Whole-genome discovery of pathogenic snRNA variants and efficient extended-exome screening
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.
Authors
- Mayumi Matsufuji (ORCID: https://orcid.org/0000-0001-7947-3852)
- Sok-Kun Tae (ORCID: https://orcid.org/0009-0002-7236-1430)
- Takashi Enokizono (ORCID: https://orcid.org/0000-0001-6377-997X)
- Yuka Nakano (ORCID: https://orcid.org/0000-0001-9983-6710)
- Hiroshi Suzumura
- Hiroshi Yoshihashi (ORCID: https://orcid.org/0000-0003-1727-625X)
- Daisuke Nakato (ORCID: https://orcid.org/0000-0003-0458-4931)
- Hitomi Yagi (ORCID: https://orcid.org/0000-0002-5199-1970)
- Fuyuki Miya (ORCID: https://orcid.org/0000-0001-6758-2015)
- Toshiki Takenouchi (ORCID: https://orcid.org/0000-0002-7311-4135)
- Emi Qian
- Natsuki Nakamura (ORCID: https://orcid.org/0000-0002-9207-196X)
- Kenichi Kashimada (ORCID: https://orcid.org/0000-0003-2505-5932)
- Akane Kondo (ORCID: https://orcid.org/0000-0002-0029-6310)
- Toshihide Kurihara (ORCID: https://orcid.org/0000-0002-5457-2720)
- Mie Inaba
- Shinji Kosugi
- Rika Kosaki
- Nobuhiko Okamoto
- Seiji Mizuno
- Mamiko Yamada
- Eri Ogawa
- Yukiko Kuroda
- Takeshi Yoshida
- Hisato Suzuki
- Meow-Keong Thong
- Kenjiro Kosaki
- Mazlan Rifhan
Institutions
- University Malaya Medical Centre (MY)
- University of Tsukuba (JP)
- Okayama University (JP)
- Keio University (JP)
- Kyoto University (JP)
- University of Malaya (MY)
- Osaka Women's and Children's Hospital (JP)
- Kanagawa Children's Medical Center (JP)
- Kagoshima City Hospital (JP)
- National Center For Child Health and Development (JP)
- The Cancer Institute Hospital (JP)
- Tachikawa Hospital (JP)
- Tokyo Metropolitan Children's Medical Center (JP)
- Shikoku Medical Center for Children and Adults (JP)
- Aichi Developmental Disability Center (JP)
- Dokkyo Medical University (JP)
- Universiti Tunku Abdul Rahman (MY)
Publication Details
- Journal
- iScience
- Published
- 2026-07-16
- DOI
- https://doi.org/10.1016/j.isci.2026.116814
- Primary Topic
- Genomics and Rare Diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Japan Agency for Medical Research and Development
- Japan Society for the Promotion of Science
- Japan Science and Technology Agency