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Meta-analysis of cardiomyopathy-associated variants in troponin genes identifies loci and intragenic hot spots that are associated with worse clinical outcomes.
Journal of Molecular and Cellular Cardiology ( IF 4.9 ) Pub Date : 2020-04-09 , DOI: 10.1016/j.yjmcc.2020.04.005 Hanna J Tadros 1 , Chelsea S Life 2 , Gustavo Garcia 2 , Elisa Pirozzi 3 , Edward G Jones 4 , Susmita Datta 5 , Michelle S Parvatiyar 6 , P Bryant Chase 7 , Hugh D Allen 8 , Jeffrey J Kim 8 , Jose R Pinto 2 , Andrew P Landstrom 9
Journal of Molecular and Cellular Cardiology ( IF 4.9 ) Pub Date : 2020-04-09 , DOI: 10.1016/j.yjmcc.2020.04.005 Hanna J Tadros 1 , Chelsea S Life 2 , Gustavo Garcia 2 , Elisa Pirozzi 3 , Edward G Jones 4 , Susmita Datta 5 , Michelle S Parvatiyar 6 , P Bryant Chase 7 , Hugh D Allen 8 , Jeffrey J Kim 8 , Jose R Pinto 2 , Andrew P Landstrom 9
Affiliation
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INTRODUCTION
Troponin (TNN)-encoded cardiac troponins (Tn) are critical for sensing calcium and triggering myofilament contraction. TNN variants are associated with development of cardiomyopathy; however, recent advances in genetic analysis have identified rare population variants. It is unclear how certain variants are associated with disease while others are tolerated.
OBJECTIVE
To compare probands with TNNT2, TNNI3, and TNNC1 variants and utilize high-resolution variant comparison mapping of pathologic and rare population variants to identify loci associated with disease pathogenesis.
METHODS
Cardiomyopathy-associated TNN variants were identified in the literature and topology mapping conducted. Clinical features were compiled and compared. Rare population variants were obtained from the gnomAD database. Signal-to-noise (S:N) normalized pathologic variant frequency against population variant frequency. Abstract review of clinical phenotypes was applied to "significant" hot spots.
RESULTS
Probands were compiled (N = 70 studies, 224 probands) as were rare variants (N = 125,748 exomes; 15,708 genomes, MAF <0.001). TNNC1-positive probands demonstrated the youngest age of presentation (20.0 years; P = .016 vs TNNT2; P = .004 vs TNNI3) and the highest death, transplant, or ventricular fibrillation events (P = .093 vs TNNT2; P = .024 vs TNNI3; Kaplan Meir: P = .025). S:N analysis yielded hot spots of diagnostic significance within the tropomyosin-binding domains, α-helix 1, and the N-Terminus in TNNT2 with increased sudden cardiac death and ventricular fibrillation (P = .004). The inhibitory region and C-terminal region in TNNI3 exhibited increased restrictive cardiomyopathy (P =.008). HCM and RCM models tended to have increased calcium sensitivity and DCM decreased sensitivity (P < .001). DCM and HCM studies typically showed no differences in Hill coefficient which was decreased in RCM models (P < .001). CM models typically demonstrated no changes to Fmax (P = .239).
CONCLUSION
TNNC1-positive probands had younger ages of diagnosis and poorer clinical outcomes. Mapping of TNN variants identified locations in TNNT2 and TNNI3 associated with heightened pathogenicity, RCM diagnosis, and increased risk of sudden death.
中文翻译：
对肌钙蛋白基因中心肌病相关变异的荟萃分析确定了与较差临床结果相关的基因座和基因内热点。
简介 肌钙蛋白 (TNN) 编码的心肌肌钙蛋白 (Tn) 对于感知钙和触发肌丝收缩至关重要。TNN 变异与心肌病的发生有关；然而，遗传分析的最新进展已经发现了罕见的群体变异。目前尚不清楚某些变异如何与疾病相关，而另一些变异却可以耐受。目的 比较具有 TNNT2、TNNI3 和 TNNC1 变异的先证者，并利用病理和罕见群体变异的高分辨率变异比较图谱来识别与疾病发病机制相关的位点。方法 在文献中鉴定出与心肌病相关的 TNN 变异，并进行拓扑图绘制。汇总并比较临床特征。罕见的群体变体是从 gnomAD 数据库中获得的。信噪比 (S:N) 相对于群体变异频率的标准化病理变异频率。对临床表型的抽象回顾适用于“重大”热点。结果先证者（N = 70 项研究，224 名先证者）和罕见变异（N = 125,748 外显子组；15,708 基因组，MAF <0.001）均已编译。TNNC1 阳性先证者表现出最年轻的就诊年龄（20.0 岁；P = .016 对比 TNNT2；P = .004 对比 TNNI3）和最高的死亡、移植或心室颤动事件（P = .093 对比 TNNT2；P = . 024 与 TNNI3；卡普兰·梅厄：P = .025）。S:N 分析在原肌球蛋白结合域、α-螺旋 1 和 TNNT2 的 N 末端内产生了具有诊断意义的热点，并增加了心源性猝死和心室颤动 (P = .004)。TNNI3 的抑制区域和 C 末端区域表现出限制性心肌病增加 (P =.008)。HCM 和 RCM 模型的钙敏感性往往较高，而 DCM 模型的敏感性较低 (P < .001)。DCM 和 HCM 研究通常显示 Hill 系数没有差异，而 RCM 模型中 Hill 系数有所下降 (P < .001)。CM 模型通常表明 Fmax 没有变化 (P = .239)。结论 TNNC1 阳性先证者的诊断年龄较年轻，临床结果较差。TNN 变异图谱确定了 TNNT2 和 TNNI3 中与致病性增强、RCM 诊断和猝死风险增加相关的位置。
更新日期：2020-04-10
中文翻译：
对肌钙蛋白基因中心肌病相关变异的荟萃分析确定了与较差临床结果相关的基因座和基因内热点。
简介 肌钙蛋白 (TNN) 编码的心肌肌钙蛋白 (Tn) 对于感知钙和触发肌丝收缩至关重要。TNN 变异与心肌病的发生有关；然而，遗传分析的最新进展已经发现了罕见的群体变异。目前尚不清楚某些变异如何与疾病相关，而另一些变异却可以耐受。目的 比较具有 TNNT2、TNNI3 和 TNNC1 变异的先证者，并利用病理和罕见群体变异的高分辨率变异比较图谱来识别与疾病发病机制相关的位点。方法 在文献中鉴定出与心肌病相关的 TNN 变异，并进行拓扑图绘制。汇总并比较临床特征。罕见的群体变体是从 gnomAD 数据库中获得的。信噪比 (S:N) 相对于群体变异频率的标准化病理变异频率。对临床表型的抽象回顾适用于“重大”热点。结果先证者（N = 70 项研究，224 名先证者）和罕见变异（N = 125,748 外显子组；15,708 基因组，MAF <0.001）均已编译。TNNC1 阳性先证者表现出最年轻的就诊年龄（20.0 岁；P = .016 对比 TNNT2；P = .004 对比 TNNI3）和最高的死亡、移植或心室颤动事件（P = .093 对比 TNNT2；P = . 024 与 TNNI3；卡普兰·梅厄：P = .025）。S:N 分析在原肌球蛋白结合域、α-螺旋 1 和 TNNT2 的 N 末端内产生了具有诊断意义的热点，并增加了心源性猝死和心室颤动 (P = .004)。TNNI3 的抑制区域和 C 末端区域表现出限制性心肌病增加 (P =.008)。HCM 和 RCM 模型的钙敏感性往往较高，而 DCM 模型的敏感性较低 (P < .001)。DCM 和 HCM 研究通常显示 Hill 系数没有差异，而 RCM 模型中 Hill 系数有所下降 (P < .001)。CM 模型通常表明 Fmax 没有变化 (P = .239)。结论 TNNC1 阳性先证者的诊断年龄较年轻，临床结果较差。TNN 变异图谱确定了 TNNT2 和 TNNI3 中与致病性增强、RCM 诊断和猝死风险增加相关的位置。
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