Genetic and Clinical Characteristics of Monogenic Diabetes in Japan: A Nationwide Study by the Japan Diabetes Society

Abstract

Context: Monogenic diabetes is often underdiagnosed because of limited genetic testing opportunities and varying screening criteria. Objective: To investigate the genetic and clinical characteristics of monogenic diabetes in Japan and assess the utility of classical screening criteria and the maturity-onset diabetes of the young (MODY) probability calculator. Design and Setting: This study included 232 probands with diabetes onset before age 35, body mass index <30 kg/m2, and negative islet autoantibodies, recruited from 2019 to 2024. Targeted sequencing of 11 causal genes was performed, followed by multiplex ligation-dependent probe amplification when indicated. Results: Pathogenic or likely pathogenic (P/LP) variants were identified in 67 (28.9%) probands: 25 in GCK, 22 in HNF1A, 7 in HNF1B, 6 in HNF4A, 4 in ABCC8, and 1 each in NEUROD1, PDX1, and INSR. Of these, 64 (95.5%) carried P/LP variants in actionable genes potentially affecting treatment strategies (GCK, HNF1A, HNF1B, HNF4A, ABCC8). P/LP variant carriers were younger at diagnosis, had lower body mass index, and better metabolic control than noncarriers. However, clinical heterogeneity was substantial. Notably, 35 cases (52.2%) did not meet classical screening criteria of young onset (≤25 years) and a three-generation family history. Although MODY probability scores were higher in probands with P/LP variants (median: 75.5% vs 58.0%; P