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A recognizable systemic connective tissue disorder with polyvalvular heart dystrophy and dysmorphism associated with
M Ritelli1, S Morlino2, E Giacopuzzi1
1Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
Clinical Genetics
|April 8, 2017
Summary
Mutations in TAB2 are linked to congenital heart defects and a connective tissue disorder similar to Ehlers-Danlos syndrome. This expands the known clinical spectrum for TAB2 gene variants.
Area of Science:
- Genetics
- Developmental Biology
- Cardiology
Background:
- TAK1-binding protein 2 (TAB2) plays a role in TGFβ-activated kinase 1 (TAK1) signaling pathways.
- Perturbations in TAB2 have been associated with congenital heart defects.
- A broader spectrum of phenotypes linked to TAB2 mutations is increasingly recognized.
Purpose of the Study:
- To investigate the role of TAB2 mutations in a family and a sporadic patient presenting with polyvalvular heart disease and connective tissue abnormalities.
- To characterize the genetic basis of a phenotype resembling Ehlers-Danlos syndrome with severe cardiac and musculoskeletal complications.
Main Methods:
- Whole-exome sequencing (WES) was performed on a family with a novel TAB2 variant.
- Analysis of a sporadic case with a de novo deletion encompassing TAB2.
- Clinical phenotyping including detailed assessment of cardiac, skeletal, and skin features.
Main Results:
- A novel TAB2 frameshift variant (c.1398dup) was identified in a family, leading to the loss of a critical C-terminal zinc finger domain.
- A sporadic patient had a de novo deletion including TAB2, confirming its role.
- The identified mutations were associated with severe polyvalvular heart disease, joint hypermobility, skin hyperextensibility, and subtle facial dysmorphism.
Conclusions:
- TAB2 mutations are associated with a phenotype that includes severe polyvalvular heart disease and features overlapping with Ehlers-Danlos syndrome.
- This study expands the clinical spectrum of TAB2-related disorders.
- The findings highlight the crucial role of the TAK1 signaling network in human development, particularly in cardiovascular and connective tissue formation.