Phenotypic spectrum of TGFB3 disease-causing variants in a Dutch-French cohort and first report of a homozygous patient

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-PicardClemence Vanlerberghe, Els Voorhoeve, J. Peter van Tintelen, Alessandra Maugeri, Pauline Arnaud

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.

Original languageEnglish
Pages (from-to)723-730
Number of pages8
JournalClinical Genetics
Issue number5
Publication statusPublished - 1 May 2020

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