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Novel ITPA variants identified by whole genome sequencing and RNA sequencing

Journal of Human Genetics volume 68, pages 649–652 (2023)Cite this article

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Abstract

Approximately 80% of rare diseases have a genetic cause, and an accurate genetic diagnosis is necessary for disease management, prognosis prediction, and genetic counseling. Whole-exome sequencing (WES) is a cost-effective approach for exploring the genetic cause, but several cases often remain undiagnosed. We combined whole genome sequencing (WGS) and RNA sequencing (RNA-seq) to identify the pathogenic variants in an unsolved case using WES. RNA-seq revealed aberrant exon 4 and exon 6 splicing of ITPA. WGS showed a previously unreported splicing donor variant, c.263+1G>A, and a novel heterozygous deletion, including exon 6. Detailed examination of the breakpoint indicated the deletion caused by recombination between Alu elements in different introns. The proband was found to have developmental and epileptic encephalopathies caused by variants in the ITPA gene. The combination of WGS and RNA-seq may be effective in diagnosing conditions in proband who could not be diagnosed using WES.

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Fig. 1
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Data availability

Raw data are available from the corresponding author upon reasonable request. Some genomic information that could be used to identify individuals cannot be shared due to ethical constraints.

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Acknowledgements

We thank the family for their participation in the study.

Funding

This work was supported by a grant for the Practical Research Project for Rare/Intractable Diseases from AMED to KM, YO, and AO (Fund ID: JP21ek010946, 22ek0109485, JP22ek0109468, JP19ek0109273), Program for Promoting Platform of Genomics based Drug Discovery to YO (Fund ID: JP22kk0305015) and JSPS KAKENHI JP19H03624 to YO.

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Author notes

  1. These authors contributed equally: Nanako Omichi, Yoshihito Kishita.

Authors and Affiliations

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

    Nanako Omichi, Yoshihito Kishita & Mina Nakama

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

    Yoshihito Kishita, Kazuhiro R. Nitta, Yukiko Yatsuka, Kei Murayama & Yasushi Okazaki

  3. Clinical Genetics Center, Gifu University Hospital, Gifu, Japan

    Mina Nakama & Hideo Sasai

  4. Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu, Japan

    Mina Nakama & Hideo Sasai

  5. Department of Applied Genomics, Kazusa DNA Research Institute, Chiba, Japan

    Hideo Sasai

  6. Department of Pediatric Cardiology, Gifu Prefectural General Medical Center, Gifu, Japan

    Atsushi Terazawa

  7. Department of Pediatrics, Gifu Prefectural General Medical Center, Gifu, Japan

    Emiko Kobayashi

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

    Takuya Fushimi, Yohei Sugiyama, Keiko Ichimoto & Kei Murayama

  9. Department of Pediatrics and Clinical Genomics, Saitama Medical University, Moroyama, Saitama, Japan

    Akira Ohtake

  10. Center for Intractable Diseases, Saitama Medical University Hospital, Moroyama, Saitama, Japan

    Akira Ohtake

  11. Center for Medical Genetics, Chiba Children’s Hospital, Chiba, Japan

    Kei Murayama

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

    Yasushi Okazaki

Authors
  1. Nanako Omichi
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  2. Yoshihito Kishita
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  4. Hideo Sasai
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  5. Atsushi Terazawa
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  6. Emiko Kobayashi
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  7. Takuya Fushimi
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  8. Yohei Sugiyama
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  9. Keiko Ichimoto
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  10. Kazuhiro R. Nitta
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  11. Yukiko Yatsuka
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  12. Akira Ohtake
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  13. Kei Murayama
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  14. Yasushi Okazaki
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Contributions

NO and YK wrote the manuscript. NO and YK performed the experiments. NO, YK, KRN, TF and YY analyzed the data. MN, HS, AT, EK, YS, KI and KM acquired clinical information. YK, AO, KM, and YO supervised the study. 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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Omichi, N., Kishita, Y., Nakama, M. et al. Novel ITPA variants identified by whole genome sequencing and RNA sequencing. J Hum Genet 68, 649–652 (2023). https://doi.org/10.1038/s10038-023-01156-y

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  • DOI: https://doi.org/10.1038/s10038-023-01156-y

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