“Simple” 1-way interchromosomal insertions involving an interstitial 1q segment are rare, and therefore, their characterization at the base pair level remains understudied. Here, we describe the genomic characterization of a previously unreported de novo interchromosomal insertion (3;1) entailing an about 12-Mb pure gain of 1q21.3q23.3 that causes typical (microcephaly, developmental delay, and facial dysmorphism) and atypical (interauricular communication, small feet with bilateral deep plantar creases, syndactyly of II-IV toes, and mild pachyonychia of all toes) clinical manifestations associated with this region. Based on our analyses, we hypothesize that the duplication of a subset of morbid genes (including LMNA, USF1, VANGL2, LOR, and POGZ) could account for most clinical findings in our patient. Furthermore, the apparent disruption of a promoter region (between CPNE9 and BRPF1) and a topologically associated domain also suggests likely pathogenic reconfiguration/position effects to contribute to the patient’s phenotype. In addition to further expanding the clinical spectrum of proximal 1q duplications and evidencing the phenotypical heterogeneity among similar carriers, our genomic findings and observations suggest that randomness – rather than lethality issues – may account for the paucity of “simple” interchromosomal insertions involving the 1q21.3q23.3 region as genomic donor and distal 3p25.3 as receptor. Moreover, the microhomology sequence found at the insertion breakpoint is consistent with a simple nonhomologous end-joining mechanism, in contrast to a chromothripsis-like event, which has previously been seen in other nonrecurrent insertions. Taken together, the data gathered in this study allowed us to inform this family about the low recurrence risk but not to predict the reproductive prognosis for hypothetical carriers. We highlight that genomic-level assessment is a powerful tool that allows the visualization of the full landscape of sporadic chromosomal injuries and can be used to improve genetic counseling.

中文翻译：

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具有多种先天性异常的女童中罕见的从头不平衡 ins(3;1)(p25.3;q21.3q23.3) 的基因组特征

涉及间质 1q 片段的“简单”1 路染色体间插入很少见，因此，它们在碱基对水平的表征仍未得到充分研究。在这里，我们描述了先前未报告的从头染色体间插入 (3;1) 的基因组特征，该插入导致 1q21.3q23.3 的纯增益约为 12 Mb，导致典型（小头畸形、发育迟缓和面部畸形）和非典型（耳间交流、双侧足底深皱襞的小脚、II-IV 脚趾并指、所有脚趾轻度厚甲）与该区域相关的临床表现。根据我们的分析，我们假设一组病态基因（包括 LMNA、USF1、VANGL2、LOR 和 POGZ）的重复可以解释我们患者的大多数临床发现。此外，启动子区域（在 CPNE9 和 BRPF1 之间）和拓扑相关域的明显破坏也表明可能导致患者表型的致病性重构/位置效应。除了进一步扩大近端 1q 重复的临床范围并证明相似携带者之间的表型异质性外，我们的基因组发现和观察表明，随机性 - 而不是致死性问题 - 可能解释了涉及 1q21.1 的“简单”染色体间插入的缺乏。 3q23.3 区域作为基因组供体，远端 3p25.3 作为受体。此外，在插入断点处发现的微同源序列与简单的非同源末端连接机制一致，这与之前在其他非重复插入中看到的类似染色体碎裂的事件相反。总之，本研究中收集的数据使我们能够告知这个家庭复发风险低，但不能预测假设携带者的生殖预后。我们强调，基因组水平的评估是一种强大的工具，可以显示散发性染色体损伤的全部情况，并可用于改进遗传咨询。