁶⁰ Department of Pulmonology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, VU University Medical Center, Amsterdam, the Netherlands.

Abstract

Purpose: Pulmonary arterial hypertension (PAH) is a rare, progressive vasculopathy with significant cardiopulmonary morbidity and mortality. Genetic testing is currently recommended for adults diagnosed with heritable, idiopathic, anorexigen-, hereditary hemorrhagic telangiectasia-, and congenital heart disease-associated PAH, PAH with overt features of venous/capillary involvement, and all children diagnosed with PAH. Variants in at least 27 genes have putative evidence for PAH causality. Rigorous assessment of the evidence is needed to inform genetic testing.

Methods: An international panel of experts in PAH applied a semi-quantitative scoring system developed by the NIH Clinical Genome Resource to classify the relative strength of evidence supporting PAH gene-disease relationships based on genetic and experimental evidence.

Results: Twelve genes (BMPR2, ACVRL1, ATP13A3, CAV1, EIF2AK4, ENG, GDF2, KCNK3, KDR, SMAD9, SOX17, and TBX4) were classified as having definitive evidence and 3 genes (ABCC8, GGCX, and TET2) with moderate evidence. Six genes (AQP1, BMP10, FBLN2, KLF2, KLK1, and PDGFD) were classified as having limited evidence for causal effects of variants. TOPBP1 was classified as having no known PAH relationship. Five genes (BMPR1A, BMPR1B, NOTCH3, SMAD1, and SMAD4) were disputed because of a paucity of genetic evidence over time.

Conclusion: We recommend that genetic testing includes all genes with definitive evidence and that caution be taken in the interpretation of variants identified in genes with moderate or limited evidence. Genes with no known evidence for PAH or disputed genes should not be included in genetic testing.

Keywords: Genetics; Genomic medicine; Molecular diagnosis; Pulmonary arterial hypertension.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Activin Receptors, Type II / genetics
Adenosine Triphosphatases / genetics
Adult
Bone Morphogenetic Protein Receptors, Type II / genetics
Bone Morphogenetic Protein Receptors, Type II / metabolism
Bone Morphogenetic Proteins / genetics
Child
Genetic Predisposition to Disease
Genetic Testing
Humans
Hypertension, Pulmonary* / diagnosis
Hypertension, Pulmonary* / genetics
Membrane Transport Proteins / genetics
Mutation
Protein Serine-Threonine Kinases / genetics
Pulmonary Arterial Hypertension* / genetics

Substances

Bone Morphogenetic Protein Receptors, Type II
ATP13A3 protein, human
Adenosine Triphosphatases
Membrane Transport Proteins
ACVRL1 protein, human
Activin Receptors, Type II
EIF2AK4 protein, human
Protein Serine-Threonine Kinases
BMP10 protein, human
Bone Morphogenetic Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding