Protein molecular modeling techniques investigating novel TAB2 variant R347X causing cardiomyopathy and congenital heart defects in multigenerational family
TR Caulfield, JE Richter Jr, EE Brown… - … Genetics & Genomic …, 2018 - Wiley Online Library
TR Caulfield, JE Richter Jr, EE Brown, AN Mohammad, DP Judge, PS Atwal
Molecular Genetics & Genomic Medicine, 2018•Wiley Online LibraryBackground Haploinsufficiency of TAB 2 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 …
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 …
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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