Table 1_Development and validation of animal variant classification guidelines to objectively evaluate genetic variant pathogenicity in domestic animals.xlsx

Assessing the pathogenicity of a disease-associated genetic variant in animals accurately is vital, both on a population and individual scale. At the population level, breeding decisions based on invalid DNA tests can lead to the incorrect inclusion or exclusion of animals and compromise the long-term health of a population, and at the level of the individual animal, lead to incorrect treatment and even life-ending decisions. Criteria to determine pathogenicity are not standardized, i.e., no guidelines for animal variants are available. Here, we aimed to develop and validate guidelines to be used by the community for Mendelian disorders in domestic animals to classify variants in categories based on standardized criteria. These so-called animal variant classification guidelines (AVCG) were based on those developed for humans by The American College of Medical Genetics and Genomics (ACMG). In a direct comparison, 83% of the pathogenic variants were correctly classified with ACMG, while this increased to 92% with AVCG. We described methods to develop datasets for benchmarking the criteria and identified the most optimal in silico variant effect predictor tools. As the reproducibility was high, we classified 72 known disease-associated variants in cats and 40 other disease-associated variants in eight additional species.

准确评估动物疾病相关遗传变异的致病性，无论在种群还是个体层面均至关重要。在种群尺度上，基于无效DNA检测结果制定的育种决策，可能导致动物被错误纳入或排除种群，进而损害种群的长期健康；而在个体层面，则会引发错误的诊疗方案，甚至作出危及生命的处置决策。当前致病性判定标准尚未统一，即尚无针对动物遗传变异的官方分类指南。本研究旨在制定并验证一套可被学界通用的、针对家养动物孟德尔遗传病的变异分类指南，基于标准化标准将遗传变异划分为不同类别。此类指南即动物变异分类指南（Animal Variant Classification Guidelines，缩写AVCG），其研发蓝本源自美国医学遗传学与基因组学学会（American College of Medical Genetics and Genomics，缩写ACMG）针对人类遗传变异制定的相关指南。直接对比验证结果显示，采用ACMG指南可正确分类83%的致病性变异，而采用AVCG指南时这一比例提升至92%。本研究还阐述了用于基准测试该分类标准的数据集构建方法，并筛选出了性能最优的计算机变异效应预测工具。鉴于该分类体系重现性优异，我们完成了72个猫类已知疾病相关变异，以及另外8个物种的40个疾病相关变异的分类工作。