Orellana Carmen, Rosello Monica, Sanchis Amparo, Pedrola Laia, Martín-Grau Carla, Gabaldón-Albero Alba, Senent Maria Leonor, Such Esperanza, García-Ruiz Cristian, Avetisyan Gayane, Martínez Francisco
Genetics Unit, Hospital Universitario y Politécnico La Fe, 46026 Valencia, Spain.
Traslational Genetics Research Group, Instituto de Investigación Sanitaria La Fe (IIS La Fe), 46026 Valencia, Spain.
Int J Mol Sci. 2025 Jan 31;26(3):1244. doi: 10.3390/ijms26031244.
Rare diseases (RDs) often have a genetic basis, yet conventional diagnostic techniques fail to identify causative genetic variations in up to 50% of cases. Structural variants (SVs), including balanced rearrangements, frequently evade detection by karyotyping, microarray, and exome sequencing. The present study utilized optical genome mapping (OGM) to investigate two patients with RDs whose genetic etiology remained unresolved despite prior genomic analyses. Patient 1 exhibited a balanced reciprocal translocation disrupting the gene, associated with Dias-Logan syndrome. Patient 2 had a mosaic 682 kb deletion near the gene, causing ectopic enhancer-promoter interactions and polydactyly, mirroring phenotypes observed in mouse models and similar human cases. These findings highlight OGM's efficacy in identifying complex SVs and underline novel pathogenic mechanisms in rare genetic disorders. Consequently, the incorporation of OGM into routine diagnostic procedures will enhance genetic diagnosis, discover new syndromes of currently unknown cause, and eventually improve the clinical management of numerous patients with rare diseases.
罕见病（RDs）通常具有遗传基础，但传统诊断技术在高达50%的病例中无法识别致病基因变异。结构变异（SVs），包括平衡重排，常常逃避核型分析、微阵列和外显子测序的检测。本研究利用光学基因组图谱（OGM）对两名罕见病患者进行研究，尽管之前进行了基因组分析，但他们的遗传病因仍未得到解决。患者1表现出一种平衡的相互易位，破坏了与迪亚斯-洛根综合征相关的基因。患者2在该基因附近有一个682 kb的嵌合缺失，导致异位增强子-启动子相互作用和多指畸形，这与在小鼠模型和类似人类病例中观察到的表型相似。这些发现突出了OGM在识别复杂SVs方面的功效，并强调了罕见遗传疾病中的新致病机制。因此，将OGM纳入常规诊断程序将提高基因诊断水平，发现目前病因不明的新综合征，并最终改善众多罕见病患者的临床管理。
