Optimizing pre-genetic diagnosis of monogenic diabetes: clinical thresholds for targeted testing

Monogenic Diabetes Mellitus (MDM) represents a minority of Diabetes Mellitus (DM) cases but poses diagnostic complexities owing to its clinical overlap with other forms of DM. Preliminary clinical screening is crucial for diagnosis due to the paucity of genetic testing facilities. We aimed to identify clinical thresholds that could enhance the likelihood of obtaining positive genetic test results while excluding young-onset T2DM in suspected cases of MDM. We analyzed the demographic, anthropometric, and biochemical details of genetically confirmed MDM participants ( n = 10) from our center and compared them with those of clinically suspected patients who tested negative for MDM ( n = 67), excluding two neonatal DM (NDM) cases. Using Receiver Operating Characteristic curves, we determined the thresholds for various parameters, prioritizing a sensitivity of ≥75 %. The upper cut-off values obtained for identifying individuals with a potential for genetic positivity were age of onset of DM 25.5 years, BMI 23.5 kg/m 2 , visceral fat 7 %, waist circumference (irrespective of gender) 86 cm, random C-peptide 1.41 ng/mL, AST 31 units/dL, ALT 41 units/dL, triglyceride 150 mg/dL, and for HDL, the lower cut-off point was 48.5 mg/dL. These defined thresholds offer a potential to enhance the efficient use of genetic testing by ensuring more targeted utilization, thus optimizing resource allocation and improving diagnostic accuracy in the assessment of MDM. • Diagnosing Monogenic Diabetes Mellitus (MDM) is challenging due to clinical overlap with other DM types • Preliminary clinical screening is crucial for diagnosis of MDM due to limited genetic testing access • We identified clinical thresholds to enhance the likelihood of positive genetic test results for MDM • Cut-off values for novel parameters (visceral fat, waist circumference, AST and ALT) identified • These thresholds help to improve pre-genetic diagnostic accuracy of MDM