Diagnosis of individuals affected by monogenic disorders was significantly improved by next-generation sequencing targeting clinically relevant genes. Whole exomes yield a large number of variants that require several filtering steps, prioritization, and pathogenicity classification. Among the criteria recommended by ACMG, those that rely on population databases critically affect analyses of individuals with underrepresented ancestries. Population-specific allelic frequencies need consideration when characterizing potential deleteriousness of variants. An orthogonal input for classification is annotation of variants previously classified as pathogenic as a criterion that provide supporting evidence widely sourced at ClinVar. We used a whole-genome dataset from a census-based cohort of 1,171 elderly individuals from São Paulo, Brazil, highly admixed, and unaffected by severe monogenic disorders, to investigate if pathogenic assertions in ClinVar are enriched with higher proportions of European ancestry, indicating bias. Potential loss of function (pLOF) variants were filtered from 4,250 genes associated with Mendelian disorders and annotated with ClinVar assertions. Over 1,800 single nucleotide pLOF variants were included, 381 had non-benign assertions. Among carriers (N = 463), average European ancestry was significantly higher than noncarriers (N = 708; p = .011). pLOFs in genomic contexts of non-European local ancestries were nearly three times less likely to have any ClinVar entry (OR = 0.353; p <.0001). Independent pathogenicity assertions are useful for variant classification in molecular diagnosis. However, European overrepresentation of assertions can promote distortions when classifying variants in non-European individuals, even in admixed samples with a relatively high proportion of European ancestry. The investigation and deposit of clinically relevant findings of diverse populations is fundamental improve this scenario.

中文翻译：

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功能缺失变异的偏见致病性断言挑战混合个体的分子诊断

通过靶向临床相关基因的下一代测序，显着改善了受单基因疾病影响的个体的诊断。整个外显子组产生大量变异，需要多个过滤步骤、优先级排序和致病性分类。在 ACMG 推荐的标准中，那些依赖于人口数据库的标准严重影响了对具有代表性不足的血统的个人的分析。在表征变异的潜在有害性时，需要考虑特定人群的等位基因频率。分类的正交输入是对先前分类为致病性的变异的注释，作为标准，提供广泛来自 ClinVar 的支持证据。我们使用了来自巴西圣保罗 1,171 名老年人的人口普查队列的全基因组数据集，高度混合且不受严重单基因疾病的影响，以研究 ClinVar 中的致病性断言是否富含更高比例的欧洲血统，表明存在偏见。从与孟德尔疾病相关的 4,250 个基因中过滤出潜在功​​能丧失 (pLOF) 变体，并用 ClinVar 断言进行注释。包括超过 1,800 个单核苷酸 pLOF 变体，381 个具有非良性断言。在运营商中（N  = 463），平均欧洲血统显着高于非携带者（N  = 708；p  = .011）。在非欧洲本地血统的基因组环境中，pLOF 具有任何 ClinVar 条目的可能性几乎低三倍（OR = 0.353；p <.0001）。独立的致病性断言对于分子诊断中的变异分类很有用。然而，在对非欧洲个体的变异进行分类时，即使在欧洲血统比例相对较高的混合样本中，欧洲对断言的过度表达也会导致失真。对不同人群的临床相关发现进行调查和保存是从根本上改善这种情况的。