拷贝数异常（CNVs）是遗传变异的主要来源，可以破坏基因或影响基因剂量。已知它们是各种疾病的致病因子或基础。然而，CNVs在遗传性乳腺癌易感性方面的作用尚未得到深入研究。为了解决这个问题，我们对98个北芬兰高风险乳腺癌病例进行了基于全外显子测序的罕见CNVs分析。在过滤后，我们使用PCR方法、光学基因组测图和长读测序等组合方法对筛选出的候选等位基因进行了验证和表征。结果发现了三种经常出现的变异：RAD52中一次发生的31 kb缺失结合着逆转录子插入（delins）、HSD17B14中的13.4 kb缺失和RAD51C的64 kb部分重复。值得注意的是，所有这些基因编码的蛋白质都参与乳腺癌发展的已知途径。我们对地理匹配的病例和对照（总共278例遗传性和1983例非选择性乳腺癌病例，以及1229例对照）进行了变异基因分型。RAD52 delins和HSD17B14缺失在具有遗传性疾病易感性迹象的病例中表现出显著富集。在278例病例中，RAD52 delins的发现频率为7/278（2.5%，P = 0.034，OR = 2.86，95% CI = 1.10-7.45），HSD17B14缺失的发现频率为8/278（2.9%，P = 0.014，OR = 3.28，95% CI = 1.31-8.23），而这两种变异在对照组中的频率为11/1229（0.9%）。这表明RAD52和HSD17B14在遗传性乳腺癌易感性中起到了作用。RAD51C重复变异非常罕见，仅在278个遗传性病例和1229个对照中各有2例（P = 0.157，OR = 4.45，95% CI = 0.62-31.70）。在这些基因中发现经常出现的CNVs，尤其是RAD52和HSD17B14变异在芬兰人群中的相对较高频率，强调了在寻找遗传疾病易感性潜在遗传因素时研究CNVs与单核苷酸变异的重要性。 版权声明：© 2023 Kumpula等。本文为开放获取文章，依照创作公共许可证分发，允许任何媒体以任何媒介传播、复制和再现，只要原始作者和出处得到适当的认可。

Copy number variants (CNVs) are a major source of genetic variation and can disrupt genes or affect gene dosage. They are known to be causal or underlie predisposition to various diseases. However, the role of CNVs in inherited breast cancer susceptibility has not been thoroughly investigated. To address this, we performed whole-exome sequencing based analysis of rare CNVs in 98 high-risk Northern Finnish breast cancer cases. After filtering, selected candidate alleles were validated and characterized with a combination of orthogonal methods, including PCR-based approaches, optical genome mapping and long-read sequencing. This revealed three recurrent alterations: a 31 kb deletion co-occurring with a retrotransposon insertion (delins) in RAD52, a 13.4 kb deletion in HSD17B14 and a 64 kb partial duplication of RAD51C. Notably, all these genes encode proteins involved in pathways previously identified as essential for breast cancer development. Variants were genotyped in geographically matched cases and controls (altogether 278 hereditary and 1983 unselected breast cancer cases, and 1229 controls). The RAD52 delins and HSD17B14 deletion both showed significant enrichment among cases with indications of hereditary disease susceptibility. RAD52 delins was identified in 7/278 cases (2.5%, P = 0.034, OR = 2.86, 95% CI = 1.10-7.45) and HSD17B14 deletion in 8/278 cases (2.9%, P = 0.014, OR = 3.28, 95% CI = 1.31-8.23), the frequency of both variants in the controls being 11/1229 (0.9%). This suggests a role for RAD52 and HSD17B14 in hereditary breast cancer susceptibility. The RAD51C duplication was very rare, identified only in 2/278 of hereditary cases and 2/1229 controls (P = 0.157, OR = 4.45, 95% CI = 0.62-31.70). The identification of recurrent CNVs in these genes, and especially the relatively high frequency of RAD52 and HSD17B14 alterations in the Finnish population, highlights the importance of studying CNVs alongside single nucleotide variants when searching for genetic factors underlying hereditary disease predisposition.Copyright: © 2023 Kumpula et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.