Defining the clinical validity of genes reported to cause pulmonary arterial hypertension.
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.
Copyright © 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.
Overview publication
| Title | Defining the clinical validity of genes reported to cause pulmonary arterial hypertension. |
| Date | 2023-11-01 |
| Issue name | Genetics in medicine : official journal of the American College of Medical Genetics |
| Issue number | v25.11:100925 |
| DOI | 10.1016/j.gim.2023.100925 |
| PubMed | 37422716 |
| Authors | |
| Info | Callejo EP, Day KM, Macaya D, Maldonado-Velez G, Archer SL, Auckland K, Austin ED, Badagliacca R, Barberà JA, Belge C, Bogaard HJ, Bonnet S, Boomars KA, Boucherat O, Chakinala MM, Condliffe R, Damico RL, Delcroix M, Desai AA, Doboszynska A, Elliott CG, Eyries M, Escribano Subías MP, Gall H, Ghio S, Ghofrani AH, Grünig E, Hamid R, Harbaum L, Hassoun PM, Hemnes AR, Hinderhofer K, Howard LS, Humbert M, Kiely DG, Langleben D, Lawrie A, Loyd JE, Moledina S, Montani D, Morrell NW, Nichols WC, Olschewski A, Olschewski H, Papa S, Pauciulo MW, Provencher S, Quarck R, Rhodes CJ, Scelsi L, Seeger W, Stewart DJ, Sweatt A, Swietlik EM, Treacy C, Trembath RC, Tura-Ceide O, Vizza CD, Vonk Noordegraaf A, Wilkins MR, Zamanian RT, Zateyshchikov D |
| Keywords | Genetics, Genomic medicine, Molecular diagnosis, Pulmonary arterial hypertension |
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