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专科部门对心肌病患者意义未明变异的重新评估与重新分类

Reassessment and reclassification of variants of unknown significance in patients with cardiomyopathy in a specialist department.

作者信息

Horgan Sinead, Kotwal Huafrin, Malan Antonetta, Sekhri Neha, Lopes Luis R

机构信息

ICVD, St Bartholomew's Hospital, London, UK

ICVD, St Bartholomew's Hospital, London, UK.

出版信息

J Med Genet. 2025 Feb 26;62(3):185-190. doi: 10.1136/jmg-2024-110208.

Abstract

BACKGROUND

The utility of diagnostic genetic testing in cardiomyopathy has grown significantly, due to the discovery of novel genes and greater awareness among healthcare professionals. However, a substantial proportion of cases (around 50%) yield no causative genetic variants or have variants of unknown significance (VUS), limiting their use in clinical management and familial screening. The increase in data quantity and quality in reference databases, coupled with variant interpretation guidelines, allows for periodic reanalysis of VUS, potentially reducing diagnostic gaps.

METHODS

This study presents a review of VUS results identified in hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM) probands over a 5-year period, using American College of Medical Genetics and Genomics criteria. A total of 248 VUS from 233 reports were reviewed, with the majority of patients with a diagnosis of HCM (n=112), followed by DCM (n=99) and ACM (n=22).

RESULTS

Four (1.6%) VUS showed sufficient evidence to upgrade to likely pathogenic/pathogenic status, while 8 (3.2%) were downgraded to benign. The majority 236 (95.2%) remained VUS after reanalysis, of which 12 (4.7%) had potential to reclassification to benign or likely pathogenic/pathogenic depending on further data.

CONCLUSION

The study emphasises the importance of periodic re-evaluation of VUS results for clinical management of probands as well as cascade testing. We show feasibility of conducting reclassification analysis in a referral centre, but highlight the need for ongoing collaboration between clinical and laboratory experts. Our work supports the current recommendation of reclassification every 3-5 years to keep pace with evolving evidence.

摘要

背景

由于新基因的发现以及医疗保健专业人员的更高认识,诊断性基因检测在心肌病中的应用显著增加。然而,相当一部分病例(约50%)未发现致病基因变异或存在意义未明的变异(VUS),限制了它们在临床管理和家族筛查中的应用。参考数据库中数据数量和质量的增加,再加上变异解读指南,使得对VUS进行定期重新分析成为可能,这有可能减少诊断差距。

方法

本研究对5年内肥厚型心肌病(HCM)、扩张型心肌病(DCM)和致心律失常性心肌病(ACM)先证者中确定的VUS结果进行了综述,采用美国医学遗传学与基因组学学会的标准。共审查了来自233份报告的248个VUS,大多数患者诊断为HCM(n = 112),其次是DCM(n = 99)和ACM(n = 22)。

结果

4个(1.6%)VUS显示有足够证据升级为可能致病/致病状态,而8个(3.2%)被降级为良性。重新分析后,大多数236个(95.2%)仍为VUS,其中12个(4.7%)根据进一步数据有可能重新分类为良性或可能致病/致病。

结论

该研究强调了对VUS结果进行定期重新评估对于先证者临床管理以及级联检测的重要性。我们展示了在转诊中心进行重新分类分析的可行性,但强调了临床和实验室专家之间持续合作的必要性。我们的工作支持目前每3至5年进行一次重新分类的建议,以跟上不断发展 的证据。

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