Human Genome and Stem Cell Research Center, University of São Paulo, São Paulo, São Paulo, Brazil.
Department of Genetics and Evolutionary Biology, Biosciences Institute, University of São Paulo, São Paulo, São Paulo, Brazil.
Am J Med Genet C Semin Med Genet. 2021 Sep;187(3):357-363. doi: 10.1002/ajmg.c.31931. Epub 2021 Jun 29.
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.
通过针对临床相关基因的下一代测序，对受单基因疾病影响的个体的诊断得到了显著改善。全外显子组产生了大量的变体，需要经过几个过滤步骤、优先级排序和致病性分类。在 ACMG 推荐的标准中，那些依赖于人群数据库的标准会严重影响对代表性不足的血统个体的分析。在描述变体的潜在有害性时，需要考虑特定人群的等位基因频率。分类的另一个正交输入是将先前分类为致病性的变体注释为标准，这为 ClinVar 广泛来源的支持证据提供了依据。我们使用了来自巴西圣保罗的一项基于人口普查的 1171 名老年个体的全基因组数据集，这些个体高度混合，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集了更高比例的欧洲血统，从而表明存在偏见。从与孟德尔疾病相关的 4250 个基因中过滤出潜在的功能丧失（pLOF）变体，并在 ClinVar 中进行了注释。包含了超过 1800 个单核苷酸 pLOF 变体，其中 381 个具有非良性断言。在携带者（N=463）中，平均欧洲血统明显高于非携带者（N=708；p=0.011）。在非欧洲本地血统的基因组背景中，pLOFs 几乎有三倍的可能性没有任何 ClinVar 条目（OR=0.353；p<0.0001）。独立的致病性断言对于分子诊断中的变体分类很有用。然而，在对非欧洲个体进行变体分类时，断言中欧洲血统的过度代表可能会导致扭曲，即使在具有相对较高欧洲血统比例的混合样本中也是如此。调查和储存来自不同人群的临床相关发现对于改善这种情况至关重要。
