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

Abstract

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. To evaluate genetic sequencing outcomes and their implications for treatment optimization in patients diagnosed with diabetes between 2017 and 2024 across all age groups. 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. 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. 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.