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Identification of causative gene variants for patients with known monogenic diabetes using a targeted next-generation sequencing panel in a single-center study

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Abstract

Aims

We aimed to verify the usefulness of targeted next-generation sequencing (NGS) technology for diagnosing monogenic diabetes in a single center.

Methods

We designed an amplicon-based NGS panel targeting 34 genes associated with known monogenic diabetes and performed resequencing in 56 patients with autoantibody-negative diabetes mellitus diagnosed at < 50 years who had not been highly obese. By bioinformatic analysis, we filtered significant variants based on allele frequency (< 0.005 in East Asians) and functional prediction. We estimated the pathogenicity of each variant upon considering the family history.

Results

Overall, 16 candidate causative variants were identified in 16 patients. Among them, two previously known heterozygous nonsynonymous single-nucleotide variants associated with monogenic diabetes were confirmed as causative variants: one each in the GCK and WFS1 genes. The former was found in two independent diabetes-affected families. Two novel putatively deleterious heterozygous variants were also assumed to be causative from the family history: one frameshift and one nonsynonymous single-nucleotide variant in the HNF4A gene. Twelve variants remained as candidates associated with the development of diabetes.

Conclusion

Targeted NGS panel testing was useful to diagnose various forms of monogenic diabetes in combination with familial analysis, but additional ingenuity would be needed for practice.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors thank the patients and their family members who participated in this study. The authors are also grateful to Ms. Tomomi Seino, Mr. Yuki Miyano, and Ms. Ryoko Murakami for technical assistance. The authors gratefully acknowledge Dr. Takashi Daitsu of Mamigasaki Children’s Clinic, Yamagata, Japan for providing us with additional information and helpful discussions about the patients. Finally, the authors also thank Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

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Authors and Affiliations

  1. Department of Neurology, Hematology, Metabolism, Endocrinology and Diabetology, Faculty of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan

    Kaoru Takase, Shinji Susa, Yurika Hada, Kyoko Nagaoka, Noe Takakubo, Shigeru Karasawa, Wataru Kameda & Kenichi Ishizawa

  2. Genomic Information Analysis Unit, Department of Genomic Cohort Research, Faculty of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan

    Hidenori Sato

  3. Takakubo Clinic, 2-9-7 Kitamachi, Warabi, Saitama, 335-0001, Japan

    Noe Takakubo

  4. Department of Pediatrics and Clinical Genomics, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama, Saitama, 350-0495, Japan

    Chikahiko Numakura

Authors
  1. Kaoru Takase
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  2. Shinji Susa
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  3. Hidenori Sato
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  4. Yurika Hada
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  5. Kyoko Nagaoka
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  6. Noe Takakubo
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  7. Shigeru Karasawa
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  8. Wataru Kameda
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  9. Chikahiko Numakura
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  10. Kenichi Ishizawa
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Contributions

All authors contributed to the study conception and design. The idea of the study was conceived by SS. Data collection was performed by YH, KN, NT, SK, WK, and CN. Data analysis was performed by HS. The first draft of the manuscript was written by KT and all authors commented on previous versions of the manuscript. KI supervised the project. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Kaoru Takase.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Human rights statement

Name of institutional or national ethical committee on human experimentation. The Ethical Review Committee of Yamagata University Faculty of Medicine.

Date of approval

June 6th, 2017.

Approval number

2017–108

Informed consent

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and/or with the Helsinki Declaration of 1964 and later versions. Informed consent or substitute for it was obtained from all patients for being included in the study. For patients between the ages of 5 and 18, written informed consent was obtained from each patient or their parents/legal guardians and informed assent was given for themselves.

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Takase, K., Susa, S., Sato, H. et al. Identification of causative gene variants for patients with known monogenic diabetes using a targeted next-generation sequencing panel in a single-center study. Diabetol Int 15, 203–211 (2024). https://doi.org/10.1007/s13340-023-00669-3

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  • DOI: https://doi.org/10.1007/s13340-023-00669-3

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