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, Genevieve 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

    14 Citations (Scopus)
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    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.

    Original languageEnglish
    Pages (from-to)723-730
    Number of pages8
    JournalClinical Genetics
    Volume97
    Issue number5
    DOIs
    Publication statusPublished - May-2020

    Keywords

    • aortic dilatation
    • aortic dissection
    • connective tissue disorder
    • Loeys-Dietz syndrome
    • TGFB3
    • transforming growth factor beta 3
    • THORACIC AORTIC-ANEURYSM
    • LOEYS-DIETZ SYNDROME
    • MUTATION
    • MARFAN
    • GENES

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