Computational and biophysical determination of pathogenicity of variants of unknown significance in cardiac thin filament

• DOI: 10.1172/jci.insight.154350
• Publication Date: 2021-10-26T16:01:03Z
• Authors: Allison B. Mason; Melissa L. Lynn; Anthony P. Baldo; Andrea E. Deranek; Jil C. Tardiff; Steven D. Schwartz
• Keywords: 0301 basic medicine; Cardiology; R; Genetic Variation; Molecular Dynamics Simulation; 3. Good health; Actin Cytoskeleton; 03 medical and health sciences; Cardiovascular Diseases; Medicine; Humans; Point Mutation; Research Article

Point mutations within sarcomeric proteins have been associated with altered function and cardiomyopathy development. Difficulties remain, however, in establishing the pathogenic potential of individual mutations, often limiting use genotype management affected families. To directly address this challenge, we utilized our all-atom computational model human full cardiac thin filament (CTF) to predict how sequence substitutions CTF might affect structure dynamics on an atomistic level. Utilizing molecular calculations, simulated 21 well-defined genetic troponin T tropomyosin variants establish a baseline changes induced observables. Computational results were verified via differential scanning calorimetry subset develop experimental correlation. Calculations performed 9 independent unknown significance (VUS), compared identify high-resolution signatures. Results for VUS set determine structural dynamic changes, variant reclassifications proposed. This unbiased, methodology can provide unique information that be incorporated into existing analyses facilitate classification both de novo those where established approaches provided conflicting information.