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.

Protein molecular modeling techniques investigating novel TAB2 variant R347X causing cardiomyopathy and congenital heart defects in multigenerational family

“…The proband also displays more cardiac issues overall than his sister, who did not have valve regurgitation or myxoid degeneration of valves. Both siblings were notable for hypermobility, which has been well recognized in previous literature (Cheng et al., ; Ritelli et al., ). Both exhibited mild myopia, which has been recorded in one individual who coincidentally also has a pathogenic nonsense variant in TAB2 , although this may well be multifactorial (Ritelli et al., ).…”

“…Both siblings were notable for hypermobility, which has been well recognized in previous literature (Cheng et al., ; Ritelli et al., ). Both exhibited mild myopia, which has been recorded in one individual who coincidentally also has a pathogenic nonsense variant in TAB2 , although this may well be multifactorial (Ritelli et al., ). The sloping shoulders seen in the sister and high‐arched palate seen in the proband seem to be unique features.…”

TAB2 c.1398dup variant leads to haploinsufficiency and impairs extracellular matrix homeostasis

“…Here, we report the molecular proof of the pathogenic considerations, which emerged by the previous description of a novel disorder resembling the 6q25.1 microdeletion syndrome and additional connective tissue features (Ritelli et al, ). In our previous work, we emphasized the pleiotropic nature of the disorder due to the heterozygous TAB2 c.1398dup variant.…”

“…This study focused on the TAB2 (RefSeq NM_015093) variant found in Family 1 in our previous work (Ritelli et al, ). The variant has been submitted to Leiden Open Variation Database (https://databases.lovd.nl/shared/phenotypes/0000175660, patient ID 00235348).…”

“…We recently described a multigeneration family with the novel TAB2 heterozygous c.1398dup variant and a systemic phenotype resembling in part the 6q25.1 microdeletion syndrome (Ritelli et al, ). The observed phenotype recapitulates the multiple biological functions of TAB2, as this family shows a protean cardiac phenotype coupled with multiple connective tissue features mirroring a perturbed ECM homeostasis.…”