title: A recognizable systemic connective tissue disorder with polyvalvular heart dystrophy and dysmorphism associated with TAB2 mutations.
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.
authors.affiliation: Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Ritelli
authors.affiliation: Division/Laboratory of Medical Genetics, Department of Molecular Medicine, University "La Sapienza", San Camillo-Forlanini Hospital, Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Morlino
authors.affiliation: Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Giacopuzzi
authors.affiliation: Unità di Citogenetica, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (Foggia), Italy.
authors.forename: L
authors.initials: L
authors.lastname: Bernardini
authors.affiliation: Unità di Citogenetica, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (Foggia), Italy.
authors.forename: B
authors.initials: B
authors.lastname: Torres
authors.affiliation: Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Santoro
authors.affiliation: Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Ravasio
authors.affiliation: Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Chiarelli
authors.affiliation: Division/Laboratory of Medical Genetics, Department of Molecular Medicine, University "La Sapienza", San Camillo-Forlanini Hospital, Rome, Italy.
authors.forename: D
authors.initials: D
authors.lastname: D'Angelantonio
authors.affiliation: Laboratory of Medical Genetics, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Novelli
authors.affiliation: Division/Laboratory of Medical Genetics, Department of Molecular Medicine, University "La Sapienza", San Camillo-Forlanini Hospital, Rome, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Grammatico
authors.affiliation: Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: M
authors.identifier: http://orcid.org/0000-0002-3105-5990
authors.initials: M
authors.lastname: Colombi
authors.affiliation: Unità di Genetica Medica, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (Foggia), Italy.
authors.forename: M
authors.initials: M
authors.lastname: Castori
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D003240:Connective Tissue Diseases / Q000235:genetics*; D005145:Face / Q000002:abnormalities*; D005192:Family Health; D005260:Female; D006330:Heart Defects, Congenital / Q000235:genetics*; D006351:Heart Valves / Q000002:abnormalities; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C410585:TAB2 protein, human
keywords: Ehlers-Danlos syndrome; FLNA; TAB2; TAK1; polyvalvular heart disease; valvular dystrophy