Fang He, Eacker Stephen M, Wu Yu, Neufeld-Kaiser Whitney, Laurino Mercy, Keel Siobán, Horwitz Marshall S, Liu Yajuan J
Department of Laboratory Medicine and Pathology, University of Washington, Seattle WA.
Phase Genomics, Seattle WA.
Genet Med Open. 2025 Mar 11;3:103423. doi: 10.1016/j.gimo.2025.103423. eCollection 2025.
Complex chromosomal rearrangements (CCRs) are rare structural variants involving 3 or more chromosomal breakpoints. Most de novo-reported CCRs pose challenges for diagnosis and management. They often require karyotyping, fluorescence in situ hybridization, and chromosomal microarray analysis (CMA) for clinical diagnosis because of the limitations of each method. Here, we report an inherited, exceptionally complex CCR involving 4 chromosomes and 13 breakpoints in a family with multisystem anomalies.
We evaluated the CCRs using karyotyping, fluorescence in situ hybridization, CMA, and 2 emerging genomic technologies: high-throughput chromosome conformation capture sequencing aka genomic proximity mapping and optical genome mapping. We also performed functional studies using transcriptome and methylome analyses.
The proband, who had intellectual disability and immune deficiency, shared CCRs with her unaffected mother involving chromosomes 1, 7, and 11 by karyotyping. However, CMA revealed a duplication and 3 deletions in the proband, in contrast to her mother's balanced genome. High-throughput chromosome conformation capture sequencing aka genomic proximity mapping and optical genome mapping detected the CCRs and copy-number alterations but also uncovered additional breakpoints at high resolution, including an insertion in 4p and 2 cryptic rearrangements at 7p. Transcriptome and methylome analyses identified likely biological pathways associated with the proband's phenotypes.
Combining cytogenetic and genomic methods provided comprehensive characterization and defined the breakpoints at high resolution in both proband and mother. This underscores the value of novel cytogenetic and genomic techniques in deciphering complex genome rearrangements and the significance of integrative genomic analysis and functional characterization in understanding clinical phenotypes.
复杂染色体重排（CCR）是涉及3个或更多染色体断点的罕见结构变异。大多数新报道的CCR在诊断和管理方面存在挑战。由于每种方法都有局限性，它们通常需要进行核型分析、荧光原位杂交和染色体微阵列分析（CMA）以进行临床诊断。在此，我们报告了一个患有多系统异常的家族中一种遗传性、异常复杂的涉及4条染色体和13个断点的CCR。
我们使用核型分析、荧光原位杂交、CMA以及两种新兴的基因组技术评估了CCR：高通量染色体构象捕获测序（即基因组邻近图谱）和光学基因组图谱。我们还使用转录组和甲基化组分析进行了功能研究。
先证者患有智力残疾和免疫缺陷，通过核型分析发现她与未受影响的母亲共享涉及1号、7号和11号染色体的CCR。然而，CMA显示先证者存在一个重复和3个缺失，与其母亲的平衡基因组不同。高通量染色体构象捕获测序（即基因组邻近图谱）和光学基因组图谱检测到了CCR和拷贝数改变，但也以高分辨率发现了额外的断点，包括4p的一个插入和7p的2个隐匿重排。转录组和甲基化组分析确定了可能与先证者表型相关的生物学途径。
结合细胞遗传学和基因组方法提供了全面的特征描述，并在先证者和母亲中以高分辨率确定了断点。这强调了新型细胞遗传学和基因组技术在解读复杂基因组重排中的价值，以及整合基因组分析和功能特征描述在理解临床表型中的重要性。
