Liu Xubing, Hu Fangyuan, Zhang Daowei, Li Zhe, He Jianquan, Zhang Shenghai, Wang Zhenguo, Zhao Yingke, Wu Jiawen, Liu Chen, Li Chenchen, Li Xin, Wu Jihong
CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, China.
NPJ Genom Med. 2024 Jan 20;9(1):6. doi: 10.1038/s41525-024-00391-2.
Inherited retinal diseases (IRDs) are a group of common primary retinal degenerative disorders. Conventional genetic testing strategies, such as panel-based sequencing and whole exome sequencing (WES), can only elucidate the genetic etiology in approximately 60% of IRD patients. Studies have suggested that unsolved IRD cases could be attributed to previously undetected structural variants (SVs) and intronic variants in IRD-related genes. The aim of our study was to obtain a definitive genetic diagnosis by employing whole genome sequencing (WGS) in IRD cases where the causative genes were inconclusive following an initial screening by panel sequencing. A total of 271 unresolved IRD patients and their available family members (n = 646) were screened using WGS to identify pathogenic SVs and intronic variants in 792 known ocular disease genes. Overall, 13% (34/271) of IRD patients received a confirmed genetic diagnosis, among which 7% were exclusively attributed to SVs, 4% to a combination of single nucleotide variants (SNVs) and SVs while another 2% were linked to intronic variants. 22 SVs, 3 deep-intronic variants, and 2 non-canonical splice-site variants across 14 IRD genes were identified in the entire cohort. Notably, all of these detected SVs and intronic variants were novel pathogenic variants. Among those, 74% (20/27) of variants were found in genes causally linked to Retinitis Pigmentosa (RP), with the gene EYS being the most frequently affected by SVs. The identification of SVs and intronic variants through WGS enhances the genetic diagnostic yield of IRDs and broadens the mutational spectrum of known IRD-associated genes.
遗传性视网膜疾病（IRDs）是一组常见的原发性视网膜退行性疾病。传统的基因检测策略，如基于基因panel的测序和全外显子组测序（WES），只能在大约60%的IRD患者中阐明遗传病因。研究表明，未解决的IRD病例可能归因于IRD相关基因中先前未检测到的结构变异（SVs）和内含子变异。我们研究的目的是在通过基因panel测序进行初步筛查后致病基因仍不明确的IRD病例中，采用全基因组测序（WGS）来获得明确的基因诊断。使用WGS对总共271例未解决的IRD患者及其可用的家庭成员（n = 646）进行筛查，以鉴定792个已知眼病基因中的致病性SVs和内含子变异。总体而言，13%（34/271）的IRD患者获得了确诊的基因诊断，其中7%完全归因于SVs，4%归因于单核苷酸变异（SNVs）和SVs的组合，另外2%与内含子变异有关。在整个队列中，在14个IRD基因中鉴定出22个SVs、3个深度内含子变异和2个非经典剪接位点变异。值得注意的是，所有这些检测到的SVs和内含子变异都是新的致病变异。其中，74%（20/27）的变异存在于与色素性视网膜炎（RP）有因果关系的基因中，EYS基因是受SVs影响最频繁的基因。通过WGS鉴定SVs和内含子变异提高了IRD的基因诊断率，并拓宽了已知IRD相关基因的突变谱。
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