A recognizable systemic connective tissue disorder with polyvalvular heart dystrophy and dysmorphism associated with TAB2 mutations

M. Ritelli, S. Morlino, E. Giacopuzzi, L. Bernardini, B. Torres, G. Santoro, V. Ravasio, N. Chiarelli, D. D'Angelantonio, A. Novelli, P. Grammatico, M. Colombi, M. Castori

Research output: Contribution to journalArticle

Abstract

Deletions encompassing TAK1-binding protein 2 (TAB2) associated with isolated and syndromic congenital heart defects. Rare missense variants are found in patients with a similar phenotype as well as in a single individual with frontometaphyseal dysplasia. We describe a family and an additional sporadic patient with polyvalvular heart disease, generalized joint hypermobility and related musculoskeletal complications, soft, velvety and hyperextensible skin, short limbs, hearing impairment, and facial dysmorphism. In the first family, whole-exome sequencing (WES) disclosed the novel TAB2 c.1398dup (p.Thr467Tyrfs*6) variant that eliminates the C-terminal zinc finger domain essential for activation of TAK1 (TGFβ-activated kinase 1)-dependent signaling pathways. The sporadic case carryed a ~2 Mb de novo deletion including 28 genes also comprising TAB2. This study reveal an association between TAB2 mutations and a phenotype resembling Ehlers-Danlos syndrome with severe polyvalvular heart disease and subtle facial dysmorphism. Our findings support the existence of a wider spectrum of clinical phenotypes associated with TAB2 perturbations and emphasize the role of TAK1 signaling network in human development.

Original languageEnglish
Pages (from-to)126-133
Number of pages8
JournalClinical Genetics
Volume93
Issue number1
DOIs
Publication statusPublished - Jan 1 2018

Keywords

  • Ehlers-Danlos syndrome
  • FLNA
  • polyvalvular heart disease
  • TAB2
  • TAK1
  • valvular dystrophy

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Ritelli, M., Morlino, S., Giacopuzzi, E., Bernardini, L., Torres, B., Santoro, G., Ravasio, V., Chiarelli, N., D'Angelantonio, D., Novelli, A., Grammatico, P., Colombi, M., & Castori, M. (2018). A recognizable systemic connective tissue disorder with polyvalvular heart dystrophy and dysmorphism associated with TAB2 mutations. Clinical Genetics, 93(1), 126-133. https://doi.org/10.1111/cge.13032