Computational prediction of protein subdomain stability in MYBPC3 enables clinical risk stratification in hypertrophic cardiomyopathy and enhances variant interpretation
Computational prediction of protein subdomain stability in MYBPC3 enables clinical risk stratification in hypertrophic cardiomyopathy and enhances variant interpretation
Abstract PurposeVariants in MYBPC3 causing loss-of-function are the most common cause of 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 improve clinical risk stratification of patients with HCM and a MYBPC3 VUS. MethodsAmong 7,963 patients in the multi-center Sarcomeric Human Cardiomyopathy Registry, 120 unique missense VUSs 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. ResultsWe 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 to 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. ConclusionsSTRUM enables clinical risk stratification of patients with HCM and a MYBPC3 VUS and has the capacity to improve prognostic predictions and clinical decision making.
Colan Steven D.、Wittekind Samuel G.、Lakdawala Neal K.、Pereira Alexandre C.、Saberi Sara、Semsarian Christopher、Michels Michelle、Mazzarotto Francesco、Ho Carolyn Y.、Day Sharlene M.、Olivotto Iacopo、Ingles Jodie、SHaRe investigators、Kannan Anamika、Helms Adam S.、Jacoby Daniel L.、Ashley Euan A.、Yob Jaime、Thompson Andrea D.、Ware James S.
Department of Cardiology, Boston Children?ˉs HospitalCincinnati Children?ˉs Hospital Medical Center, Heart InstituteCardiovascular Medicine, Brigham and Women?ˉs Hospital, Harvard Medical SchoolHeart Institute (InCor), University of Sao Paolo Medical SchoolCardiovascular Medicine, University of MichiganAgnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of SydneyDepartment of CardiologyNational Heart & Lung Institute & Royal Brompton Cardiovascular Research Centre, Imperial College London||Cardiomyopathy Unit, Careggi University Hospital||Department of Clinical and Experimental Medicine, University of FlorenceCardiovascular Medicine, Brigham and Women?ˉs Hospital, Harvard Medical SchoolCardiovascular Medicine, University of PennsylvaniaCardiomyopathy Unit, Careggi University Hospital||Department of Clinical and Experimental Medicine, University of FlorenceCardio Genomics Program at Centenary Institute, The University of SydneyCardiovascular Medicine, University of MichiganCardiovascular Medicine, University of MichiganCardiovascular Medicine, Yale UniversityCenter for Inherited Heart Disease, Stanford UniversityCardiovascular Medicine, University of PennsylvaniaCardiovascular Medicine, University of MichiganNational Heart & Lung Institute & Royal Brompton Cardiovascular Research Centre, Imperial College London
医学研究方法基础医学临床医学
Hypertrophic cardiomyopathyMyosin Binding Protein C3 (MYBPC3)GeneticsVariants of uncertain significance
Colan Steven D.,Wittekind Samuel G.,Lakdawala Neal K.,Pereira Alexandre C.,Saberi Sara,Semsarian Christopher,Michels Michelle,Mazzarotto Francesco,Ho Carolyn Y.,Day Sharlene M.,Olivotto Iacopo,Ingles Jodie,SHaRe investigators,Kannan Anamika,Helms Adam S.,Jacoby Daniel L.,Ashley Euan A.,Yob Jaime,Thompson Andrea D.,Ware James S..Computational prediction of protein subdomain stability in MYBPC3 enables clinical risk stratification in hypertrophic cardiomyopathy and enhances variant interpretation[EB/OL].(2025-03-28)[2025-05-09].https://www.biorxiv.org/content/10.1101/2020.11.29.402974.点此复制
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