Congenital motor nystagmus (CMN) is characterized by early-onset bilateral ocular oscillations without other ocular deficits. To date, mutations in only one gene have been identified to be responsible for CMN, i.e., FRMD7 for X-linked CMN. Four loci for autosomal dominant CMN, including NYS7 (OMIM 614826), have been mapped but the causative genes have yet to be identified. NYS7 was mapped to 1q32.1 based on independent genome-wide linkage scan on two large families with CMN. In this study, mutations in all known protein-coding genes, both intronic sequence with predicted effect and coding sequence, in the linkage interval were excluded by whole-genome sequencing. Then, long-read genome sequencing based on the Nanopore platform was performed with a sample from each of the two families. Two deletions with an overlapping region of 775,699 bp, located in a region without any known protein-coding genes, were identified in the two families in the linkage region. The two deletions as well as their breakpoints were confirmed by Sanger sequencing and co-segregated with CMN in the two families. The 775,699 bp deleted region contains uncharacterized non-protein-coding expressed sequences and pseudogenes but no protein-coding genes. However, Hi-C data predicted that the deletions span two topologically associated domains and probably lead to a change in the 3D genomic architecture. These results provide novel evidence of a strong association between structural variations in non-coding genomic regions and human hereditary diseases like CMN with a potential mechanism involving changes in 3D genome architecture, which provides clues regarding the molecular pathogenicity of CMN.

先天性运动性眼球震颤（CMN）的特征是早发性双侧眼球震荡，没有其他眼球缺陷。迄今为止，已经鉴定出仅一种基因的突变与CMN有关，即FRMD7用于X链接的CMN。已经绘制了四个常染色体显性优势CMN的基因座，包括NYS7（OMIM 614826），但致病基因尚未确定。根据独立的全基因组连锁扫描，在两个带有CMN的大家族中将NYS7定位到1q32.1。在这项研究中，全基因组测序排除了所有已知的蛋白质编码基因的突变，包括具有预测作用的内含子序列和编码序列的连锁间隔。然后，使用来自两个家族中每个家族的样品进行基于Nanopore平台的长基因组测序。在连锁区域的两个家族中鉴定出两个缺失，其具有775,699 bp的重叠区域，位于没有任何已知蛋白质编码基因的区域。通过Sanger测序证实了这两个缺失及其断点，并与CMN在两个家族中共同分离。775,699 bp的缺失区域包含未表征的非蛋白质编码表达序列和假基因，但不含蛋白质编码基因。但是，Hi-C数据预测该缺失跨越两个拓扑相关的域，并可能导致3D基因组架构发生变化。这些结果提供了新的证据，证明非编码基因组区域中的结构变异与人类遗传性疾病（如CMN）之间有很强的联系，其潜在机制涉及3D基因组结构的变化，这为CMN的分子致病性提供了线索。699 bp缺失区域包含未表征的非蛋白质编码表达序列和假基因，但不含蛋白质编码基因。但是，Hi-C数据预测该缺失跨越两个拓扑相关的域，并可能导致3D基因组架构发生变化。这些结果提供了新的证据，证明非编码基因组区域中的结构变异与人类遗传性疾病（如CMN）之间有很强的联系，其潜在机制涉及3D基因组结构的变化，这为CMN的分子致病性提供了线索。699 bp缺失区域包含未表征的非蛋白质编码表达序列和假基因，但不含蛋白质编码基因。但是，Hi-C数据预测该缺失跨越两个拓扑相关的域，并可能导致3D基因组架构发生变化。这些结果提供了新的证据，证明非编码基因组区域中的结构变异与人类遗传性疾病（如CMN）之间有很强的联系，其潜在机制涉及3D基因组结构的变化，这为CMN的分子致病性提供了线索。