Supplementary Material for: T1D GRS: a tool for identifying children and adolescents with monogenic diabetes

Introduction It is important to diagnose monogenic diabetes because gene-tailored treatment is available. In children and adolescents, monogenic diabetes must mostly be differentiated from Type 1 diabetes. People with Type 1 and monogenic diabetes have different genetic risks for Type 1 diabetes. This study evaluates the effectiveness of the Type 1 Diabetes Genetic Risk Score (T1D GRS) in prioritising children with newly diagnosed hyperglycaemia for monogenic diabetes genetic testing. Methods The T1D GRS2 and 10SNP GRS scores were assessed in 808 children and adolescents with newly diagnosed hyperglycaemia, 165 monogenic diabetes patients, and 24 healthy individuals. Genetic testing was performed in all autoantibody negative cases and cases with clinically unclassified diabetes. The usefulness of T1D GRS in prioritisation for genetic testing was evaluated retrospectively. Results Applying T1D GRS2 alongside negative autoantibodies tripled the pick-up rate, with only slight reduction in sensitivity (from 77.8% to 72.2%) compared to using autoantibodies alone. Most monogenic diabetes cases missed by this prioritisation had low levels of a single autoantibody and were likely false positives in autoantibody testing. While these monogenic cases not prioritised by GRS2 and autoantibodies were diagnosed based on clinical phenotype, two HNF1B-MODY cases were identified solely thanks to their low GRS2 scores. Conclusions Combining T1D GRS with autoantibody testing improves the efficiency of genetic testing by reducing unnecessary investigations while maintaining high sensitivity. When combined with clinical evaluation, this approach enables earlier and more targeted identification of candidates for monogenic diabetes testing.