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

Kaoru Takase; Shinji Susa; Hidenori Sato; Yurika Hada; Kyoko Nagaoka; Noe Takakubo; Shigeru Karasawa; Wataru Kameda; Chikahiko Numakura; Kenichi Ishizawa

doi:10.1007/s13340-023-00669-3

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. 2023 Nov 15;15(2):203-211. doi: 10.1007/s13340-023-00669-3. eCollection 2024 Apr.

Authors

Affiliations

¹ Department of Neurology, Hematology, Metabolism, Endocrinology and Diabetology, Faculty of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata, 990-9585 Japan.
² Genomic Information Analysis Unit, Department of Genomic Cohort Research, Faculty of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata, 990-9585 Japan.
³ Takakubo Clinic, 2-9-7 Kitamachi, Warabi, Saitama 335-0001 Japan.
⁴ Department of Pediatrics and Clinical Genomics, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama, Saitama 350-0495 Japan.

PMID: 38524932
PMCID: PMC10959868 (available on 2024-11-15)
DOI: 10.1007/s13340-023-00669-3

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.

Supplementary information: The online version contains supplementary material available at 10.1007/s13340-023-00669-3.

Keywords: Childhood onset diabetes; Genetic analysis; Monogenic diabetes; Next-generation sequencing; Targeted panel sequencing.

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