Copy number variations (CNVs) constitute an important class of variation in the human genome and the interpretation of their pathogenicity considering different frequencies across populations is still a challenge for geneticists. Since the CNV databases are predominantly composed of European and non-admixed individuals, and Brazilian genetic constitution is admixed and ethnically diverse, diagnostic screenings on Brazilian variants are greatly difficulted by the lack of populational references. We analyzed a clinical sample of 268 Brazilian individuals, including patients with neurodevelopment disorders and/or congenital malformations. The pathogenicity of CNVs was classified according to their gene content and overlap with known benign and pathogenic variants. A total of 1,504 autosomal CNVs (1,207 gains and 297 losses) were classified as benign (92.9%), likely benign (1.6%), VUS (2.6%), likely pathogenic (0.2%) and pathogenic (2.7%). Some of the CNVs were recurrent and with frequency increased in our sample, when compared to populational open resources of structural variants: 14q32.33, 22q11.22, 1q21.1, and 1p36.32 gains. Thus, these highly recurrent CNVs classified as likely benign or VUS were considered non-pathogenic in our Brazilian sample. This study shows the relevance of introducing CNV data from diverse cohorts to improve on the interpretation of clinical impact of genomic variations.

中文翻译：

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来自巴西患者的拷贝数变异 (CNV) 鉴定、解释和数据库

拷贝数变异 (CNV) 是人类基因组中一类重要的变异，考虑到不同人群的不同频率，对其致病性的解释仍然是遗传学家面临的挑战。由于 CNV 数据库主要由欧洲和非混合个体组成，而巴西的遗传构成混合且种族多样，由于缺乏人群参考，对巴西变异的诊断筛查非常困难。我们分析了 268 名巴西人的临床样本，包括患有神经发育障碍和/或先天性畸形的患者。CNVs的致病性根据其基因含量以及与已知良性和致病性变异的重叠进行分类。总共 1,504 个常染色体 CNVs (1, 207 项收益和 297 项损失）被归类为良性 (92.9%)、可能良性 (1.6%)、VUS (2.6%)、可能致病性 (0.2%) 和致病性 (2.7%)。与结构变异的群体开放资源相比，我们样本中的一些 CNV 是复发的并且频率增加：14q32.33、22q11.22、1q21.1 和 1p36.32 增益。因此，在我们的巴西样本中，这些被归类为可能为良性或 VUS 的高度复发的 CNV 被认为是非致病性的。该研究显示了引入来自不同队列的 CNV 数据以改进对基因组变异临床影响的解释的相关性。22q11.22、1q21.1 和 1p36.32 收益。因此，在我们的巴西样本中，这些被归类为可能为良性或 VUS 的高度复发的 CNV 被认为是非致病性的。该研究显示了引入来自不同队列的 CNV 数据以改进对基因组变异临床影响的解释的相关性。22q11.22、1q21.1 和 1p36.32 收益。因此，在我们的巴西样本中，这些被归类为可能为良性或 VUS 的高度复发的 CNV 被认为是非致病性的。该研究显示了引入来自不同队列的 CNV 数据以改进对基因组变异临床影响的解释的相关性。