PDF(Pubmed)
Abstract：
Background: TGFB3 variants cause Loeys-Dietz syndrome type 5, a syndromic form of thoracic aortic aneurysm and dissection. The exact disease phenotype is hard to delineate because of few identified cases and highly variable clinical representation. Methodology: We provide the results of a haplotype analysis and a medical record review of clinical features of 27 individuals from 5 different families, originating from the Campine region in Flanders, carrying the NM_003239.5(TGFB3):c.787G>C p.(Asp263His) likely pathogenic variant, dbSNP:rs796051886, ClinVar:203492. The Asp263 residue is essential for integrin binding to the Arg-Gly-Asp (RGD) motif of the TGFβ3-cytokine. Results: The haplotype analysis revealed a shared haplotype of minimum 1.92 Mb and maximum 4.14 Mb, suggesting a common founder originating >400 years ago. Variable clinical features included connective tissue manifestations, non-aneurysmal cardiovascular problems such as hypertrophic cardiomyopathy, bicuspid aortic valve, mitral valve disease, and septal defects. Remarkably, only in 4 out of the 27 variant-harboring individuals, significant aortic involvement was observed. In one family, a 31-year-old male presented with type A dissection. In another family, the male proband (65 years) underwent a Bentall procedure because of bicuspid aortic valve insufficiency combined with sinus of Valsalva of 50 mm, while an 80-year-old male relative had an aortic diameter of 43 mm. In a third family, the father of the proband (75 years) presented with ascending aortic aneurysm (44 mm). Conclusion: The low penetrance (15%) of aortic aneurysm/dissection suggests that haploinsufficiency alone by the TGFB3 variant may not result in aneurysm development but that additional factors are required to provoke the aneurysm phenotype.
摘要：
背景：TGFB3变异导致Loeys-Dietz综合征5型，一种胸主动脉瘤和夹层的综合征形式。确切的疾病表型很难描述，因为很少有确定的病例和高度可变的临床表现。方法：我们提供了来自5个不同家庭的27个个体的临床特征的单倍型分析和病历回顾的结果。起源于法兰德斯的坎平地区，携带NM_003239.5（TGFB3）：c.787G>Cp。（Asp263His）可能致病变异，dbSNP：rs796051886，ClinVar：203492。Asp263残基对于整联蛋白结合TGFβ3-细胞因子的Arg-Gly-Asp(RGD)基序是必需的。结果：单倍型分析揭示了最小1.92Mb和最大4.14Mb的共享单倍型，暗示一个共同的创始人起源于400多年前。可变的临床特征包括结缔组织表现，非动脉瘤性心血管问题，如肥厚型心肌病，二叶主动脉瓣,二尖瓣疾病,和间隔缺损。值得注意的是,只有在27个变异个体中的4个，观察到明显的主动脉受累.在一个家庭里,一名31岁男性出现A型解剖。在另一个家庭，男性先证者（65岁）因主动脉瓣二尖瓣关闭不全合并50mmValsalva窦而接受了Bentall手术，而一名80岁的男性亲属的主动脉直径为43毫米。在第三个家庭中，先证者的父亲（75岁）出现升主动脉瘤（44毫米）。结论：主动脉瘤/夹层的低外显率（15％）表明TGFB3变体单独的单倍体功能不全可能不会导致动脉瘤的发展，但需要其他因素来引起动脉瘤表型。
