The Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN; Center for Individualized Medicine, Mayo Clinic, Rochester, MN.
The Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN; Cardiovascular Department, Azienda Sanitaria Universitaria Giuliano Isontina(ASUGI), University of Trieste, Trieste, Italy.
Mayo Clin Proc. 2024 Nov;99(11):1732-1743. doi: 10.1016/j.mayocp.2024.05.027. Epub 2024 Oct 10.
To determine the prevalence, penetrance, and disease expression of cardiomyopathy-related genetic variants in an unselected, richly phenotyped Mayo Clinic population in the setting of preemptive sequencing, with return of incidental findings following the American College of Medical Genetics and Genomics recommendations.
We analyzed a quaternary medical center-based biobank cohort (n=983) for reportable variants in 15 cardiomyopathy genes. Prioritization of genetic variants was performed using an internally developed pipeline to identify potentially reportable variants. Prioritized variants were then manually curated. The correlation of likely pathogenic/pathogenic (LP/P) variants with clinical phenotypes and outcomes was established. Artificial intelligence-enabled electrocardiographic predictions of reduced left ventricular ejection fraction and hypertrophic cardiomyopathy were applied to genotype-positive (G+) participants.
Of the 983 patients, 11 (1%) were G+, with 11 LP/P variants found in the MYBPC3, DSG2, MYH7, DSP, and PKP2 genes. All G+ participants underwent electrocardiography, and 10 (90%) underwent echocardiography. Most patients (10 [90%]) did not have a prior diagnosis of cardiomyopathy. Definitive disease penetrance (heart failure or cardiomyopathy) was present in 4 (36%), while 3 (27%) had possible penetrance (structural heart disease identified by echocardiography). Arrhythmias and/or cardiac conduction disease was present in 4 of 11 G+ individuals (36%). Artificial intelligence-electrocardiography was positive for hypertrophic cardiomyopathy or reduced left ventricular ejection fraction in 5 of the G+ participants (45%), of whom 4 (80%) had definitive or possible disease penetrance.
Cardiomyopathy-associated LP/P variants are present in a small subset of a quaternary medical center population, and disease penetrance in G+ individuals is high in the form of cardiac structural abnormalities and heart failure.
在进行抢先测序的情况下，以美国医学遗传学与基因组学学院的建议为指导，在一个未选择的、表型丰富的梅奥诊所人群中，确定与心肌病相关的遗传变异的流行率、外显率和疾病表现。
我们分析了一个基于四级医疗中心的生物库队列（n=983），以确定 15 个心肌病基因中可报告的变异。使用内部开发的管道对遗传变异进行优先级排序，以识别潜在可报告的变异。然后对优先变异进行人工整理。确定与临床表型和结局相关的可能致病性/致病性（LP/P）变异。将人工智能支持的心电图预测左心室射血分数降低和肥厚型心肌病应用于基因型阳性（G+）参与者。
在 983 名患者中，有 11 名（1%）为 G+，在 MYBPC3、DSG2、MYH7、DSP 和 PKP2 基因中发现了 11 个 LP/P 变异。所有 G+参与者均接受了心电图检查，其中 10 名（90%）接受了超声心动图检查。大多数患者（10 [90%]）之前没有心肌病的诊断。明确的疾病外显率（心力衰竭或心肌病）存在于 4 名（36%）患者中，而 3 名（27%）患者可能有外显率（超声心动图显示结构性心脏病）。心律失常和/或心脏传导疾病存在于 11 名 G+个体中的 4 名（36%）。人工智能心电图对 5 名 G+参与者中的 4 名（80%）检测出肥厚型心肌病或左心室射血分数降低，其中 4 名（80%）有明确或可能的疾病外显率。
在一个四级医疗中心人群的一小部分中存在与心肌病相关的 LP/P 变异，G+个体的疾病外显率很高，表现为心脏结构异常和心力衰竭。
