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Identification of a pathogenic RNU4-2 variant in patients with mitochondrial disease: Broadening the spectrum of non-coding RNA gene variants in mitochondrial dysfunction

Journal of Human Genetics volume 70, pages 541–543 (2025)Cite this article

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Abstract

Mitochondrial diseases are characterized by impaired energy production due to mitochondrial dysfunction. Despite advances in sequencing technologies, many cases remain genetically undiagnosed. We report two cases of mitochondrial disease harboring identical de novo variant in the non-coding RNA gene RNU4-2, previously associated with neurodevelopmental disorders. Re-analysis of whole genome sequencing data from 357 patients ascertained as possibly having mitochondrial disease (see Methods: Supplementary Data S1) identified two cases with a pathogenic RNU4-2 variant (GRCh38: chr.12:120291839: T > TA; NR_003137.2: n.64_65insT). Both patients exhibited decreased oxygen consumption rates and clinical features including developmental delay, microcephaly, short stature. This study provides the first evidence linking RNU4-2 variant to mitochondrial disease, expanding the phenotypic spectrum associated with this gene. Our findings highlight the importance of re-analyzing genomic data and considering non-coding RNA gene variants in mitochondrial disease diagnostics, potentially improving the diagnosis of previously unsolved cases.

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Fig. 1

Data availability

The data sets generated and/or analyzed in the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank the family for their participation in this study.

Funding

This work was supported by JSPS KAKENHI Grant Numbers JP23H00424, JP25kk0305024s0203, JP25ek0109672s0403 and JP25ek0109625h0003; MEXT-Supported Program for the Private University Research Branding Project, the Practical Research Project (JP23ek0109625, and JP23ek0109672) for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development, and grant for Moonshot Goal7 (25zf0127001s0505), AMED.

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Authors and Affiliations

  1. Diagnostics and Therapeutics of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan

    Kohta Nakamura, Yoshihito Kishita, Atsuko Imai-Okazaki, Yukiko Yatsuka, Ayumu Sugiura, Naoyuki Matsumoto, Kei Murayama & Yasushi Okazaki

  2. Department of Life Science, Faculty of Science and Engineering, Kindai University, Osaka, Japan

    Yoshihito Kishita

  3. Department of Pediatrics, Tokyo Women’s Medical University, Yachiyo Medical Center, Yachiyo, Japan

    Taku Omata

  4. Fukushima Medical University Pediatric Neurology, Fukushima, Japan

    Maki Nodera

  5. Institute of Neurogenomics, Computational Health Center, Helmholtz Zentrum München, Neuherberg, Germany

    Holger Prokisch

  6. School of Medicine, Institute of Human Genetics, Technical University of Munich, Munich, Germany

    Holger Prokisch

  7. Department of Pediatrics, Saitama Medical University, Saitama, Japan

    Hiroshi Matsumoto & Akira Ohtake

  8. Department of Clinical Genomics, Saitama Medical University, Saitama, Japan

    Akira Ohtake

  9. Department of Metabolism, Chiba Children’s Hospital, Chiba, Japan

    Kei Murayama

  10. Laboratory for Comprehensive Genomic Analysis, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan

    Yasushi Okazaki

Authors
  1. Kohta Nakamura
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  2. Yoshihito Kishita
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  10. Hiroshi Matsumoto
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Contributions

KN and YK wrote the manuscript. AI, TO, MN, AO, KM and YO provided the clinical information KN, YK, YY, AS and NM analyzed the data. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Yasushi Okazaki.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The study was approved by the regional Ethics Committees of Juntendo University, Saitama Medical University, Chiba Children’s Hospital, and Kindai University. Written informed consent was obtained from the parents. All methods were performed by relevant guidelines and regulations.

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Nakamura, K., Kishita, Y., Imai-Okazaki, A. et al. Identification of a pathogenic RNU4-2 variant in patients with mitochondrial disease: Broadening the spectrum of non-coding RNA gene variants in mitochondrial dysfunction. J Hum Genet 70, 541–543 (2025). https://doi.org/10.1038/s10038-025-01356-8

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  • DOI: https://doi.org/10.1038/s10038-025-01356-8

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