State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, 54 Xianlie Road, Guangzhou, 510060, China.
Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
Hum Genet. 2020 Aug;139(8):1057-1064. doi: 10.1007/s00439-020-02156-0. Epub 2020 Apr 4.
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.
先天性眼球震颤（CMN）的特征是早期双侧眼球震颤，无其他眼部缺陷。迄今为止，只有一个基因的突变被确定为 CMN 的原因，即 FRMD7 导致 X 连锁 CMN。已定位到四个常染色体显性 CMN 的基因座，包括 NYS7（OMIM 614826），但尚未确定致病基因。NYS7 基于两个具有 CMN 的大型家族的独立全基因组连锁扫描，被映射到 1q32.1。在这项研究中，通过全基因组测序排除了连锁区间内所有已知的蛋白编码基因、具有预测效应的内含子序列和编码序列的突变。然后，使用来自两个家族的每个家族的样本进行基于 Nanopore 平台的长读基因组测序。在连锁区域中，在两个家族中发现了两个重叠区域为 775,699 bp 的缺失，该区域没有任何已知的蛋白编码基因。两个缺失以及它们的断点通过 Sanger 测序得到确认，并与两个家族中的 CMN 共分离。775,699 bp 缺失区域包含未表征的非蛋白编码表达序列和假基因，但没有蛋白编码基因。然而，Hi-C 数据预测缺失跨越两个拓扑关联域，可能导致 3D 基因组结构发生变化。这些结果为非编码基因组区域的结构变异与 CMN 等人类遗传性疾病之间的强关联提供了新的证据，其潜在机制涉及 3D 基因组结构的变化，为 CMN 的分子发病机制提供了线索。
