2398-P: Identifying Clinical Discriminators of GCK-MODY in a Type 2 Diabetes–Dominant Population in Taiwan

Introduction and Objective: Young-onset type 2 diabetes (YOD) is increasingly prevalent, whereas glucokinase maturity-onset diabetes of the young (GCK-MODY)—a common MODY subtype across ethnicities—remains underrecognized. Because widespread genetic testing is impractical, overlapping clinical features often lead to misclassification and overtreatment. We aimed to identify clinical discriminators of GCK-MODY in a youth-onset, type 2 diabetes (T2DM)-predominant population to inform targeted genetic testing. Methods: This hospital-based observational study enrolled individuals with diabetes onset at ≤40 years and a family history of diabetes. Whole-exome sequencing (WES) focused on 27 MODY-related genes was performed, with variants classified per American College of Medical Genetics and Genomics criteria. Clinical and metabolic features were compared between patients without pathogenic/likely pathogenic variants and those with GCK-MODY. Results: WES was performed in 150 young individuals with diabetes (51.3% males). Pathogenic or likely pathogenic (P/LP) variants were identified in 21 participants (14%), most commonly GCK (n=10, 48% of variant-positive cases); the remaining variants involved other established MODY-related genes. Compared with young-onset diabetes patients without P/LP variants, individuals with GCK-MODY exhibited a distinct metabolic profile, including lower body mass index, waist circumference, triglycerides, and C-peptide levels. A model incorporating sex, waist circumference, triglycerides, and C-peptide demonstrated good discrimination for GCK-MODY (AUC = 0.842). Conclusion: Phenotype-driven identification of GCK-MODY using simple clinical and metabolic markers may improve the efficiency of genetic testing, reduce misclassification and overtreatment, and support precision management in youth-onset diabetes populations dominated by T2DM. Disclosure Y. Sheen: None. H. Tsai: None. H.P. Chen: None. J. Chen: None. Funding Taichung Veterans General Hospital and National Health Research Institutes, Taiwan