一种新的TP53串联重复在儿童Li-Fraumeni综合征

IF 1.8 Q3 MEDICINE, RESEARCH & EXPERIMENTAL
Feng Xu, E. Aref-Eshghi, Jinhua Wu, J. Schubert, G. Wertheim, T. Bhatti, J. Pogoriler, Maha Patel, K. Cao, Ariel Long, Zhiqian Fan, E. Denenberg, Elizabeth A. Fanning, D. Wilmoth, Minjie Luo, L. Conlin, A. Dain, Sarah E Baldino, Kristin Zelley, N. Balamuth, S. MacFarland, Marilyn M. Li, Y. Zhong
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引用次数: 2

摘要

Li-Fraumeni综合征(LFS)是影响儿童和成人的最常见的癌症易感综合征之一。患有LFS的人一生中患各种癌症的风险增加,包括软组织肉瘤、骨肉瘤、乳腺癌、白血病、脑肿瘤和肾上腺皮质癌。肿瘤抑制基因TP53的杂合种系致病变异是已知的LFS的致病遗传缺陷。单核苷酸变异(snv)是最常见的变异,包括发生在蛋白质高度保守的DNA结合区域的错义替换,其次是无义和剪接位点变异。TP53的总拷贝数变化是罕见的,占所有变异的1%以下。利用下一代测序(NGS)技术,我们在一名转移性骨肉瘤患儿中发现了父系遗传的种系TP53基因内复制,该患儿后来发展为急性髓性白血病(AML)。转录组测序(RNA-seq)表明,重复是串联的,包括2号外显子起始密码子上游的非翻译区(UTR)的2 - 6和28 nt。28 nt的包含预计会导致移码,在6号外显子下游有一个停止密码子18,导致等位基因功能丧失。本案例强调了使用NGS面板同时识别重要拷贝数变异以及snv /索引的重要性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A novel TP53 tandem duplication in a child with Li–Fraumeni syndrome
Li–Fraumeni syndrome (LFS) is one of the most common cancer predisposition syndromes that affects both children and adults. Individuals with LFS are at an increased risk of developing various types of cancer over their lifetime including soft tissue sarcomas, osteosarcomas, breast cancer, leukemia, brain tumors, and adrenocortical carcinoma. Heterozygous germline pathogenic variants in the tumor suppressor gene TP53 are the known causal genetic defect for LFS. Single-nucleotide variants (SNVs) including missense substitutions that occur in the highly conserved DNA binding domain of the protein are the most common alterations, followed by nonsense and splice site variants. Gross copy-number changes in TP53 are rare and account for <1% of all variants. Using next-generation sequencing (NGS) panels, we identified a paternally inherited germline intragenic duplication of TP53 in a child with metastatic osteosarcoma who later developed acute myeloid leukemia (AML). Transcriptome sequencing (RNA-seq) demonstrated the duplication was tandem, encompassing exons 2–6 and 28 nt of the untranslated region (UTR) upstream of the start codon in exon 2. The inclusion of the 28 nt is expected to result in a frameshift with a stop codon 18 codons downstream from the exon 6, leading to a loss-of-function allele. This case highlights the significance of simultaneous identification of both significant copy-number variants as well as SNVs/indels using NGS panels.
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来源期刊
Cold Spring Harbor Molecular Case Studies
Cold Spring Harbor Molecular Case Studies MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
3.20
自引率
0.00%
发文量
54
期刊介绍: Cold Spring Harbor Molecular Case Studies is an open-access, peer-reviewed, international journal in the field of precision medicine. Articles in the journal present genomic and molecular analyses of individuals or cohorts alongside their clinical presentations and phenotypic information. The journal''s purpose is to rapidly share insights into disease development and treatment gained by application of genomics, proteomics, metabolomics, biomarker analysis, and other approaches. The journal covers the fields of cancer, complex diseases, monogenic disorders, neurological conditions, orphan diseases, infectious disease, gene therapy, and pharmacogenomics. It has a rapid peer-review process that is based on technical evaluation of the analyses performed, not the novelty of findings, and offers a swift, clear path to publication. The journal publishes: Research Reports presenting detailed case studies of individuals and small cohorts, Research Articles describing more extensive work using larger cohorts and/or functional analyses, Rapid Communications presenting the discovery of a novel variant and/or novel phenotype associated with a known disease gene, Rapid Cancer Communications presenting the discovery of a novel variant or combination of variants in a cancer type, Variant Discrepancy Resolution describing efforts to resolve differences or update variant interpretations in ClinVar through case-level data sharing, Follow-up Reports linked to previous observations, Plus Review Articles, Editorials, and Position Statements on best practices for research in precision medicine.
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