Key result
A novel heterozygous nonsense variant in TAB2, c.1039 C>T (p.R347X), was identified in two siblings and shown via molecular modeling to truncate the protein, causing adult-onset cardiomyopathy and congenital heart defects.
Case Report (n=2)
Identifies a novel TAB2 variant (p.R347X) causing cardiomyopathy and congenital heart defects, expanding the known phenotypic spectrum of TAB2 mutations.
Supports TAB2 screening in familial cardiomyopathy; leaves open prevalence and penetrance in larger cohorts.
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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Caulfield et al. (2018) conducted a case report in Cardiomyopathy and congenital heart defects (n=2). TAB2 c.1039 C>T (p.R347X) variant vs. Wild-type TAB2 (in molecular modeling) was evaluated. A novel heterozygous nonsense variant in TAB2, c.1039 C>T (p.R347X), was identified in two siblings and shown via molecular modeling to truncate the protein, causing adult-onset cardiomyopathy and congenital heart defects.
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