Charcot-Marie-Tooth 的下一代测序:关于改进 ACMG 变异评估指南的建议。

IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Journal of Medical Genetics Pub Date : 2024-08-29 DOI:10.1136/jmg-2024-110019
Alessandro Geroldi, Alessia Mammi, Andrea Gaudio, Serena Patrone, Andrea La Barbera, Paola Origone, Clarissa Ponti, Francesca Sanguineri, Sara Massucco, Lucio Marinelli, Marina Grandis, Angelo Schenone, Paola Mandich, Emilia Bellone, Fabio Gotta
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引用次数: 0

摘要

背景:大规模并行测序技术在 Charcot-Marie-Tooth (CMT) 分子分析中的应用,能够快速、经济地鉴定出大量潜在的重要变异,用于诊断目的。我们的目标是减少变异体的数量,只关注那些具有致病意义的变异体。2015 年美国医学遗传学和基因组学学院(ACMG)指南有助于实现这一目标,但现在显而易见的是,对这些规则进行病理学或基因特异性审查至关重要,以避免盲目应用标准可能导致的误读。本研究展示了修订后的 ACMG 标准如何与 CMT 特异性文献数据和专业知识相结合,从而改变变异体的最终分类:方法:我们根据目前对 CMT 的了解对 ACMG 标准进行了回顾,并提出了根据 CMT 的特殊性对其进行调整的建议:结果:在分析的 226 例指数患者中,诊断率为 20%。值得注意的是,有 9% 的病例在应用修订后的标准后最终诊断发生了改变,这往往导致变异型病原体分类的缺失:结论:高通量测序技术的普及使没有特定疾病专业知识的实验室也能进行基因检测。针对特定疾病的 ACMG 标准是防止意义不确定的变异体扩散和误读变异体的重要工具。
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Next-generation sequencing in Charcot-Marie-Tooth: a proposal for improvement of ACMG guidelines for variant evaluation.

Background: The application of massive parallel sequencing technologies in the molecular analysis of Charcot-Marie-Tooth (CMT) has enabled the rapid and cost-effective identification of numerous potentially significant variants for diagnostic purposes. The objective is to reduce the number of variants, focusing only on those with pathogenic significance. The 2015 American College of Medical Genetics and Genomics (ACMG) guidelines aid in achieving this goal, but it is now evident that a pathology or gene-specific review of these rules is essential to avoid misinterpretations that may result from blindly applying the criteria. This study demonstrates how revised ACMG criteria, combined with CMT-specific literature data and expertise, can alter the final classification of a variant.

Methods: We reviewed ACMG criteria based on current knowledge of CMT and provided suggestions for adapting them to the specificities of CMT.

Results: Of the 226 index patients analysed, a diagnostic yield of 20% was obtained. It is worth noting that the 9% of cases had their final diagnosis changed with the application of the revised criteria, often resulting in the loss of the pathogenic classification of a variant.

Conclusions: The widespread availability of high-throughput sequencing technologies has enabled genetic testing even for laboratories without specific disease expertise. Disease-specific ACMG criteria can be a valuable tool to prevent the proliferation of variants of uncertain significance and the misinterpretation of variants.

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来源期刊
Journal of Medical Genetics
Journal of Medical Genetics 医学-遗传学
CiteScore
7.60
自引率
2.50%
发文量
92
审稿时长
4-8 weeks
期刊介绍: Journal of Medical Genetics is a leading international peer-reviewed journal covering original research in human genetics, including reviews of and opinion on the latest developments. Articles cover the molecular basis of human disease including germline cancer genetics, clinical manifestations of genetic disorders, applications of molecular genetics to medical practice and the systematic evaluation of such applications worldwide.
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