Dataset Information

Homozygous missense MYBPC3 Pro873His mutation associated with increased risk for heart failure development in hypertrophic cardiomyopathy.

ABSTRACT: Hypertrophic cardiomyopathy (HCM) is a primary autosomal-dominant disorder of the myocardium with variable expressivity and penetrance. Occasionally, homozygous sarcomere genetic variants emerge while genotyping HCM patients. In these cases, a more severe HCM phenotype is generally seen. Here, we report a case of HCM that was diagnosed clinically at 39 years of age. Initial symptoms were shortness of breath during exertion. Successively, he developed a wide array of severe clinical manifestations, which progressed to an ominous end-stage heart failure that resulted in heart transplantation. Genotype analysis revealed a missense MYBPC3 variant NM_000256.3:c.2618C>A,p.(Pro873His) that presented in the homozygous form. Conflicting interpretations of pathogenicity have been reported for the Pro873His MYBPC3 variant described here. Our patient, presenting with two copies of the variant and devoid of a normal allele, progressed to end-stage heart failure, which supports the notion of a deleterious effect of this variant in the homozygous form.

SUBMITTER: Kissopoulou A

PROVIDER: S-EPMC6073032 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Homozygous missense MYBPC3 Pro873His mutation associated with increased risk for heart failure development in hypertrophic cardiomyopathy.

Kissopoulou Antheia A Trinks Cecilia C Green Anna A Karlsson Jan-Erik JE Jonasson Jon J Gunnarsson Cecilia C

ESC heart failure 20180416 4

Hypertrophic cardiomyopathy (HCM) is a primary autosomal-dominant disorder of the myocardium with variable expressivity and penetrance. Occasionally, homozygous sarcomere genetic variants emerge while genotyping HCM patients. In these cases, a more severe HCM phenotype is generally seen. Here, we report a case of HCM that was diagnosed clinically at 39 years of age. Initial symptoms were shortness of breath during exertion. Successively, he developed a wide array of severe clinical manifestation ...[more]

PMID: 29663722

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Project description:Background: Development of advanced heart failure (HF) symptoms is the most common adverse pathway in hypertrophic cardiomyopathy (HCM) patients. Currently, there is a limited ability to identify HCM patients at risk of HF. Objectives: In this study, we present a machine learning (ML)-based model to identify individual HCM patients who are at high risk of developing advanced HF symptoms. Methods: From a consecutive cohort of HCM patients evaluated at the Tufts HCM Institute from 2001 to 2018, we extracted a set of 64 potential risk factors measured at baseline. Only patients with New York Heart Association (NYHA) functional class I/II and LV ejection fraction (LVEF) by echocardiography >35% were included. The study cohort (n = 1,427 patients) was split into three disjoint subsets: development (50%), model selection (10%), and independent validation (40%). The least absolute shrinkage and selection operator was used to select the most influential clinical variables. An ensemble of ML classifiers, including logistic regression, was used to identify patients with high risk of developing a HF outcome. Study outcomes were defined as progression to NYHA class III/IV, drop in LVEF below 35%, septal reduction procedure, and/or heart transplantation. Results: During a mean follow-up of 4.7 ± 3.7 years, advanced HF occurred in 283 (20% out of 1,427) patients. The model features included patients' sex, NYHA class (I or II), HCM type (i.e., obstructive or not), LV wall thickness, LVEF, presence of HF symptoms (e.g., dyspnea, presyncope), comorbidities (atrial fibrillation, hypertension, mitral regurgitation, and systolic anterior motion), and type of cardiac medications. The developed risk stratification model showed strong differentiation power to identify patients at advanced HF risk in the testing dataset (c-statistics = 0.81; 95% confidence interval [CI]: 0.76, 0.86). The model allowed correct identification of high-risk patients with accuracy 74% (CI: 0.70, 0.78), sensitivity 80% (CI: 0.77, 0.83), and specificity 72% (CI: 0.68, 0.76). The model performance was comparable among different sex and age groups. Conclusions: A 5-year risk prediction of progressive HF in HCM patients can be accurately estimated using ML analysis of patients' clinical and imaging parameters. A set of 17 clinical and imaging variables were identified as the most important predictors of progressive HF in HCM.

Project description:BackgroundHypertrophic cardiomyopathy (HCM) is frequently caused by mutations in myosin-binding protein C3 ( MYBPC3) resulting in a premature termination codon (PTC). The underlying mechanisms of how PTC mutations in MYBPC3 lead to the onset and progression of HCM are poorly understood. This study's aim was to investigate the molecular mechanisms underlying the pathogenesis of HCM associated with MYBPC3 PTC mutations by utilizing human isogenic induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs).MethodsIsogenic iPSC lines were generated from HCM patients harboring MYBPC3 PTC mutations (p.R943x; p.R1073P_Fsx4) using genome editing. Comprehensive phenotypic and transcriptome analyses were performed in the iPSC-CMs.ResultsWe observed aberrant calcium handling properties with prolonged decay kinetics and elevated diastolic calcium levels in the absence of structural abnormalities or contracile dysfunction in HCM iPSC-CMs as compared to isogenic controls. The mRNA expression levels of MYBPC3 were significantly reduced in mutant iPSC-CMs, but the protein levels were comparable among isogenic iPSC-CMs, suggesting that haploinsufficiency of MYBPC3 does not contribute to the pathogenesis of HCM in vitro. Furthermore, truncated MYBPC3 peptides were not detected. At the molecular level, the nonsense-mediated decay pathway was activated, and a set of genes involved in major cardiac signaling pathways was dysregulated in HCM iPSC-CMs, indicating an HCM gene signature in vitro. Specific inhibition of the nonsense-mediated decay pathway in mutant iPSC-CMs resulted in reversal of the molecular phenotype and normalization of calcium-handling abnormalities.ConclusionsiPSC-CMs carrying MYBPC3 PTC mutations displayed aberrant calcium signaling and molecular dysregulations in the absence of significant haploinsufficiency of MYBPC3 protein. Here we provided the first evidence of the direct connection between the chronically activated nonsense-mediated decay pathway and HCM disease development.

Dataset Information

Homozygous missense MYBPC3 Pro873His mutation associated with increased risk for heart failure development in hypertrophic cardiomyopathy.

Publications

Homozygous missense MYBPC3 Pro873His mutation associated with increased risk for heart failure development in hypertrophic cardiomyopathy.

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