Meta-Analysis of Penetrance and Systematic Review on Transition to Disease in Genetic Hypertrophic Cardiomyopathy.
Meta-Analysis of Penetrance and Systematic Review on Transition to Disease in Genetic Hypertrophic Cardiomyopathy.
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DOI：
10.1161/circulationaha.123.065987
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发表时间：
2024-01-09
期刊：
影响因子：
37.8
通讯作者：
Ho, Carolyn Y.
中科院分区：
文献类型：
--
作者：
Topriceanu, Constantin-Cristian;Pereira, Alexandre C.;Moon, James C.;Captur, Gabriella;Ho, Carolyn Y.
肥厚型心肌病(HCM)以不明原因的左心室肥厚为特征，通常由肌节蛋白编码基因的致病或可能致病变异(P/LP)引起。并不是所有的亚临床变异携带者都会表现出临床上的显性疾病，因为外显率(发生疾病的肌节或肌节相关P/LP变异携带者的比例)是可变的，与年龄有关，而且不能可靠地预测。对文献进行了系统的搜索。我们使用随机效应广义线性混合模型荟萃分析来比较两种不同背景下肌节或肌节相关基因的横截面患病率和外显率：基于临床的研究与基于人群或社区的研究。此外，还分析了纵向的家庭/临床研究，以调查在随访期间从亚临床到显性肥厚型肉芽肿的表型转换率。总共对455篇全文手稿和文章进行了评估。在家庭/临床研究中，诊断为肥厚型心肌炎的患者中肌节变异的发生率为34%。在级联筛查中发现的携带P/LP变异的非先证者亲属中，所有基因的外显率为57%(95%可信区间，52%~63%)，诊断为肥厚型心肌炎的平均年龄为38岁(95%可信区间，36%~40%)。肌球蛋白轻链3的外显率为≈32%，肌球蛋白结合蛋白C3的≈为55%，肌钙蛋白T2和肌钙蛋白I3的≈为60%，肌球蛋白重链7的≈为65%。基于人群的遗传学研究表明，在背景人群中存在P/LP肌节变异，但患病率很低，为1%。在偶然发现的P/LP变异携带者中，红细胞压积的外显率也显著较低，≈为11%，范围从社区动脉粥样硬化风险中的0%到英国生物库中的18%。在纵向家系研究中，从平均16岁的≈开始，在平均8年的随访期内，所有基因的表型转换率为15%。然而，短期基因特异性表型转换在MYBPC3的≈为12%和MYH7的≈为23%之间变化。P/LP变异体的外显率是高度可变的，并受目前未定义的和上下文相关的遗传和环境因素的影响。还需要更多的纵向研究，以提高我们对家庭和社区中真实的终生外显性的理解，并确定从亚临床到显性HCM转变的驱动因素。
Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy and is classically caused by pathogenic or likely pathogenic variants (P/LP) in genes encoding sarcomere proteins. Not all subclinical variant carriers will manifest clinically overt disease because penetrance (proportion of sarcomere or sarcomere-related P/LP variant carriers who develop disease) is variable, age dependent, and not reliably predicted. A systematic search of the literature was performed. We used random-effects generalized linear mixed model meta-analyses to contrast the cross-sectional prevalence and penetrance of sarcomere or sarcomere-related genes in 2 different contexts: clinically-based studies on patients and families with HCM versus population or community-based studies. Longitudinal family/clinical studies were additionally analyzed to investigate the rate of phenotypic conversion from subclinical to overt HCM during follow-up. In total, 455 full-text manuscripts and articles were assessed. In family/clinical studies, the prevalence of sarcomere variants in patients diagnosed with HCM was 34%. The penetrance across all genes in nonproband relatives carrying P/LP variants identified during cascade screening was 57% (95% CI, 52%–63%), and the mean age at HCM diagnosis was 38 years (95% CI, 36%–40%). Penetrance varied from ≈32% for MYL3 (myosin light chain 3) to ≈55% for MYBPC3 (myosin-binding protein C3), ≈60% for TNNT2 (troponin T2) and TNNI3 (troponin I3), and ≈65% for MYH7 (myosin heavy chain 7). Population-based genetic studies demonstrate that P/LP sarcomere variants are present in the background population but at a low prevalence of <1%. The penetrance of HCM in incidentally identified P/LP variant carriers was also substantially lower at ≈11%, ranging from 0% in Atherosclerosis Risk in Communities to 18% in UK Biobank. In longitudinal family studies, the pooled phenotypic conversion across all genes was 15% over an average of ≈8 years of follow-up, starting from a mean of ≈16 years of age. However, short-term gene-specific phenotypic conversion varied between ≈12% for MYBPC3 and ≈23% for MYH7. The penetrance of P/LP variants is highly variable and influenced by currently undefined and context-dependent genetic and environmental factors. Additional longitudinal studies are needed to improve our understanding of true lifetime penetrance in families and in the community and to identify drivers of the transition from subclinical to overt HCM.
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影响因子：
3
作者：
Andersen PS;Hedley PL;Page SP;Syrris P;Moolman-Smook JC;McKenna WJ;Elliott PM;Christiansen M
通讯作者：
Christiansen M
影响因子：
2.6
作者：
Mattos BP;Scolari FL;Torres MA;Simon L;Freitas VC;Giugliani R;Matte Ú
通讯作者：
Matte Ú
影响因子：
3.5
作者：
Höller V;Seebacher H;Zach D;Schwegel N;Ablasser K;Kolesnik E;Gollmer J;Waltl G;Rainer PP;Verheyen S;Zirlik A;Verheyen N
通讯作者：
Verheyen N
影响因子：
3.5
作者：
Antoniutti G;Caimi-Martinez FG;Álvarez-Rubio J;Morlanes-Gracia P;Pons-Llinares J;Rodríguez-Picón B;Fortuny-Frau E;Torres-Juan L;Heine-Suner D;Ripoll-Vera T
通讯作者：
Ripoll-Vera T