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

Jun Hosoe, Fuyuki Miya, Hiroko Kadowaki, Toyofumi Fujiwara, Ken Suzuki, Takashi Kato, Hironori Waki, Takayoshi Sasako, Katsuya Aizu, Natsumi Yamamura, Fusako Sasaki, Makoto Kurano, Kazuo Hara, Masaki Tanaka, Hiroyuki Ishiura, Shoji Tsuji, Kenjiro Honda, Jun Yoshimura, Shinichi Morishita, Fumiko MatsuzawaSei Ichi Aikawa, Keith A. Boroevich, Masaomi Nangaku, Yukinori Okada, Tatsuhiko Tsunoda, Nobuhiro Shojima, Toshimasa Yamauchi, Takashi Kadowaki

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number108461
JournalDiabetes Research and Clinical Practice
Volume169
DOIs
Publication statusPublished - 2020 Nov
Externally publishedYes

Keywords

  • Genetic diagnosis
  • Maturity-onset diabetes of the young
  • Monogenic diabetes
  • Next-generation sequencing
  • Severe insulin resistance

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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