A tandem duplication of BRCA1 exons 1-19 through DHX8 exon 2 in four families with hereditary breast and ovarian cancer syndrome
A tandem duplication of BRCA1 exons 1-19 through DHX8 exon 2 in four families with hereditary breast and ovarian cancer syndrome
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DOI：
10.1007/s10549-018-4957-x
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发表时间：
2018-12-01
影响因子：
3.8
通讯作者：
Steinemann, Doris
中科院分区：
文献类型：
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作者：
Du, Chen;Mark, Dorothea;Steinemann, Doris
本研究的目的是对BRCA1基因外显子1-19在4个独立的家系中的一种新的结构变异进行鉴定，并提供有诊断价值的信息，包括断裂点的位置及其临床意义的线索。通过阵列比较基因组杂交分析、荧光原位杂交、下一代作图和远距离聚合酶链式反应进行断点测序。结果我们的数据显示在17号染色体上存在串联重复，包括BRCA1基因的第1-19外显子，以及DHX8基因的部分基因NBR2、NBR1、TMEM106A、LOC100130581、ARL4D、MIR2117。这种结构变异表现为BRCA1基因第19内含子和DHX8基因第3内含子(HGVS：chr17(Hg19)：g.41210776_41568516dup)断裂点的串联重复。结论MLPA分析初步认为BRCA1基因外显子1-19重复，是BRCA1和DHX8基因具有断裂点的结构变异。虽然目前被归类为一种意义未知的变异，但我们的家系数据表明，这种重复可能是一种良性变异，或者至少是显著降低的外显性，因为它与BRCA1基因中另一个已知的全致病变异发生在反式中。
PurposeThe purpose of this study is to characterize a novel structural variant, a large duplication involving exons 1-19 of the BRCA1 gene in four independent families, and to provide diagnostically valuable information including the position of the breakpoints as well as clues to its clinical significance.MethodsThe duplication of exons 1-19 of the BRCA1 gene was initially detected by routine laboratory testing including MLPA analysis and next generation sequencing. For detailed characterization we performed array-comparative genome hybridization analysis, fluorescent in situ hybridization, next generation mapping, and long-distance PCR for break-point sequencing.ResultsOur data revealed a tandem duplication on chromosome 17 that encompassed 357kb and included exons 1-19 of the BRCA1 gene and the genes NBR2, NBR1, TMEM106A, LOC100130581, ARL4D, MIR2117 up to parts of the DHX8 gene. This structural variant appeared as a tandem duplication with breakpoints in intron 19 of the BRCA1 gene and in intron 3 of the DHX8 gene (HGVS:chr17(hg19):g.41210776_41568516dup). Segregation analysis indicated that this structural rearrangement is phased in trans with a known pathogenic exon deletion of the BRCA1 gene in one family.ConclusionsThe copy number variation initially recognized as duplication of exon 1-19 of the BRCA1 gene by MLPA analysis is a structural variation with breakpoints in the BRCA1 and DHX8 genes. Although currently to be classified as a variant of unknown significance, our family data indicates that this duplication may be a benign variation or at least of markedly reduced penetrance since it occurs in trans with another known fully pathogenic variant in the BRCA1 gene.