PDF(Pubmed)
Abstract：
Chromosomal structural rearrangements consist of anomalies in genomic architecture that may or may not be associated with genetic material gain and loss. Evaluating the precise breakpoint is crucial from a diagnostic point of view, highlighting possible gene disruption and addressing to appropriate genotype-phenotype association. Structural rearrangements can either occur randomly within the genome or present with a recurrence, mainly due to peculiar genomic features of the surrounding regions. We report about three non-related individuals, harboring chromosomal structural rearrangements interrupting SETBP1, leading to gene haploinsufficiency. Two out of them resulted negative to Chromosomal Microarray Analysis (CMA), being the rearrangement balanced at a microarray resolution. The third one, presenting with a complex three-chromosome rearrangement, had been previously diagnosed with SETBP1 haploinsufficiency due to a partial gene deletion at one of the chromosomal breakpoints. We thoroughly characterized the rearrangements by means of Optical Genome Mapping (OGM) and Whole Genome Sequencing (WGS), providing details about the involved sequences and the underlying mechanisms. We propose structural variants as a recurrent event in SETBP1 haploinsufficiency, which may be overlooked by laboratory routine genomic analyses (CMA and Whole Exome Sequencing) or only partially determined when associated with genomic losses at breakpoints. We finally introduce a possible role of SETBP1 in a Noonan-like phenotype.
摘要：
染色体结构重排由基因组结构中的异常组成，这些异常可能与遗传物质的得失有关，也可能与遗传物质的得失无关。从诊断的角度来看，评估精确的断点至关重要，突出可能的基因破坏，并解决适当的基因型-表型关联。结构重排可以在基因组中随机发生，也可以复发，主要是由于周围区域特有的基因组特征。我们报告了三个不相关的人，携带染色体结构重排中断SETBP1，导致基因单倍体不足。其中两个染色体微阵列分析（CMA）结果为阴性，是在微阵列分辨率下平衡的重排。第三个,呈现复杂的三染色体重排，先前因染色体断点之一的部分基因缺失而被诊断为SETBP1单倍性不足。我们通过光学基因组作图（OGM）和全基因组测序（WGS）彻底表征了重排，提供有关所涉及的序列和潜在机制的详细信息。我们提出结构变异作为SETBP1单倍体功能不全的复发事件，实验室常规基因组分析（CMA和全外显子组测序）可能会忽略，或仅在与断点处的基因组丢失相关时部分确定。我们最后介绍了SETBP1在Noonan样表型中的可能作用。
