致心律失常性右心室心肌病遗传风险的基因组优先人群中心室心律失常的预测风险
Predicted Risk of Ventricular Arrhythmias in a Genome-First Population With Genetic Risk for Arrhythmogenic Right Ventricular Cardiomyopathy.
作者信息
Carruth Eric D, Murray Brittney, Tichnell Crystal, Young Katelyn, Calkins Hugh, James Cynthia A, Haggerty Christopher M
机构信息
Department of Genomic Health (E.D.C.), Geisinger, Danville, PA.
Division of Cardiology, Department of Medicine, Johns Hopkins Medical Center, Baltimore, MD (B.M., C.T., H.C., C.A.J.).
出版信息
Circ Arrhythm Electrophysiol. 2025 Mar;18(3):e013231. doi: 10.1161/CIRCEP.124.013231. Epub 2025 Feb 24.
BACKGROUND
Population genomic screening for desmosome variants associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) may facilitate early disease detection and protective intervention. The validated ARVC risk calculator offers a novel means to risk stratify individuals with diagnosed ARVC, but predicted risk in the context of genomic screening identification has not been explored.
METHODS
Individuals harboring a pathogenic/likely pathogenic variant in a desmosome gene (, , , or ) were identified through the Geisinger MyCode Genomic Screening and Counseling program. The ARVC risk calculator was applied to patients with a subsequent evaluation of right ventricular function. This predicted risk was compared with outcomes in the first 5 years (range, 0.3-5.0 years) after genetic result return.
RESULTS
Of 254 individuals with a clinically confirmed pathogenic/likely pathogenic desmosome variant, 113 (median age, 56 [interquartile range, 42-66]; 71% female) had cardiac imaging in follow-up and no prior sustained ventricular arrhythmia (VA). Eighty-two (73%) had no ARVC task force criteria (TFC) besides the variant (possible diagnosis), 22 (19%) had a single additional minor criterion (borderline diagnosis), and 9 (8%) met criteria for definite diagnosis. The median 5-year predicted VA risk was 3.9% (2.3%-6.6%), notably lower than that of the calculator derivation cohort (20.6%). The risk of fast VA was 1.6% (1.0%-2.9%). The predicted VA risk was higher in individuals with any nongenetic ARVC task force criteria (6.3% [2.5-13.2%]) versus those without (3.7% [2.2-5.6%]; =0.01), and in individuals with variants (6.1% [3.9-7.8%] versus 3.4% [2.2-5.3%]; =0.01). Over a median 3.0 years of follow-up (≤5 years only), no sustained VA events were observed in this cohort.
CONCLUSIONS
The predicted 5-year risk of VA in individuals ascertained via population genomic screening for desmosome variants is low (3.9%; 1.6% for fast VA) but may vary by affected gene and ARVC task force criteria burden.
背景
对与致心律失常性右室心肌病（ARVC）相关的桥粒变体进行群体基因组筛查，可能有助于早期疾病检测和保护性干预。经过验证的ARVC风险计算器为已确诊ARVC的个体提供了一种新的风险分层方法，但在基因组筛查识别背景下的预测风险尚未得到探索。
方法
通过盖辛格MyCode基因组筛查与咨询项目，识别出携带桥粒基因（、、、或）中致病/可能致病变体的个体。将ARVC风险计算器应用于随后进行右室功能评估的患者。将这种预测风险与基因检测结果返回后的前5年（范围为0.3 - 5.0年）的结果进行比较。
结果
在254例临床确诊携带致病/可能致病桥粒变体的个体中，113例（中位年龄56岁[四分位间距42 - 66岁]；71%为女性）在随访中有心脏成像且既往无持续性室性心律失常（VA）。82例（73%）除变体外无ARVC工作组标准（TFC）（可能诊断），22例（19%）有一项额外的次要标准（临界诊断），9例（8%）符合确诊标准。5年预测VA风险中位数为3.9%（2.3% - 6.6%），显著低于计算器推导队列（20.6%）。快速VA风险为1.6%（1.0% - 2.9%）。有任何非基因ARVC工作组标准的个体预测VA风险更高（6.3%[2.5 - 13.2%]），而无此类标准的个体为3.7%[2.2 - 5.6%]；P = 0.01），携带变体的个体也是如此（6.1%[3.9 - 7.8%]对携带变体的个体为3.4%[2.2 - 5.3%]；P = 0.01）。在中位3.0年的随访期内（仅≤5年），该队列中未观察到持续性VA事件。
结论
通过群体基因组筛查确定的携带桥粒变体个体的预测5年VA风险较低（3.9%；快速VA为1.6%），但可能因受影响基因和ARVC工作组标准负担而异。
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