Li Dong, Strong Alanna, Hou Cuiping, Downes Helen, Pritchard Amanda Barone, Mazzeo Pamela, Zackai Elaine H, Conlin Laura K, Hakonarson Hakon
Center for Applied Genomics, The Children's Hospital of Philadelphia, Abramson Research Building, Suite 1016I, 3615 Civic Center Boulevard, Philadelphia, PA, 19104-4318, USA.
Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Mol Cytogenet. 2022 Aug 5;15(1):33. doi: 10.1186/s13039-022-00610-4.
Complex chromosomal rearrangements involve the restructuring of genetic material within a single chromosome or across multiple chromosomes. These events can cause serious human disease by disrupting coding DNA and gene regulatory elements via deletions, duplications, and structural rearrangements. Here we describe a 5-year-old female with severe developmental delay, dysmorphic features, multi-suture craniosynostosis, and growth failure found to have a complex series of balanced intra- and inter-chromosomal rearrangements involving chromosomes 4, 11, 13, and X. Initial clinical studies were performed by karyotype, chromosomal microarray, and FISH with research-based short-read genome sequencing coupled with sanger sequencing to precisely map her breakpoints to the base pair resolution to understand the molecular basis of her phenotype. Genome analysis revealed two pathogenic deletions at 4p16.1-p15.32 and 4q31.1, accounting for her developmental delay and dysmorphism. We identified over 60 breakpoints, many with blunt ends and limited homology, supporting a role for non-homologous end joining in restructuring and resolution of the seminal chromoplexy event. We propose that the complexity of our patient's genomic rearrangements with a high number of breakpoints causes dysregulation of gene expression by three-dimensional chromatin interactions or topologically associating domains leading to growth failure and craniosynostosis. Our work supports an important role for genome sequencing in understanding the molecular basis of complex chromosomal rearrangements in human disease.
复杂染色体重排涉及单个染色体或多个染色体内部遗传物质的重组。这些事件可通过缺失、重复和结构重排破坏编码DNA和基因调控元件，从而导致严重的人类疾病。在此，我们描述了一名5岁女性，她有严重发育迟缓、畸形特征、多缝颅缝早闭和生长发育不良，被发现有一系列复杂的染色体内部和染色体间平衡重排，涉及4号、11号、13号和X染色体。最初的临床研究通过核型分析、染色体微阵列分析和荧光原位杂交，并结合基于研究的短读长基因组测序以及桑格测序，将她的断点精确定位到碱基对分辨率，以了解其表型的分子基础。基因组分析揭示了4p16.1-p15.32和4q31.1处的两个致病性缺失，这解释了她的发育迟缓和畸形。我们鉴定出60多个断点，许多断点末端钝圆且同源性有限，这支持了非同源末端连接在重大染色体重排事件的重组和解决中发挥作用。我们提出，我们患者基因组重排的复杂性以及大量断点通过三维染色质相互作用或拓扑相关结构域导致基因表达失调，进而导致生长发育不良和颅缝早闭。我们的工作支持了基因组测序在理解人类疾病中复杂染色体重排分子基础方面的重要作用。
