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

Abstract

Monogenic diabetes is often underdiagnosed because of limited genetic testing opportunities and varying screening criteria. 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. 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. 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 < .001), early insulin initiation substantially lowered the probability scores, warranting caution. We established a nationwide genetic testing platform and identified carriers of actionable variants, offering possibilities for precision medicine. Neither classical criteria nor the MODY probability calculator identified all monogenic cases, highlighting the need for broader genetic testing.