美国医学遗传学和基因组学学院(ACMG)-推荐了五个变异分类类别(致病性,可能致病,不确定的意义,可能是良性的,和良性)已广泛用于医学遗传学。然而,这些指南在实践中受到了根本性的限制,因为它们关注的是孟德尔疾病基因,并且它们对变异的二分法分类是因果关系还是因果关系.在这里,我们试图将ACMG指南扩展到一个通用变体分类框架,该框架不仅考虑了临床表型的连续性,而且变异的遗传效应的连续性,以及相关基因的不同病理作用。
作为一种疾病模型,我们采用了慢性胰腺炎(CP),在临床上表现为从单基因到多因素的光谱。铭记任何一般概念建议都应基于可靠的数据,我们的分析集中在四个研究最广泛的CP基因上,PRSS1,CFTR,SPINK1和CTRC。基于几个交叉基因和交叉变异的比较,我们首先根据疾病原因将不同的基因分为两个不同的类别:CP致因(PRSS1和SPINK1)和CP易感(CFTR和CTRC).然后我们采用了两个新的分类类别,“易感”和“可能易感”,在CP易感基因的背景下,替换ACMG的“致病性”和“可能致病性”类别,从而将这些基因中所有病理相关的变异分类为“易感”。在引起CP的基因的情况下,这两个新的分类类别用于扩展ACMG的五个类别,同时引入了两个阈值(等位基因频率和功能)来区分“致病性”和“易感”变体。
使用CP作为疾病模型,我们将ACMG指南扩展为五类分类系统(易感,可能是易感因素,不确定的意义,可能是良性的,和良性)和七类分类系统(致病性,可能致病,易感,可能是易感因素,不确定的意义,可能是良性的,和良性)在疾病易感基因和致病基因的背景下,分别。一起来看,这两个系统构成了一个通用的变体分类框架,原则上,应该跨越任何疾病相关基因的整个变异谱。我们的五类和七类分类系统与ACMG指南的最大一致性应该有助于其实际应用。
The American College of Medical Genetics and Genomics (ACMG)-recommended five variant classification categories (pathogenic, likely pathogenic, uncertain significance, likely benign, and benign) have been widely used in medical genetics. However, these guidelines are fundamentally constrained in practice owing to their focus upon Mendelian disease genes and their dichotomous classification of variants as being either causal or not. Herein, we attempt to expand the ACMG guidelines into a general variant classification framework that takes into account not only the continuum of clinical phenotypes, but also the continuum of the variants\' genetic effects, and the different pathological roles of the implicated genes.
As a disease model, we employed chronic pancreatitis (CP), which manifests clinically as a spectrum from monogenic to multifactorial. Bearing in mind that any general conceptual proposal should be based upon sound data, we focused our analysis on the four most extensively studied CP genes, PRSS1, CFTR, SPINK1 and CTRC. Based upon several cross-gene and cross-variant comparisons, we first assigned the different genes to two distinct categories in terms of disease causation: CP-causing (PRSS1 and SPINK1) and CP-predisposing (CFTR and CTRC). We then employed two new classificatory categories, \"predisposing\" and \"likely predisposing\", to replace ACMG\'s \"pathogenic\" and \"likely pathogenic\" categories in the context of CP-predisposing genes, thereby classifying all pathologically relevant variants in these genes as \"predisposing\". In the case of CP-causing genes, the two new classificatory categories served to extend the five ACMG categories whilst two thresholds (allele frequency and functional) were introduced to discriminate \"pathogenic\" from \"predisposing\" variants.
Employing CP as a disease model, we expand ACMG guidelines into a five-category classification system (predisposing, likely predisposing, uncertain significance, likely benign, and benign) and a seven-category classification system (pathogenic, likely pathogenic, predisposing, likely predisposing, uncertain significance, likely benign, and benign) in the context of disease-predisposing and disease-causing genes, respectively. Taken together, the two systems constitute a general variant classification framework that, in principle, should span the entire spectrum of variants in any disease-related gene. The maximal compliance of our five-category and seven-category classification systems with the ACMG guidelines ought to facilitate their practical application.