Welch, CL;
Aldred, MA;
Balachandar, S;
Dooijes, D;
Eichstaedt, CA;
Graf, S;
Houweling, AC;
Machado, RD;
Pandya, D;
Prapa, M;
et al.
Welch, CL; Aldred, MA; Balachandar, S; Dooijes, D; Eichstaedt, CA; Graf, S; Houweling, AC; Machado, RD; Pandya, D; Prapa, M; Shaukat, M; Southgate, L; Tenorio-Castano, J; ClinGen PH VCEP; Chung, WK; International Consortium for Genetic Studies in Pulmonary Arteri
(2023)
Defining the Clinical Validity of Genes Reported to Cause Pulmonary Arterial Hypertension.
Genet Med, 25 (11).
p. 100925.
ISSN 1530-0366
https://doi.org/10.1016/j.gim.2023.100925
SGUL Authors: Southgate, Laura
PDF
Accepted Version
Restricted to Repository staff only until 5 July 2024. Available under License Creative Commons Attribution Non-commercial No Derivatives. Download (936kB) |
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 three 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 due to a paucity of genetic evidence over time. CONCLUSIONS: 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.
Item Type: | Article | ||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Additional Information: | © 2023. This manuscript version is made available under the CC-BY-NC-ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/ | ||||||||||||||||||||||||||||||
Keywords: | genetics, genomic medicine, molecular diagnosis, pulmonary arterial hypertension, ClinGen PH VCEP, International Consortium for Genetic Studies in Pulmonary Arterial Hypertension (PAH-ICON) at the Pulmonary Vascular Research Institute (PVRI), 0604 Genetics, 1103 Clinical Sciences, Genetics & Heredity | ||||||||||||||||||||||||||||||
SGUL Research Institute / Research Centre: | Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) | ||||||||||||||||||||||||||||||
Journal or Publication Title: | Genet Med | ||||||||||||||||||||||||||||||
ISSN: | 1530-0366 | ||||||||||||||||||||||||||||||
Language: | eng | ||||||||||||||||||||||||||||||
Dates: |
|
||||||||||||||||||||||||||||||
Publisher License: | Creative Commons: Attribution-Noncommercial-No Derivative Works 4.0 | ||||||||||||||||||||||||||||||
Projects: |
|
||||||||||||||||||||||||||||||
PubMed ID: | 37422716 | ||||||||||||||||||||||||||||||
Go to PubMed abstract | |||||||||||||||||||||||||||||||
URI: | https://openaccess.sgul.ac.uk/id/eprint/115602 | ||||||||||||||||||||||||||||||
Publisher's version: | https://doi.org/10.1016/j.gim.2023.100925 |
Statistics
Actions (login required)
Edit Item |