TY - JOUR
T1 - First Genotype-Phenotype Study in TBX4 Syndrome Gain-of-Function Mutations Causative for Lung Disease
AU - Prapa, Matina
AU - Lago-Docampo, Mauro
AU - Swietlik, Emilia M.
AU - Montani, David
AU - Eyries, M. lanie
AU - Humbert, Marc
AU - Welch, Carrie L.
AU - Chung, Wendy K.
AU - Berger, Rolf M. F.
AU - Bogaard, Harm Jan
AU - Danhaive, Olivier
AU - Escribano-Subías, Pilar
AU - Gall, Henning
AU - Girerd, Barbara
AU - Hernandez-Gonzalez, Ignacio
AU - Holden, Simon
AU - Hunt, David
AU - Jansen, Samara M. A.
AU - Kerstjens-Frederikse, Wilhelmina
AU - Kiely, David G.
AU - Lapunzina, Pablo
AU - McDermott, John
AU - NIHR BioResource for Translational Research-Rare Diseases32
AU - Moledina, Shahin
AU - Pepke-Zaba, Joanna
AU - Polwarth, Gary J.
AU - Schotte, Gwen
AU - Tenorio-Castaño, Jair
AU - Thompson, A. A. Roger
AU - National Cohort Study of Idiopathic and Heritable PAH33
AU - Wharton, John
AU - Wort, Stephen J.
AU - Megy, Karyn
AU - Mapeta, Rutendo
AU - Treacy, Carmen M.
AU - Martin, Jennifer M.
AU - Li, Wei
AU - Swift, Andrew J.
AU - Upton, Paul D.
AU - PAH Biobank Enrolling Centers' Investigators33
AU - Morrell, Nicholas W.
AU - Gräf, Stefan
AU - Valverde, Diana
PY - 2022/12/15
Y1 - 2022/12/15
N2 - 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-functio 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.
AB - 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-functio 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85145387345&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/35852389
U2 - https://doi.org/10.1164/rccm.202203-0485OC
DO - https://doi.org/10.1164/rccm.202203-0485OC
M3 - Article
C2 - 35852389
SN - 1073-449X
VL - 206
SP - 1522
EP - 1533
JO - American journal of respiratory and critical care medicine
JF - American journal of respiratory and critical care medicine
IS - 12
ER -