Novel variants of monogenic diabetes and impact of genetic diagnosis on treatment strategies

Monogenic diabetes (MD) is a rare form of diabetes resulting from single-gene defects. While diagnostic guidelines are well established for young patients, individuals >25 years are frequently overlooked, despite the clinical value of molecular diagnosis for personalized therapy. Aim: To evaluate genetic sequencing outcomes and their implications for treatment optimization in patients diagnosed with diabetes between 2017 and 2024 across all age groups. Methods: Among 509 individuals tested for suspected MD, 78 (60.3% female) had a confirmed molecular diagnosis. Genetic testing was performed in patients with negative pancreatic autoantibodies, a family history of diabetes, or stable hyperglycemia without insulin requirement. Results: The median age at MD diagnosis was 18.3 (4-68.1) years, with a median diabetes duration of 4.5 (0-50) years. Forty-three patients (55.1%) were diagnosed before age 25 and thirty-five (45.6%) after 25 years. GCK variants predominated in both groups (81.4% and 74.3%, respectively), followed by HNF1A, HNF4A, and HNF1B. After molecular confirmation, 75% (18/24) of eligible patients underwent actionable treatment changes according to genotype, while six did not benefit from therapy adjustment. Conclusion: These findings demonstrate a high diagnostic yield (15.3%) for MD and emphasize the need to broaden testing criteria to enable precise, gene-guided and on time treatment decisions.