Penetrance of Hypertrophic Cardiomyopathy in Sarcomere Protein Mutation Carriers
Penetrance of Hypertrophic Cardiomyopathy in Sarcomere Protein Mutation Carriers
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DOI：
10.1016/j.jacc.2020.06.011
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发表时间：
2020-08-04
影响因子：
24
通讯作者：
Elliott, Perry M.
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文献类型：
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作者：
Lorenzini, Massimiliano;Norrish, Gabrielle;Elliott, Perry M.
背景对肌节蛋白（SP）基因突变引起的肥厚型心肌病（HCM）患者亲属进行预测性遗传筛查是目前的护理标准，但是关于长期的数据很少，本研究的目的是确定SP突变携带者新的HCM诊断的发生率。方法这是一项回顾性分析成人和儿童SP突变携带者结果：作者评价了来自156个家庭的285名个体（中位年龄14.2岁[四分位数范围：6.8至31.6岁]，141名[49.5%]男性个体）; 145名（50.9%）接受了心脏磁共振（CMR）。致病基因的频率如下：MYBPC 3 n = 123（43.2%），MYH 7 n = 69（24.2%），TNNI 3 n = 39（13.7%），TNNT 2 n = 34（11.9%），TPM 1 n = 9（3.2%），MYL 2 n = 6（2.1%），ACTC 1 n = 1（0.4%），多突变n = 4（1.4%）。中位随访时间为8.0年（四分位距：4.0 - 13.3年），86例（30.2%）患者发生HCM; 50例患者中有16例（32.0%）符合CMR诊断标准，但不符合超声心动图诊断标准。15年随访时估计的HCM复发率为46%（95%置信区间[CI]：38%至54%）。在一个多变量模型中，调整了年龄和CMR分层，HCM发展的独立预测因素是男性（风险比[HR]：2.91; 95% CI：1.82 - 4.65）和心电图（ECG）异常（HR：4.02; 95% CI：2.51 - 6.44）; TNNI 3变异体的风险最低（HR：0.19; 95% CI：0.07至0.55，与MYBPC 3相比）。结论在第一次阴性筛查后，大约50%的SP突变携带者在15年的随访中发展为HCM。男性和心电图异常与HCM的高风险相关。在长期筛查中应考虑定期CMR。(c)2020作者由Elsevier代表美国心脏病学会基金会发布。这是一个在CC BY许可证下的开放获取文章（http：//creativecommons.org/licenses/by/4.0/）。
BACKGROUND Predictive genetic screening of relatives of patients with hypertrophic cardiomyopathy (HCM) caused by sarcomere protein (SP) gene mutations is current standard of care, but there are few data on long-term outcomes in mutation carriers without HCM.OBJECTIVES The aim of this study was to determine the incidence of new HCM diagnosis in SP mutation carriers.METHODS This was a retrospective analysis of adult and pediatric SP mutation carriers identified during family screening who did not fulfill diagnostic criteria for HCM at first evaluation.RESULTS The authors evaluated 285 individuals from 156 families (median age 14.2 years [interquartile range: 6.8 to 31.6 years], 141 [49.5%] male individuals); 145 (50.9%) underwent cardiac magnetic resonance (CMR). Frequency of causal genes was as follows: MYBPC3 n = 123 (43.2%), MYH7 n = 69 (24.2%), TNNI3 n = 39 (13.7%), TNNT2 n = 34 (11.9%), TPM1 n = 9 (3.2%), MYL2 n = 6 (2.1%), ACTC1 n = 1 (0.4%), multiple mutations n = 4 (1.4%). Median follow-up was 8.0 years (interquartile range: 4.0 to 13.3 years) and 86 (30.2%) patients developed HCM; 16 of 50 (32.0%) fulfilled diagnostic criteria on CMR but not echocardiography. Estimated HCM penetrance at 15 years of follow-up was 46% (95% confidence interval [CI]: 38% to 54%). In a multivariable model adjusted for age and stratified for CMR, independent predictors of HCM development were male sex (hazard ratio [HR]: 2.91; 95% CI: 1.82 to 4.65) and abnormal electrocardiogram (ECG) (HR: 4.02; 95% CI: 2.51 to 6.44); TNNI3 variants had the lowest risk (HR: 0.19; 95% CI: 0.07 to 0.55, compared to MYBPC3).CONCLUSIONS Following a first negative screening, approximately 50% of SP mutation carriers develop HCM over 15 years of follow-up. Male sex and an abnormal ECG are associated with a higher risk of developing HCM. Regular CMR should be considered in long-term screening. (c) 2020 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).