Matina Prapa, Mauro Lago-Docampo, Emilia M. Swietlik, David Montani, Melanie Eyries, Marc Humbert, Carrie L. Welch, Wendy K. Chung, Rolf M. F. Berger, Harm Jan Bogaard, Olivier Danhaive, Pilar Escribano-Subıas, Henning Gall, Barbara Girerd, Ignacio Hernandez-Gonzalez, Simon Holden, David Hunt, Samara M. A. Jansen, Wilhelmina Kerstjens-Frederikse, David G. Kiely, Pablo Lapunzina, John McDermott, Shahin Moledina, Joanna Pepke-Zaba, Gary J. Polwarth, Gwen Schotte, Jair Tenorio-Castano, A. A. Roger Thompson, John Wharton, Stephen J. Wort, Karyn Megy, Rutendo Mapeta, Carmen M. Treacy, Jennifer M. Martin, Wei Li, Andrew J. Swift, Paul D. Upton, Nicholas W. Morrell, Stefan Graf, Diana Valverde, NIHR BioResource for Translational Research–Rare Diseases, National Cohort Study of Idiopathic and Heritable PAH, PAH Biobank Enrolling Centers’ Investigators
Multiple Institutions
Multiple Countries
American Journal of Respiratory and Critical Care Medicine
Am J Respir Crit Care Med 2022; 206: 1522-1533
DOI: 10.1164/rccm.202203-0485OC
Abstract
Rationale: Despite the increased recognition of TBX4 (T-BOX transcription factor 4)-associated pulmonary arterial hypertension (PAH), genotype-phenotype associations are lacking and may provide important insights.
Objectives: To compile and functionally characterize all TBX4 variants reported to date and undertake a comprehensive genotype-phenotype analysis.
Methods: We assembled a multicenter cohort of 137 patients harboring monoallelic TBX4 variants and assessed the pathogenicity of missense variation (n = 42) using a novel luciferase reporter assay containing T-BOX binding motifs. We sought genotype-phenotype correlations and undertook a comparative analysis with patients with PAH with BMPR2 (Bone Morphogenetic Protein Receptor type 2) causal variants (n = 162) or no identified variants in PAH-associated genes (n = 741) genotyped via the National Institute for Health Research BioResource-Rare Diseases.
Measurements and Main Results: Functional assessment of TBX4 missense variants led to the novel finding of gain-of-function effects associated with older age at diagnosis of lung disease compared with loss-of-function effects (P = 0.038). Variants located in the T-BOX and nuclear localization domains were associated with earlier presentation (P = 0.005) and increased incidence of interstitial lung disease (P = 0.003). Event-free survival (death or transplantation) was shorter in the T-BOX group (P = 0.022), although age had a significant effect in the hazard model (P = 0.0461). Carriers of TBX4 variants were diagnosed at a younger age (P < 0.001) and had worse baseline lung function (FEV1, FVC) (P = 0.009) than the BMPR2 and no identified causal variant groups.
Conclusions: We demonstrated that TBX4 syndrome is not strictly the result of haploinsufficiency but can also be caused by gain of function. The pleiotropic effects of TBX4 in lung disease may be in part explained by the differential effect of pathogenic mutations located in critical protein domains.
Category
Genetic Factors Associated with Pulmonary Vascular Disease
Class III. Pulmonary Hypertension Associated with Lung Disease
Age Focus: Pediatric Pulmonary Vascular Disease or Adult Pulmonary Vascular Disease
Fresh or Filed Publication: Filed (PHiled). Greater than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes