Clinical usefulness of multigene screening with phenotype-driven bioinformatics analysis for the diagnosis of patients with monogenic diabetes or severe insulin resistance

Diabetes Res Clin Pract. 2020 Nov:169:108461. doi: 10.1016/j.diabres.2020.108461. Epub 2020 Sep 22.


Aims: Monogenic diabetes is clinically heterogeneous and differs from common forms of diabetes (type 1 and 2). We aimed to investigate the clinical usefulness of a comprehensive genetic testing system, comprised of targeted next-generation sequencing (NGS) with phenotype-driven bioinformatics analysis in patients with monogenic diabetes, which uses patient genotypic and phenotypic data to prioritize potentially causal variants.

Methods: We performed targeted NGS of 383 genes associated with monogenic diabetes or common forms of diabetes in 13 Japanese patients with suspected (n = 10) or previously diagnosed (n = 3) monogenic diabetes or severe insulin resistance. We performed in silico structural analysis and phenotype-driven bioinformatics analysis of candidate variants from NGS data.

Results: Among the patients suspected having monogenic diabetes or insulin resistance, we diagnosed 3 patients as subtypes of monogenic diabetes due to disease-associated variants of INSR, LMNA, and HNF1B. Additionally, in 3 other patients, we detected rare variants with potential phenotypic effects. Notably, we identified a novel missense variant in TBC1D4 and an MC4R variant, which together may cause a mixed phenotype of severe insulin resistance.

Conclusions: This comprehensive approach could assist in the early diagnosis of patients with monogenic diabetes and facilitate the provision of tailored therapy.

Keywords: Genetic diagnosis; Maturity-onset diabetes of the young; Monogenic diabetes; Next-generation sequencing; Severe insulin resistance.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Computational Biology
  • Diabetes Mellitus / diagnosis*
  • Diabetes Mellitus / genetics*
  • Female
  • GTPase-Activating Proteins / genetics
  • Genetic Testing / methods*
  • Genotype
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Infant
  • Insulin Resistance / genetics*
  • Japan
  • Male
  • Mass Screening / methods
  • Middle Aged
  • Mutation, Missense
  • Phenotype
  • Young Adult


  • GTPase-Activating Proteins
  • TBC1D4 protein, human