Phenotypic Expression and Outcomes in Individuals With Rare Genetic Variants of Hypertrophic Cardiomyopathy,Journal of the American College of Cardiology

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Phenotypic Expression and Outcomes in Individuals With Rare Genetic Variants of Hypertrophic Cardiomyopathy
Journal of the American College of Cardiology ( IF 21.7 ) Pub Date : 2021-09-06 , DOI: 10.1016/j.jacc.2021.07.017
Antonio de Marvao ₁ , Kathryn A McGurk ₂ , Sean L Zheng ₃ , Marjola Thanaj ₁ , Wenjia Bai ₄ , Jinming Duan ₅ , Carlo Biffi ₆ , Francesco Mazzarotto ₇ , Ben Statton ₁ , Timothy J W Dawes ₈ , Nicolò Savioli ₁ , Brian P Halliday ₃ , Xiao Xu ₃ , Rachel J Buchan ₃ , A John Baksi ₃ , Marina Quinlan ₁ , Paweł Tokarczuk ₁ , Upasana Tayal ₃ , Catherine Francis ₃ , Nicola Whiffin ₉ , Pantazis I Theotokis ₁ , Xiaolei Zhang ₂ , Mikyung Jang ₃ , Alaine Berry ₁ , Antonis Pantazis ₃ , Paul J R Barton ₁₀ , Daniel Rueckert ₁₁ , Sanjay K Prasad ₃ , Roddy Walsh ₁₂ , Carolyn Y Ho ₁₃ , Stuart A Cook ₁₄ , James S Ware ₁₀ , Declan P O'Regan ₁

Affiliation

MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, London, United Kingdom.
National Heart and Lung Institute, Imperial College London, London, United Kingdom.
National Heart and Lung Institute, Imperial College London, London, United Kingdom; Cardiovascular Research Centre at Royal Brompton and Harefield Hospitals, London, United Kingdom.
Biomedical Image Analysis Group, Department of Computing, Imperial College London, London, United Kingdom; Department of Brain Sciences, Imperial College London, London, United Kingdom.
MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, London, United Kingdom; Biomedical Image Analysis Group, Department of Computing, Imperial College London, London, United Kingdom; School of Computer Science, University of Birmingham, Birmingham, United Kingdom.
MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, London, United Kingdom; Biomedical Image Analysis Group, Department of Computing, Imperial College London, London, United Kingdom.
National Heart and Lung Institute, Imperial College London, London, United Kingdom; Cardiovascular Research Centre at Royal Brompton and Harefield Hospitals, London, United Kingdom; Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy; Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy.
MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, London, United Kingdom; National Heart and Lung Institute, Imperial College London, London, United Kingdom.
National Heart and Lung Institute, Imperial College London, London, United Kingdom; Cardiovascular Research Centre at Royal Brompton and Harefield Hospitals, London, United Kingdom; Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, London, United Kingdom; National Heart and Lung Institute, Imperial College London, London, United Kingdom; Cardiovascular Research Centre at Royal Brompton and Harefield Hospitals, London, United Kingdom.
Biomedical Image Analysis Group, Department of Computing, Imperial College London, London, United Kingdom; Faculty of Informatics and Medicine, Klinikum Rechts der Isar, TU Munich, Munich, Germany.
Department of Experimental Cardiology, Amsterdam UMC, AMC Heart Centre, Amsterdam, the Netherlands.
Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, London, United Kingdom; National Heart and Lung Institute, Imperial College London, London, United Kingdom; Cardiovascular Research Centre at Royal Brompton and Harefield Hospitals, London, United Kingdom; National Heart Centre Singapore, Singapore; Duke-NUS Graduate Medical School, Singapore.

Background

Hypertrophic cardiomyopathy (HCM) is caused by rare variants in sarcomere-encoding genes, but little is known about the clinical significance of these variants in the general population.

Objectives

The goal of this study was to compare lifetime outcomes and cardiovascular phenotypes according to the presence of rare variants in sarcomere-encoding genes among middle-aged adults.

Methods

This study analyzed whole exome sequencing and cardiac magnetic resonance imaging in UK Biobank participants stratified according to sarcomere-encoding variant status.

Results

The prevalence of rare variants (allele frequency <0.00004) in HCM-associated sarcomere-encoding genes in 200,584 participants was 2.9% (n = 5,712; 1 in 35), and the prevalence of variants pathogenic or likely pathogenic for HCM (SARC-HCM-P/LP) was 0.25% (n = 493; 1 in 407). SARC-HCM-P/LP variants were associated with an increased risk of death or major adverse cardiac events compared with controls (hazard ratio: 1.69; 95% confidence interval [CI]: 1.38-2.07; P < 0.001), mainly due to heart failure endpoints (hazard ratio: 4.23; 95% CI: 3.07-5.83; P < 0.001). In 21,322 participants with both cardiac magnetic resonance imaging and whole exome sequencing, SARC-HCM-P/LP variants were associated with an asymmetric increase in left ventricular maximum wall thickness (10.9 ± 2.7 mm vs 9.4 ± 1.6 mm; P < 0.001), but hypertrophy (≥13 mm) was only present in 18.4% (n = 9 of 49; 95% CI: 9%-32%). SARC-HCM-P/LP variants were still associated with heart failure after adjustment for wall thickness (hazard ratio: 6.74; 95% CI: 2.43-18.7; P < 0.001).

Conclusions

In this population of middle-aged adults, SARC-HCM-P/LP variants have low aggregate penetrance for overt HCM but are associated with an increased risk of adverse cardiovascular outcomes and an attenuated cardiomyopathic phenotype. Although absolute event rates are low, identification of these variants may enhance risk stratification beyond familial disease.

中文翻译：

肥厚型心肌病罕见遗传变异个体的表型表达和结果

背景

肥厚型心肌病 (HCM) 是由肌节编码基因的罕见变异引起的，但人们对这些变异在普通人群中的临床意义知之甚少。

目标

本研究的目的是根据中年成年人肌节编码基因中罕见变异的存在情况来比较终生结果和心血管表型。

方法

这项研究分析了英国生物银行参与者的全外显子组测序和心脏磁共振成像，这些参与者根据肌节编码变异状态进行分层。

结果

罕见变异的流行（等位基因频率 <0 id=0>P < 0.001），主要是由于心力衰竭终点（风险比：4.23；95% CI：3.07-5.83； P < 0.001）。在 21,322 名接受心脏磁共振成像和全外显子组测序的参与者中，SARC-HCM-P/LP 变异与左心室最大壁厚度的不对称增加相关（10.9 ± 2.7 毫米 vs 9.4 ± 1.6 毫米； P < 0.001），但肥大（≥13 mm）仅占 18.4%（n = 49 人中的 9 人；95% CI：9%-32%）。调整壁厚度后，SARC-HCM-P/LP 变异仍与心力衰竭相关（风险比：6.74；95% CI：2.43-18.7； P < 0.001）。