A case with concurrent duplication, triplication, and uniparental isodisomy at 1q42.12-qter supporting microhomology-mediated break-induced replication model for replicative rearrangements.
A case with concurrent duplication, triplication, and uniparental isodisomy at 1q42.12-qter supporting microhomology-mediated break-induced replication model for replicative rearrangements.
复制标题
DOI：
10.1186/s13039-017-0316-6
复制
发表时间：
2017
影响因子：
1.3
通讯作者：
Imoto I
中科院分区：
文献类型：
--
作者：
Kohmoto T;Okamoto N;Naruto T;Murata C;Ouchi Y;Fujita N;Inagaki H;Satomura S;Okamoto N;Saito M;Masuda K;Kurahashi H;Imoto I
复杂的基因组重排（CGRs）由间质三倍性合并单代异染色体（isoUPD）组成，在多发性先天性异常(MCA)/智力残疾（ID）患者中很少报道。单端DNA断裂修复与微同源介导的断裂诱导复制（MMBIR）最近被认为是导致间质拷贝数增加和远端isoUPD的可能机制，尽管只有少数病例在人类先天性MCA疾病中提供了支持性证据。在这里，我们报告了基于染色体微阵列（CMA）的第一例已知病例的鉴定，该病例在1q42.12-q42.2处同时存在间质重复，在1q42.2-q43处存在三倍复制，随后在1q染色体的其余部分（1q43-qter）存在isoUPD。在与1q42.12-q43重叠的远端1q重复/三倍重复中，有不同的临床特征被报道，我们25岁的MCA/ID患者表现出一些经常被描述的特征。进一步的分析，包括在序列水平上对CGR内断点连接的精确映射，表明在我们的病例中与isoUPD相关的CGR是一个具有侧翼重复的三重复制，其特征是具有特别长的重复-倒三重复制（DUP-TRP/INV-DUP）结构的三重复制。由于在三复制区和侧翼复制区之间的连接处都观察到微同源性，因此我们的病例为最近提出的基于复制的机制（如MMBIR）提供了支持性证据，该机制是cgr + isoUPD形成的基础，与染色体疾病有关。据我们所知，这是第一例在1q观察到的CGRs + isoUPD，具有DUP-TRP/INV-DUP结构和长近端重复，这支持基于mmbir的基因组重排模型。基于临床和常规细胞遗传学结果之间的差异，建议在怀疑具有复杂染色体异常的病例中使用含有单核苷酸多态性探针的CMA进行分子细胞遗传学分析，并进一步分析断点连接。本文的在线版本（doi:10.1186/s13039-017-0316-6）包含补充材料，仅供授权用户使用。
Complex genomic rearrangements (CGRs) consisting of interstitial triplications in conjunction with uniparental isodisomy (isoUPD) have rarely been reported in patients with multiple congenital anomalies (MCA)/intellectual disability (ID). One-ended DNA break repair coupled with microhomology-mediated break-induced replication (MMBIR) has been recently proposed as a possible mechanism giving rise to interstitial copy number gains and distal isoUPD, although only a few cases providing supportive evidence in human congenital diseases with MCA have been documented. Here, we report on the chromosomal microarray (CMA)-based identification of the first known case with concurrent interstitial duplication at 1q42.12-q42.2 and triplication at 1q42.2-q43 followed by isoUPD for the remainder of chromosome 1q (at 1q43-qter). In distal 1q duplication/triplication overlapping with 1q42.12-q43, variable clinical features have been reported, and our 25-year-old patient with MCA/ID presented with some of these frequently described features. Further analyses including the precise mapping of breakpoint junctions within the CGR in a sequence level suggested that the CGR found in association with isoUPD in our case is a triplication with flanking duplications, characterized as a triplication with a particularly long duplication-inverted triplication-duplication (DUP-TRP/INV-DUP) structure. Because microhomology was observed in both junctions between the triplicated region and the flanking duplicated regions, our case provides supportive evidence for recently proposed replication-based mechanisms, such as MMBIR, underlying the formation of CGRs + isoUPD implicated in chromosomal disorders. To the best of our knowledge, this is the first case of CGRs + isoUPD observed in 1q and having DUP-TRP/INV-DUP structure with a long proximal duplication, which supports MMBIR-based model for genomic rearrangements. Molecular cytogenetic analyses using CMA containing single-nucleotide polymorphism probes with further analyses of the breakpoint junctions are recommended in cases suspected of having complex chromosomal abnormalities based on discrepancies between clinical and conventional cytogenetic findings. The online version of this article (doi:10.1186/s13039-017-0316-6) contains supplementary material, which is available to authorized users.