Case-based learning: a case of maturity-onset diabetes of the young 5 (MODY5) due to 17q12 microdeletion with a diminished plasma glucagon level.

Maturity-onset diabetes of the young type 5 (MODY5), causally associated with loss-of-function of the HNF1B gene, is a rare form of monogenic diabetes that has been underdiagnosed in part because microdeletions of chromosome 17q12 encompassing the HNF1B gene cannot be detected by sequencing-based approaches, which accounts for about 50% of MODY5 cases. We herein describe a 37-year-old Japanese woman who manifested diabetic ketosis at the onset. The coexistence of features associated with MODY5, including abnormal renal function, impaired insulin secretion, pancreatic hypoplasia and hypomagnesemia, prompted us to decode her genomic information using whole-exome sequencing, where we were not able to identify any pathogenic HNF1B gene mutations. We further examined her genomic integrity using multiplex ligation probe amplification (MLPA) analysis, leading to identification of the 17q12 microdeletion which was further supported by array comparative genomic hybridization (array-CGH). Her insulin secretory capacity was insufficient, whereas her total daily dose of insulin was 11 U/day (0.25 U/Kg/day), indicating that she was relatively sensitive to insulin. As a possible explanation, we found that her plasma glucagon level was below the detection limit. Since inactivation of acetyl-CoA carboxylase 1 (ACACA), encoded in close proximity to the HNF1B gene, was reported to blunt glucagon secretion, the concurrent deletion of the ACACA gene may be in part responsible for this manifestation. In conclusion, the genetic analyses of MODY5 cases require the judicious use of appropriate genetic technologies. In addition, alpha-cell dysfunction may at least in part account for the variable clinical manifestations of MODY5.

Supplementary information: The online version contains supplementary material available at 10.1007/s13340-025-00804-2.