Whole-genome discovery of pathogenic snRNA variants and efficient extended-exome screening
Year: 2026
Type: article
Abstract: Pathogenic variants in small nuclear RNA (snRNA) genes have recently emerged as a major cause of Mendelian disorders, particularly neurodevelopmental disorders, yet they remain difficult to detect in routine diagnostics because conventional whole-exome sequencing (WES) does not capture snRNA loci. Here, we reanalyzed whole-genome sequencing (WGS) data from 1,578 unsolved probands and identified pathogenic variants in multiple snRNA genes, including RNU4-2 , RNU2-2 , RNU5B-1 , and RNU4ATAC , accounting for 1.2% (19 patients) of previously unsolved cases. We then developed an snRNA-extended WES approach by incorporating capture probes targeting 50 snRNA genes into a standard exome design. Benchmarking demonstrated robust, uniform coverage across all targeted snRNA loci without increasing sequencing depth. Applying this approach to patient samples reliably detected disease-causing snRNA variants previously identified by WGS. Our results establish snRNA-extended WES as a cost-effective and scalable strategy to improve diagnostic yield and bridge the gap between recent gene discoveries and clinical genomic practice.
Source: iScience
Authors: Yuka Nakano, Hisato Suzuki, Yukiko Kuroda, Hiroshi Yoshihashi, Nobuhiko Okamoto, Akane Kondo, Rika Kosaki, Kenichi Kashimada, Toshihide Kurihara, Meow-Keong Thong, Sok-Kun Tae, Mazlan Rifhan, Takashi Enokizono, Hiroshi Suzumura, Takeshi Yoshida, Shinji Kosugi, Seiji Mizuno, Mie Inaba, Natsuki Nakamura, Mayumi Matsufuji, Eri Ogawa, Hitomi Yagi, Mamiko Yamada, Emi Qian, Daisuke Nakato, Toshiki Takenouchi, Kenjiro Kosaki, Fuyuki Miya
Institutions: Keio University, University of Tsukuba, Kanagawa Children's Medical Center, Tokyo Metropolitan Children's Medical Center, Osaka Women's and Children's Hospital, National Hospital Organization, Shikoku Medical Center for Children and Adults, National Center For Child Health and Development, University Malaya Medical Centre, University of Malaya, Universiti Tunku Abdul Rahman Sungai Long Campus, Universiti Tunku Abdul Rahman, Dokkyo Medical University, Kyoto University, Aichi Developmental Disability Center, Kagoshima City Hospital, Tachikawa Hospital, Federation of National Public Service Personnel Mutual Aid Associations, Okayama University, Institute of Science Tokyo Hospital
Language: English
Topic: Genomics and Rare Diseases
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,240
Awards: 難病のゲノム医療実現に向けた全ゲノム解析の実施基盤の構築と実践, 重症新生児に対する迅速なゲノム診断の医療実装に関する研究開発, G5268479076, 未診断疾患イニシアチブ(Initiative on Rare and Undiagnosed
Diseases(IRUD)): 希少・未診断疾患に対する診断プログラム基盤の
開発と患者還元を推進する研究, 構造異常・スプライシング異常・メチル化異常の革新的検出系による未診断疾患患者の診断率向上とN-of-1創薬への導出, Exploration of longevity-related factors using blood somatic mutation and genomic association analysis in centenarians
OpenAlex ID: W7168898096