Rosamilia Michael B, Markunas Alexandra M, Kishnani Priya S, Landstrom Andrew P
Division of Cardiology, Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, USA.
Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, USA.
JACC Adv. 2024 Feb;3(2). doi: 10.1016/j.jacadv.2023.100767. Epub 2023 Dec 15.
Thousands of genetic variants have been identified in cardiomyopathy-associated genes. Diagnostic genetic testing is key for evaluation of individuals with suspected cardiomyopathy. While accurate variant pathogenicity assignment is important for diagnosis, the frequency of and factors associated with clinically relevant assessment changes are unclear.
The authors aimed to characterize pathogenicity assignment change in cardiomyopathy-associated genes and to identify factors associated with this change.
We identified 10 sarcomeric and 6 desmosomal genetic cardiomyopathy-associated genes along with comparison gene sets. We analyzed clinically meaningful changes in pathogenicity assignment between any of the following: pathogenic/likely pathogenic (P/LP), conflicting interpretations of pathogenicity or variant of unknown significance (C/VUS), and benign/likely benign. We explored association of minor allele frequency (MAF) differences between well, and traditionally poorly, represented ancestries in genetic studies with assessment stability. Analyses were performed using ClinVar and GnomAD data.
Of the 30,975 cardiomyopathy-associated gene variants in ClinVar, 2,276 of them (7.3%) had a clinically meaningful change in pathogenicity assignment over the study period, 2011 to 2021. Sixty-seven percent of variants that underwent a clinically significant change moved from P/LP or benign/likely benign to C/VUS. Among cardiomyopathy variants downgraded from P/LP, 35% had a MAF above 1 × 10 in non-Europeans and below 1 × 10 in Europeans.
Over the past 10 years, 7.3% of cardiomyopathy gene variants underwent a clinically meaningful change in pathogenicity assignment. Over 30% of downgrades from P/LP may be attributable to higher MAF in Non-Europeans than Europeans. This finding suggests that low ancestral diversity in genetic studies has increased diagnostic uncertainty in cardiomyopathy gene variants.
在心肌病相关基因中已鉴定出数千种基因变异。诊断性基因检测是评估疑似心肌病个体的关键。虽然准确的变异致病性判定对于诊断很重要，但临床相关评估变化的频率及相关因素尚不清楚。
作者旨在描述心肌病相关基因中致病性判定的变化，并确定与此变化相关的因素。
我们确定了10个肌节和6个桥粒基因性心肌病相关基因以及比较基因组。我们分析了以下任何一种情况之间致病性判定的临床意义变化：致病/可能致病（P/LP）、致病性冲突解读或意义未明变异（C/VUS）以及良性/可能良性。我们探讨了基因研究中代表性良好和传统上代表性较差的祖先之间的次要等位基因频率（MAF）差异与评估稳定性的关联。使用ClinVar和GnomAD数据进行分析。
在ClinVar中30975个心肌病相关基因变异中，在2011年至2021年的研究期间，其中2276个（7.3%）在致病性判定上有临床意义的变化。经历临床显著变化的变异中有67%从P/LP或良性/可能良性转变为C/VUS。在从P/LP降级的心肌病变异中，35%在非欧洲人中的MAF高于1×10 ，在欧洲人中低于1×10 。
在过去10年中，7.3%的心肌病基因变异在致病性判定上有临床意义的变化。超过30%从P/LP的降级可能归因于非欧洲人中的MAF高于欧洲人。这一发现表明，基因研究中低祖先多样性增加了心肌病基因变异的诊断不确定性。
