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Phenotypic spectrum of TGFB3 disease-causing variants in a Dutch-French cohort and first report of a homozygous patient |
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| Authors: | Luisa Marsili Eline Overwater Nadine Hanna Geneviève Baujat Marieke J.H. Baars Catherine Boileau Dominique Bonneau Anne Claire Brehin Yline Capri Ho Y. Cheung Eelco Dulfer Marion Gerard Laurent Gouya Yvonne Hilhorst-Hofstee Arjan C. Houweling Bertrand Isidor Lauriane Le Gloan Leonie A. Menke Sylvie Odent Fanny Morice-Picard Clemence Vanlerberghe Els Voorhoeve J. Peter van Tintelen Alessandra Maugeri Pauline Arnaud |
| Affiliation: | 1. Clinique de Génétique, CHU Lille, Lille, France;2. Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands;3. Département de Génétique, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Paris, France Laboratory for Vascular Translational Science, INSERM U1148, Université Paris Diderot, Hôpital Bichat, Paris, France;4. Service de Génétique, INSERM U781, Hôpital Necker-Enfants Malades, Institut Imagine, University Sorbonne-Paris-Cité, Paris, France;5. Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands;6. Département de Génétique, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Paris, France Laboratory for Vascular Translational Science, INSERM U1148, Université Paris Diderot, Hôpital Bichat, Paris, France Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Faculté Paris Diderot, LVTS INSERM U 1148, Centre de Référence Pour le Syndrome de Marfan et Apparentés, Paris, France;7. Service de génétique, CHU d'Anger, Angers, France;8. Department of Genetics, Normandy Centre for Genomic and Personalized Medicine, Normandie University, UNIROUEN, Inserm U1245 and Rouen University Hospital, Rouen, France;9. Department of Genetics, APHP-Robert DEBRE University Hospital, Denis Diderot School of Medicine, Paris University, Paris, France;10. Department of Medical Genetics, University Medical Center Groningen, Groningen, The Netherlands;11. Service de Génétique, CHU Caen, Caen, France;12. Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Faculté Paris Diderot, LVTS INSERM U 1148, Centre de Référence Pour le Syndrome de Marfan et Apparentés, Paris, France;13. Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands;14. Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands;15. Service de Génétique Médicale, CHU Nantes, Nantes, France;16. Clinique Cardiologique et des Maladies Vasculaires, CHU Nantes, Nantes, France;17. CHU de Rennes, Service de Génétique Clinique, Université Rennes, CNRS UMR6290 IGDR (Institut de Génétique et Développement de Rennes), Rennes, France;18. Service de dermatologie, Unité de Dermato-Pédiatrie du CHU de Bordeaux, Bordeaux, France;19. Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands Department of Genetics, Utrecht University Medical Center, Utrecht University, Utrecht, The Netherlands;20. Département de Génétique, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Paris, France |
| Abstract: | Disease-causing variants in TGFB3 cause an autosomal dominant connective tissue disorder which is hard to phenotypically delineate because of the small number of identified cases. The purpose of this retrospective cross-sectional multicenter study is to elucidate the genotype and phenotype in an international cohort of TGFB3 patients. Eleven (eight novel) TGFB3 disease-causing variants were identified in 32 patients (17 families). Aortic root dilatation and mitral valve disease represented the most common cardiovascular findings, reported in 29% and 32% of patients, respectively. Dissection involving distal aortic segments occurred in two patients at age 50 and 52 years. A high frequency of systemic features (65% high-arched palate, 63% arachnodactyly, 57% pectus deformity, 52% joint hypermobility) was observed. In familial cases, incomplete penetrance and variable clinical expressivity were noted. Our cohort included the first described homozygous patient, who presented with a more severe phenotype compared to her heterozygous relatives. In conclusion, TGFB3 variants were associated with a high percentage of systemic features and aortic disease (dilatation/dissection) in 35% of patients. No deaths occurred from cardiovascular events or pregnancy-related complications. Nevertheless, homozygosity may be driving a more severe phenotype. |
| Keywords: | aortic dilatation aortic dissection connective tissue disorder Loeys-Dietz syndrome TGFB3 transforming growth factor beta 3 |