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.

中文翻译：

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结构重排作为 SETBP1 单倍体不足的复发致病机制

染色体结构重排由基因组结构的异常组成，这些异常可能与遗传物质的获得和损失有关，也可能无关。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内随机发生，也可以重复出现，这主要是由于周围区域的特殊基因组特征所致。我们报告了三个不相关的个​​体，它们携带中断 SETBP1 的染色体结构重排，导致基因单倍体不足。其中两个结果对染色体微阵列分析（CMA）呈阴性，即在微阵列分辨率下重排平衡。第三个病例出现复杂的三染色体重排，之前曾被诊断为由于染色体断点之一的部分基因缺失而导致 SETBP1 单倍体不足。我们通过光学基因组图谱（OGM）和全基因组测序（WGS）彻底表征了重排，提供了有关序列和潜在机制的详细信息。我们认为结构变异是 SETBP1 单倍体不足中的一个反复发生的事件，它可能会被实验室常规基因组分析（CMA 和全外显子组测序）所忽视，或者当与断点处的基因组丢失相关时只能部分确定。我们最后介绍了 SETBP1 在类 Noonan 表型中的可能作用。