A practical guide to interpreting germline variants that drive hematopoietic malignancies, bone marrow failure, and chronic cytopenias
A practical guide to interpreting germline variants that drive hematopoietic malignancies, bone marrow failure, and chronic cytopenias
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DOI：
10.1016/j.gim.2021.12.008
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发表时间：
2022-04-05
影响因子：
8.8
通讯作者：
Godley, Lucy A.
中科院分区：
文献类型：
--
作者：
Feurstein, Simone;Hahn, Christopher N.;Godley, Lucy A.
目的：美国医学遗传学和基因组学学会和分子病理学协会的胚系变异解释指南通过标准化变异解释作为一个广泛的框架来实施。这些规则被设计为指定的，但这个过程并没有对与遗传性血液系统恶性肿瘤、骨髓衰竭和红细胞减少相关的200个基因中的大多数执行。由于缺乏关于如何执行这些基因规范的指南，变体解释的可靠性和重复性较差。方法：采用小等位基因频率计算、准病例对照研究、先证者计数、受试者工作特征曲线绘制等多种方法，比较不同的遗传预测工具，为变异解释设计建议。结果：我们在此为建立微小等位基因频率的阈值、计算机预测、先证者的计数、识别具有最小良性变异的功能域、使用限制性Z分数和功能证据、预测无意义介导的衰退和评估表型特异性提供了实用的建议。结论：任何解释与遗传性血液系统恶性肿瘤、骨髓衰竭和红细胞减少相关的变异的人都可以使用这些指南来制定可靠、准确和可重复的种系变异解释标准。？？2021年，由美国医学遗传学和基因组学院主办。由爱思唯尔公司出版。
Purpose: The American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines for germline variant interpretation are implemented as a broad framework by standardizing variant interpretation. These rules were designed to be specified, but this process has not been performed for most of the 200 genes associated with inherited hematopoietic malignancies, bone marrow failure, and cytopenias. Because guidelines on how to perform these gene specifications are lacking, variant interpretation is less reliable and reproducible. Methods: We have used a variety of methods such as calculations of minor allele frequencies, quasi-case???control studies to establish thresholds, proband counting, and plotting of receiver operating characteristic curves to compare different in silico prediction tools to design recommendations for variant interpretation. Results: We herein provide practical recommendations for the creation of thresholds for minor allele frequencies, in silico predictions, counting of probands, identification of functional domains with minimal benign variation, use of constraint Z-scores and functional evidence, prediction of nonsense-mediated decay, and assessment of phenotype specificity. Conclusion: These guidelines can be used by anyone interpreting variants associated with inherited hematopoietic malignancies, bone marrow failure, and cytopenias to develop criteria for reliable, accurate, and reproducible germline variant interpretation. ?? 2021 by American College of Medical Genetics and Genomics. Published by Elsevier Inc.