通过全基因组测序鉴定儿童癌症患者新型平衡从头染色体易位中的基因破坏。
Identifying gene disruptions in novel balanced de novo constitutional translocations in childhood cancer patients by whole-genome sequencing.
作者信息
Ritter Deborah I, Haines Katherine, Cheung Hannah, Davis Caleb F, Lau Ching C, Berg Jonathan S, Brown Chester W, Thompson Patrick A, Gibbs Richard, Wheeler David A, Plon Sharon E
机构信息
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
出版信息
Genet Med. 2015 Oct;17(10):831-5. doi: 10.1038/gim.2014.189. Epub 2015 Jan 8.
PURPOSE
We applied whole-genome sequencing (WGS) to children diagnosed with neoplasms and found to carry apparently balanced constitutional translocations to discover novel genic disruptions.
METHODS
We applied the structural variation (SV) calling programs CREST, BreakDancer, SV-STAT, and CGAP-CNV, and we developed an annotative filtering strategy to achieve nucleotide resolution at the translocations.
RESULTS
We identified the breakpoints for t(6;12)(p21.1;q24.31), disrupting HNF1A in a patient diagnosed with hepatic adenomas and maturity-onset diabetes of the young (MODY). Translocation as the disruptive event of HNF1A, a gene known to be involved in MODY3, has not been previously reported. In a subject with Hodgkin lymphoma and subsequent low-grade glioma, we identified t(5;18)(q35.1;q21.2), disrupting both SLIT3 and DCC, genes previously implicated in both glioma and lymphoma.
CONCLUSION
These examples suggest that implementing clinical WGS in the diagnostic workup of patients with novel but apparently balanced translocations may reveal unanticipated disruption of disease-associated genes and aid in prediction of the clinical phenotype.
目的
我们对诊断患有肿瘤且携带明显平衡的染色体易位的儿童应用全基因组测序（WGS），以发现新的基因破坏。
方法
我们应用了结构变异（SV）检测程序CREST、BreakDancer、SV-STAT和CGAP-CNV，并开发了一种注释过滤策略，以实现易位处的核苷酸分辨率。
结果
我们确定了t(6;12)(p21.1;q24.31)的断点，该断点破坏了一名被诊断患有肝腺瘤和青年成年起病型糖尿病（MODY）患者的HNF1A。HNF1A作为已知与MODY3相关的基因，其因易位而被破坏的情况此前尚未见报道。在一名患有霍奇金淋巴瘤及随后的低级别胶质瘤的患者中，我们确定了t(5;18)(q35.1;q21.2)，该易位破坏了SLIT3和DCC，这两个基因此前均与胶质瘤和淋巴瘤有关。
结论
这些例子表明，在对具有新的但明显平衡的易位的患者进行诊断检查时实施临床WGS，可能会揭示疾病相关基因的意外破坏，并有助于预测临床表型。
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