TY - JOUR
T1 - Defining the clinical validity of genes reported to cause pulmonary arterial hypertension
AU - ClinGen PH VCEP
AU - International Consortium for Genetic Studies in Pulmonary Arterial Hypertension (PAH-ICON) at the Pulmonary Vascular Research Institute (PVRI)
AU - Welch, Carrie L.
AU - Aldred, Micheala A.
AU - Balachandar, Srimmitha
AU - Dooijes, Dennis
AU - Eichstaedt, Christina A.
AU - Gräf, Stefan
AU - Houweling, Arjan C.
AU - Machado, Rajiv D.
AU - Pandya, Divya
AU - Prapa, Matina
AU - Shaukat, Memoona
AU - Southgate, Laura
AU - Tenorio-Castano, Jair
AU - Callejo, Emily P.
AU - Day, Kristina M.
AU - Macaya, Daniela
AU - Maldonado-Velez, Gabriel
AU - Chung, Wendy K.
AU - Archer, Stephen L.
AU - Auckland, Kathryn
AU - Austin, Eric D.
AU - Badagliacca, Roberto
AU - Barberà, Joan-Albert
AU - Belge, Catharina
AU - Bogaard, Harm Jan
AU - Bonnet, S. bastien
AU - Boomars, Karin A.
AU - Boucherat, Olivier
AU - Chakinala, Murali M.
AU - Condliffe, Robin
AU - Damico, Rachel Lynn
AU - Delcroix, Marion
AU - Desai, Ankit A.
AU - Doboszynska, Anna
AU - Elliott, C. Greg
AU - Eyries, Melanie
AU - Escribano Subías, Maria Pilar
AU - Gall, Henning
AU - Ghio, Stefano
AU - Ghofrani, Ardeschir-Hossein
AU - Grünig, Ekkehard
AU - Hamid, Rizwan
AU - Harbaum, Lars
AU - Hassoun, Paul M.
AU - Hemnes, Anna R.
AU - Hinderhofer, Katrin
AU - Howard, Luke S.
AU - Humbert, Marc
AU - Kiely, David G.
AU - Noordegraaf, Anton Vonk
N1 - Funding Information: 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.This work was financially supported by grants awarded to M.A.A. from the National Institutes of Health (NIH; U24HG009650) and NHLBI R35HL140019. S.B. is supported by an AHA predoctoral fellowship #834024. L.S. is supported by the Springboard Scheme Funders, namely, the Academy of Medical Sciences (AMS); the Wellcome Trust; the Government Department of Business, Energy, and Industrial Strategy (BEIS); and the British Heart Foundation and Diabetes UK [SBF005\1115]. J.T. is supported by Spanish FEDER-ISCIII grant PI21/01593. Conceptualization, data curation, formal analysis, investigation, methodology, visualization, writing original draft, review, and editing: C.L.W. M.A.A. S.B. D.D. C.A.E. S.G. A.C.H. R.D.M. D.P. M.P. M.S. L.S. J.T.-C. W.K.C.; Project administration: C.L.W. W.K.C. Funding Information: This work was financially supported by grants awarded to M.A.A. from the National Institutes of Health (NIH; U24HG009650) and NHLBI R35HL140019. S.B. is supported by an AHA predoctoral fellowship #834024. L.S. is supported by the Springboard Scheme Funders, namely, the Academy of Medical Sciences ( AMS ); the Wellcome Trust; the Government Department of Business, Energy, and Industrial Strategy ( BEIS ); and the British Heart Foundation and Diabetes UK [SBF005\1115]. J.T. is supported by Spanish FEDER- ISCIII grant PI21/01593. Publisher Copyright: © 2023 American College of Medical Genetics and Genomics
PY - 2023/11/1
Y1 - 2023/11/1
N2 - 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.
AB - 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.
KW - Genetics
KW - Genomic medicine
KW - Molecular diagnosis
KW - Pulmonary arterial hypertension
UR - http://www.scopus.com/inward/record.url?scp=85169798442&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.gim.2023.100925
DO - https://doi.org/10.1016/j.gim.2023.100925
M3 - Article
C2 - 37422716
SN - 1098-3600
VL - 25
JO - Genetics in medicine
JF - Genetics in medicine
IS - 11
M1 - 100925
ER -