Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
Division/Laboratory of Medical Genetics, Department of Molecular Medicine, University "La Sapienza", San Camillo-Forlanini Hospital, Rome, Italy.
Clin Genet. 2018 Jan;93(1):126-133. doi: 10.1111/cge.13032. Epub 2017 Aug 21.
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.
包含 TAK1 结合蛋白 2（TAB2）缺失与孤立性和综合征性先天性心脏缺陷相关。在具有相似表型的患者以及患有额眶骨发育不良的单一个体中发现罕见的错义变异。我们描述了一个家系和另外一个散发性多瓣膜性心脏病、全身性关节过度活动症以及相关的肌肉骨骼并发症、柔软、天鹅绒般和超伸展性皮肤、短肢、听力障碍和面部畸形的患者。在第一个家系中，全外显子组测序（WES）揭示了新型 TAB2 c.1398dup（p.Thr467Tyrfs*6）变体，该变体消除了对 TAK1（转化生长因子β激活激酶 1）依赖性信号通路激活至关重要的 C 末端锌指结构域。散发性病例携带了一个约 2Mb 的从头缺失，包括 28 个基因，也包括 TAB2。这项研究揭示了 TAB2 突变与类似于埃勒斯-当洛斯综合征的表型之间的关联，该表型伴有严重的多瓣膜性心脏病和微妙的面部畸形。我们的发现支持 TAB2 扰动与更广泛的临床表型相关，并强调了 TAK1 信号网络在人类发育中的作用。
