Whole-genome mate-pair sequencing of apparently balanced chromosome rearrangements reveals complex structural variations: two case studies
Whole-genome mate-pair sequencing of apparently balanced chromosome rearrangements reveals complex structural variations: two case studies
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明显平衡的染色体重排的全基因组配偶对测序揭示了复杂的结构变异：两个案例研究
DOI：
10.1186/s13039-020-00487-1
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发表时间：
2020-05-06
影响因子：
1.3
通讯作者：
Cheng, De-Hua
中科院分区：
文献类型：
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作者：
Tan, Ya-Qi;Tan, Yue-Qiu;Cheng, De-Hua
众所周知，在未受影响的个体中，明显平衡的染色体重排（abcr）具有较高的生殖风险，如不孕症、异常后代和妊娠流产。然而，在遗传咨询和生殖干预中应谨慎行事，因为常规细胞遗传学无法解决的隐性不平衡缺陷和基因组结构变异可能无法检测到。在这里，我们研究了两个家族性的abcr病例。在家庭1中，这对夫妇经历了两次流产和引产。单核苷酸多态性（SNP）阵列分析显示10q26.13q26.3位点存在10.8 Mb的杂合缺失，19q13.41-q13.43位点存在5.5 Mb的重复。未受影响的父亲通过核型鉴定为三方复杂染色体重排的携带者[t (6;10;19)(p22;q26;q13)]。全基因组配对测序显示衍生染色体19 （der19）上有一个神秘的断点，表明核型是一个更复杂的结构重排，包括四个断点。FAM24B、CACNG8和kiaa0556三个基因被破坏，但在携带者中未引起任何异常表型。在家庭2中，这对夫妇遭遇了自然流产。该家庭有一名患病儿童，患有多种先天性畸形，核型不平衡，46，XY,der (11) t (6;11)（q13;p11.2）。女性伴侣为平衡易位携带者，核型为46，XX,t (6;11)(q13;p11.2) dn。进一步的SNP阵列和荧光原位杂交（FISH）发现在6号染色体和11号染色体之间有一个隐插入。最后，全基因组配对测序揭示了一个极其复杂的基因组结构变异，包括11号染色体上的一个隐性缺失和12个断点，以及6号染色体上的1个断点。结论我们研究了2例罕见的abcr病例，证明了全基因组配对测序在分析基因组复合体结构变异方面的有效性。对于常规细胞遗传学技术检测到的abcr，应考虑基于全基因组测序（WGS）的方法进行准确的诊断、有效的遗传咨询和正确的生殖干预，以避免复发风险。
BackgroundApparently balanced chromosome rearrangements (ABCRs) in non-affected individuals are well-known to possess high reproductive risks such as infertility, abnormal offspring, and pregnancy loss. However, caution should be exercised in genetic counseling and reproductive intervention because cryptic unbalanced defects and genome structural variations beyond the resolution of routine cytogenetics may not be detected.Case presentationHere, we studied two familial cases of ABCRs were recruited in this study. In family 1, the couple suffered two abortions pregnancies and underwent labor induction. Single nucleotide polymorphism (SNP) array analysis of the aborted sample from the second pregnancy revealed a 10.8 Mb heterozygous deletion at 10q26.13q26.3 and a 5.5 Mb duplication at 19q13.41-q13.43. The non-affected father was identified as a carrier of three-way complex chromosomal rearrangement [t (6;10;19)(p22;q26;q13)] by karyotyping. Whole-genome mate-pair sequencing revealed a cryptic breakpoint on the derivative chromosome 19 (der19), indicating that the karyotype was a more complex structural rearrangement comprising four breakpoints. Three genes,FAM24B, CACNG8,andKIAA0556,were disrupted without causing any abnormal phenotype in the carrier. In family 2, the couple suffered from a spontaneous miscarriage. This family had an affected child with multiple congenital deformities and an unbalanced karyotype, 46,XY,der (11) t (6;11)(q13;p11.2). The female partner was identified as a balanced translocation carrier with the karyotype 46,XX,t (6;11)(q13;p11.2) dn. Further SNP array and fluorescent in situ hybridization (FISH) indicated a cryptic insertion between chromosome 6 and chromosome 11. Finally, whole-genome mate-pair sequencing revealed an extremely complex genomic structural variation, including a cryptic deletion and 12 breakpoints on chromosome 11, and 1 breakpoint on chromosome 6 .ConclusionsOur study investigated two rare cases of ABCRs and demonstrated the efficacy of whole-genome mate-pair sequencing in analyzing the genome complex structural variation. In case of ABCRs detected by conventional cytogenetic techniques, whole genome sequencing (WGS) based approaches should be considered for accurate diagnosis, effective genetic counseling, and correct reproductive intervention to avoid recurrence risks.