First Genotype-Phenotype Study in TBX4 Syndrome: Gain-of-Function Mutations Causative for Lung Disease.
- Resource Type
- Academic Journal
- Authors
- Prapa M; Department of Medicine and.; St. George's University Hospitals National Health Service (NHS) Foundation Trust, London, United Kingdom.; Lago-Docampo M; CINBIO, Universidade de Vigo, Vigo, Spain.; Rare Diseases and Pediatric Medicine, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, Vigo, Spain.; Swietlik EM; Department of Medicine and.; Addenbrooke's Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom.; Royal Papworth Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom.; Montani D; Université Paris-Saclay, AP-HP, Service de Pneumologie, Centre de référence de l'hypertension pulmonaire, INSERM UMR_S 999, Hôpital Bicêtre, Le Kremlin-Bicêtre, Paris, France.; Eyries M; Département de génétique, hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, and UMR_S 1166-ICAN, INSERM, UPMC Sorbonne Universités, Paris, France.; Humbert M; Université Paris-Saclay, AP-HP, Service de Pneumologie, Centre de référence de l'hypertension pulmonaire, INSERM UMR_S 999, Hôpital Bicêtre, Le Kremlin-Bicêtre, Paris, France.; Welch CL; Department of Pediatrics and.; Chung WK; Department of Pediatrics and.; Department of Medicine, Columbia University Irving Medical Center, New York, New York.; Berger RMF; Centre for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children's Hospital, and.; Bogaard HJ; Department of Pulmonary Medicine, Amsterdam University Medical Centre, Vrije Universiteit Amsterdam, Amsterdam Cardiovascular Sciences, the Netherlands.; Danhaive O; Division of Neonatology, St.-Luc University Hospital, Catholic University of Louvain, Brussels, Belgium.; Department of Pediatrics, University of California San Francisco, San Francisco, California.; Escribano-Subías P; Unidad Multidisciplinar de Hipertensión Pulmonar, Servicio de Cardiología, Hospital Universitario 12 de Octubre, Madrid, Spain.; CIBERCV, Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, ISCIII, Madrid, Spain.; Gall H; Centre for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children's Hospital, and.; Girerd B; Université Paris-Saclay, AP-HP, Service de Pneumologie, Centre de référence de l'hypertension pulmonaire, INSERM UMR_S 999, Hôpital Bicêtre, Le Kremlin-Bicêtre, Paris, France.; Hernandez-Gonzalez I; Departamento de Cardiología, Hospital Universitario Río Hortega, Valladolid, Spain.; Holden S; Department of Clinical Genetics, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.; Hunt D; Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, United Kingdom.; Jansen SMA; Department of Pulmonary Medicine, Amsterdam University Medical Centre, Vrije Universiteit Amsterdam, Amsterdam Cardiovascular Sciences, the Netherlands.; Kerstjens-Frederikse W; Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.; Kiely DG; Department of Infection, Immunity, and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom.; Sheffield Pulmonary Vascular Disease Unit, Royal Hallamshire Hospital, Sheffield, United Kingdom.; Lapunzina P; Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz-UAM, Madrid, Spain.; CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.; ITHACA, European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability, Brussels, Belgium.; McDermott J; Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester University NHS Foundation Trust, Manchester, United Kingdom.; Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester, United Kingdom.; Moledina S; Great Ormond Street Hospital, London, United Kingdom.; Pepke-Zaba J; Royal Papworth Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom.; Polwarth GJ; Royal Papworth Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom.; Schotte G; Department of Pulmonary Medicine, Amsterdam University Medical Centre, Vrije Universiteit Amsterdam, Amsterdam Cardiovascular Sciences, the Netherlands.; Tenorio-Castaño J; Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz-UAM, Madrid, Spain.; CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.; ITHACA, European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability, Brussels, Belgium.; Thompson AAR; Department of Infection, Immunity, and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom.; Sheffield Pulmonary Vascular Disease Unit, Royal Hallamshire Hospital, Sheffield, United Kingdom.; Wharton J; National Heart and Lung Institute, Imperial College London, London, United Kingdom.; Wort SJ; National Heart and Lung Institute, Imperial College London, London, United Kingdom.; Megy K; Department of Medicine and.; Addenbrooke's Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom.; Mapeta R; Department of Medicine and.; Addenbrooke's Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom.; Treacy CM; Department of Medicine and.; Martin JM; Department of Medicine and.; Li W; Department of Medicine and.; Swift AJ; Department of Infection, Immunity, and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom.; Upton PD; Department of Medicine and.; Morrell NW; Department of Medicine and.; Addenbrooke's Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom.; Royal Papworth Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom.; National Institute of Health Research (NIHR) BioResource for Translational Research, Cambridge Biomedical Campus, Cambridge, United Kingdom.; Gräf S; Department of Medicine and.; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.; National Institute of Health Research (NIHR) BioResource for Translational Research, Cambridge Biomedical Campus, Cambridge, United Kingdom.; Valverde D; CINBIO, Universidade de Vigo, Vigo, Spain.; Rare Diseases and Pediatric Medicine, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, Vigo, Spain.
- Source
- Publisher: American Thoracic Society Country of Publication: United States NLM ID: 9421642 Publication Model: Print Cited Medium: Internet ISSN: 1535-4970 (Electronic) Linking ISSN: 1073449X NLM ISO Abbreviation: Am J Respir Crit Care Med Subsets: MEDLINE
- Subject
- Language
- English
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 (FEV 1 , 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.