Whole genome sequencing enables new genetic diagnosis for inherited retinal diseases by identifying pathogenic variants

作者：Xubing Liu, Fangyuan Hu, Daowei Zhang, Zhe Li, Jianquan He, Shenghai Zhang, Zhenguo Wang, Yingke Zhao, Jiawen Wu, Jiawen Wu, Chen Liu, Chenchen Li, Xin Li, Jihong Wu, Jihong Wu · 发表于：npj Genomic Medicine · 年份：2024 · DOI：10.1038/s41525-024-00391-2 · 被引用次数：36 · 研究领域：Retinal Development and Disorders、Retinal Diseases and Treatments、Cellular transport and secretion

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 identificatio...