Invitae, San Francisco, CA, USA.
Volunteer Clinical Faculty, University of California, San Francisco, CA, USA.
Genet Med. 2019 Jan;21(1):114-123. doi: 10.1038/s41436-018-0033-5. Epub 2018 Jun 12.
We investigated the frequencies and characteristics of intragenic copy-number variants (CNVs) in a deep sampling of disease genes associated with monogenic disorders.
Subsets of 1507 genes were tested using next-generation sequencing to simultaneously detect sequence variants and CNVs in >143,000 individuals referred for genetic testing. We analyzed CNVs in gene panels for hereditary cancer syndromes and cardiovascular, neurological, or pediatric disorders.
Our analysis identified 2844 intragenic CNVs in 384 clinically tested genes. CNVs were observed in 1.9% of the entire cohort but in a disproportionately high fraction (9.8%) of individuals with a clinically significant result. CNVs accounted for 4.7-35% of pathogenic variants, depending on clinical specialty. Distinct patterns existed among CNVs in terms of copy number, location, exons affected, clinical classification, and genes affected. Separately, analysis of de-identified data for 599 genes unrelated to the clinical phenotype yielded 4054 CNVs. Most of these CNVs were novel rare events, present as duplications, and enriched in genes associated with recessive disorders or lacking loss-of-function mutational mechanisms.
Universal intragenic CNV analysis adds substantial clinical sensitivity to genetic testing. Clinically relevant CNVs have distinct properties that distinguish them from CNVs contributing to normal variation in human disease genes.
我们调查了与单基因疾病相关的疾病基因中基因内拷贝数变异（CNV）的频率和特征。
使用下一代测序对 1507 个基因的子集进行测试，以同时检测 >143,000 名接受基因检测的个体中的序列变异和 CNV。我们分析了遗传性癌症综合征以及心血管、神经或儿科疾病基因面板中的 CNV。
我们的分析在 384 个经临床测试的基因中确定了 2844 个基因内 CNV。CNV 见于整个队列的 1.9%，但在具有临床显著结果的个体中比例过高（9.8%）。CNV 占致病性变异的 4.7-35%，具体取决于临床专业。CNV 在拷贝数、位置、受影响的外显子、临床分类和受影响的基因方面存在不同的模式。另外，对 599 个与临床表型无关的基因的去识别数据进行分析，得到了 4054 个 CNV。这些 CNV 中的大多数是新的罕见事件，表现为重复，并富集在与隐性疾病相关的基因中，或缺乏功能丧失突变机制。
通用基因内 CNV 分析为基因检测增加了显著的临床灵敏度。与导致人类疾病基因正常变异的 CNV 相比，临床相关的 CNV 具有不同的特性。
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