Computational prediction of protein subdomain stability in MYBPC3 enables clinical risk stratification in hypertrophic cardiomyopathy and enhances variant interpretation
Year: 2021
Type: article
Abstract: PURPOSE: Variants in MYBPC3 causing loss of function are the most common cause of hypertrophic cardiomyopathy (HCM). However, a substantial number of patients carry missense variants of uncertain significance (VUS) in MYBPC3. We hypothesize that a structural-based algorithm, STRUM, which estimates the effect of missense variants on protein folding, will identify a subgroup of HCM patients with a MYBPC3 VUS associated with increased clinical risk. METHODS: Among 7,963 patients in the multicenter Sarcomeric Human Cardiomyopathy Registry (SHaRe), 120 unique missense VUS in MYBPC3 were identified. Variants were evaluated for their effect on subdomain folding and a stratified time-to-event analysis for an overall composite endpoint (first occurrence of ventricular arrhythmia, heart failure, all-cause mortality, atrial fibrillation, and stroke) was performed for patients with HCM and a MYBPC3 missense VUS. RESULTS: We demonstrated that patients carrying a MYBPC3 VUS predicted to cause subdomain misfolding (STRUM+, ΔΔG ≤ -1.2 kcal/mol) exhibited a higher rate of adverse events compared with those with a STRUM- VUS (hazard ratio = 2.29, P = 0.0282). In silico saturation mutagenesis of MYBPC3 identified 4,943/23,427 (21%) missense variants that were predicted to cause subdomain misfolding. CONCLUSION: STRUM identifies patients with HCM and a MYBPC3 VUS who may be at higher clinical risk and provides supportive evidence for pathogenicity.
Source: Genetics in Medicine
Authors: Andrea D. Thompson, Adam S. Helms, Anamika Kannan, Jaime Yob, Neal K. Lakdawala, Samuel G. Wittekind, Alexandre C. Pereira, Daniel L. Jacoby, Steven D. Colan, Euan A. Ashley, Sara Saberi, James S. Ware, Jodie Ingles, Christopher Semsarian, Michelle Michels, Francesco Mazzarotto, Iacopo Olivotto, Carolyn Y. Ho, Sharlene M. Day, SHaRe investigators
Institutions: University of Michigan, University of Pennsylvania, Brigham and Women's Hospital, Harvard University, Cincinnati Children's Hospital Medical Center, Universidade de São Paulo, Instituto do Coração - HCFMUSP, Yale University, Boston Children's Hospital, Stanford Medicine, Stanford University, Imperial College London, The University of Sydney, Centenary Institute, Erasmus MC, Azienda Ospedaliero-Universitaria Careggi, University of Florence
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,900
Funders: University of Michigan, Wellcome Trust, MyoKardia, National Institute for Health and Care Research, British Heart Foundation, Imperial College London, Ministero della Salute, Regione Toscana, National Institutes of Health, Medical Research Council, National Health and Medical Research Council, National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences
Awards: G1267581739, HCMR Novel Markers of Prognosis in Hypertrophic Cardiomyopathy, G4249056089, Genome-Engineered Stem Cell Models to Determine Disease Mechanisms in MYBPC3 Hypertrophic Cardiomyopathy, Using Genetics For Early Phenotyping & Prevention of Hypertrophic Cardiomyopathy, G5201182482, Genomic dissection of inherited cardiomyopathies: identifying alleles, genes and mechanisms, for patient stratification., G6868616705, G6968959027, G6971475997, Clinical and Genetic Basis of Inherited Heart Diseases and Sudden Cardiac Death, G8355103724, G849084591, Genomic dissection of inherited cardiomyopathies: identifying alleles, genes and mechanisms, for patient stratification., Yale Clinical and Translational Science Award, Multidisciplinary Cardiovascular Research Training
OpenAlex ID: W3148611012