Brown Angela, Zamanpoor Mansour, Love Donald R, Prosser Debra O
Wellington Regional Genetics Laboratory, Wellington Hospital, Wellington, New Zealand.
Diagnostic Genetics, LabPLUS, Auckland City Hospital, Auckland, New Zealand.
Sultan Qaboos Univ Med J. 2019 Nov;19(4):e324-e334. doi: 10.18295/squmj.2019.19.04.008. Epub 2019 Dec 22.
Molecular diagnostic laboratories screen for mutations in disease-causing genes in order to confirm a clinical diagnosis. The classification of DNA variants as 'pathogenic' or 'likely pathogenic' mutations creates a workflow bottleneck, which becomes increasingly challenging as greater number of genes are screened. The classification challenge is also acute if there are conflicting reports regarding pathogenicity and differing classification criteria between laboratories. This study aimed to compare two procedures for the classification of variants in the () gene.
This bioinformatic study was conducted at LabPLUS, Auckland, New Zealand, from February to June 2017. DNA was extracted from peripheral blood samples of 30 patients and gene library construction was carried out using a commercially available targeted panel for the and genes. The genes were subsequently sequenced and the sequence data analysed. The guidelines published by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) provides a comprehensive framework for the interpretation of variants in genes that are associated with Mendelian disorders. The use of these guidelines were compared to the variant classifications that were achieved by reference to those reported in the BRCA Exchange database.
The results showed concordance between the two classification protocols for a panel of 30 gene variants, although the transparency in following the ACMG/AMP guidelines provides a diagnostic laboratory with a generalisable approach that allows laboratory-directed revisions to be undertaken in light of new information.
The ACMG/AMP-based guidelines were applied to a cohort of patients with gene variants. The use of these guidelines provides a system which creates consistency in variant interpretation and supports subsequent clinical management.
分子诊断实验室筛查致病基因中的突变，以确诊临床疾病。将DNA变异分类为“致病的”或“可能致病的”突变造成了工作流程的瓶颈，随着筛查基因数量的增加，这一挑战变得越来越严峻。如果实验室之间关于致病性的报告相互矛盾且分类标准不同，那么分类挑战也会很严峻。本研究旨在比较两种对（）基因变异进行分类的方法。
这项生物信息学研究于2017年2月至6月在新西兰奥克兰的LabPLUS进行。从30名患者的外周血样本中提取DNA，并使用市售的针对和基因的靶向捕获试剂盒构建基因文库。随后对这些基因进行测序并分析序列数据。美国医学遗传学与基因组学学会和分子病理学协会（ACMG/AMP）发布的指南为解释与孟德尔疾病相关基因的变异提供了一个全面的框架。将这些指南的使用情况与参考BRCA Exchange数据库中报告的变异分类结果进行了比较。
结果显示，对于一组30个基因变异，两种分类方案具有一致性，尽管遵循ACMG/AMP指南的透明度为诊断实验室提供了一种通用方法，使实验室能够根据新信息进行针对性的修订。
基于ACMG/AMP的指南应用于一组携带基因变异的患者。使用这些指南提供了一个系统，该系统在变异解释方面创造了一致性，并支持后续的临床管理。
