Identification Of Pathogenic Mutations And Application Of Polygenic Risk Scores In Early-Onset Diabetes Patients

Abstract Background: Maturity-onset Diabetes of the Young (MODY) presents a diagnostic challenge, with a large proportion of cases lacking identifiable genetic mutations, which could lead to sub-optimal medical treatment and, subsequently, a decline in patients’ life quality. This study investigates the utility of polygenic risk score (PRS) in distinguishing monogenic diabetes from early-onset type 1 diabetes (T1D) and type 2 diabetes (T2D) cases to enhance diagnostic accuracy. Methods: We investigated the genetic basis of early-onset diabetes in a Latvian cohort comprising 66 patients, contrasted with 174 non-diabetic controls, using whole-genome sequencing (WGS). Results: We identified 22 causative mutations in three MODY genes (GCK, HNF1A, and HNF4A), eight of them being novel. We selected and tested the best-performing population specific T1D and T2D PRS models on the established diabetic cohort and controls. Patients without genetically confirmed MODY had a significantly higher risk for T1D compared to controls. A 75% centile of T1D-PRS included only 8.7% of the genetically confirmed MODY patients, compared to 34% of patients without mutations, providing good specificity for the identification of indicative T1D at this PRS range. While T2D-PRS was increased in the diabetic cohort, it did not demonstrate an ability to discriminate between MODY-positive and negative subgroups. Conclusions: Our study demonstrates that the application of WGS improves diagnostic accuracy and highlights the potential of T1D-PRS as a critical tool for the stratification of MODY-suspected patients.