Caulfield Thomas R, Richter John E, Brown Emily E, Mohammad Ahmed N, Judge Daniel P, Atwal Paldeep S
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Mayo Graduate School, Neurobiology of Disease, Mayo Clinic, Jacksonville, FL, USA.
Mol Genet Genomic Med. 2018 Apr 26;6(4):666-72. doi: 10.1002/mgg3.401.
Haploinsufficiency of TAB2 is known to cause congenital heart defects and cardiomyopathy due to its important roles in cardiovascular tissue, both during development and through adult life. We report a sibling pair displaying adult-onset cardiomyopathy, hypermobility, and mild myopia. Our proband, a 39-year-old male, presents only with the above symptoms, while his 36-year-old sister was also notable for a ventricular septal defect in her infancy.
Whole-exome sequencing was utilized to identify the molecular basis of the phenotype found in two siblings. A molecular modeling technique that takes advantage of conformational sampling advances (Maxwell's demon molecular dynamics and Monte Carlo) were used to make a model of the mutant variant for comparative analytics to the wild-type.
Exome sequencing revealed a novel, heterogeneous pathogenic variant in TAB2, c.1039 C>T (p.R347X), that was present in both individuals. This pathogenic variant removes just over half the residues from the TAB2 protein and severely impacts its functional ability, which we describe in detail.
Analysis of the proband's family showed a history of cardiomyopathy, but no congenital heart defects or connective tissue disease. We highlight the heterogeneity in phenotype of TAB2 pathogenic variants and confirm the pathogenicity of this new variant through neoteric protein modeling techniques.
已知TAB2单倍体不足会导致先天性心脏缺陷和心肌病，因为其在心血管组织发育及成年期均发挥重要作用。我们报告了一对患有成年期发病的心肌病、关节活动过度和轻度近视的同胞兄妹。我们的先证者是一名39岁男性，仅表现出上述症状，而他36岁的妹妹在婴儿期还患有室间隔缺损。
利用全外显子组测序来确定这两名同胞兄妹中发现的表型的分子基础。采用一种利用构象采样进展的分子建模技术（麦克斯韦妖分子动力学和蒙特卡罗方法）构建突变体变体模型，以便与野生型进行比较分析。
外显子组测序在两名个体中均发现了TAB2基因中的一种新的、异质性的致病变体，即c.1039 C>T（p.R347X）。这种致病变体从TAB2蛋白中去除了超过一半的残基，并严重影响其功能能力，我们对此进行了详细描述。
对先证者家族的分析显示有心肌病病史，但无先天性心脏缺陷或结缔组织疾病。我们强调了TAB2致病变体表型的异质性，并通过新型蛋白质建模技术证实了这种新变体的致病性。
