Identifying Pathogenic Variants of Monogenic Diabetes Using Targeted Panel Sequencing in an East Asian Population.

PURPOSE: Monogenic diabetes is a specific type of diabetes in which precision medicine could be applied. In this study, we used targeted panel sequencing to investigate pathogenic variants in Korean patients clinically suspected to have monogenic diabetes. METHODS: The eligibility criteria for inclusion were non-type 1 diabetes patients with an age of onset ≤ 30 years and a BMI (body mass index) ≤ 30 kg/m2. Among the 2,090 non-type 1 diabetes patients, 109 were suspected to have monogenic diabetes and subjected to genetic testing. We analyzed 30 monogenic diabetes genes using targeted panel sequencing. The pathogenicity of the genetic variants was evaluated according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines. RESULTS: Among the 109 suspected monogenic diabetes patients, 23 (21.1%) patients harbored pathogenic/likely pathogenic variants. A total of 14 pathogenic/likely pathogenic variants of common maturity onset diabetes of the young (MODY) genes were identified in GCK, HNF1A, HNF4A, and HNF1B. Other pathogenic/likely pathogenic variants were identified in WFS1, INS, ABCC8 and FOXP3. The mitochondrial DNA 3243 A>G variant was identified in five participants. Patients with pathogenic/likely pathogenic variants had a significantly higher MODY probability, a lower BMI, and a lower C-peptide level than those without pathogenic/likely pathogenic variants (P=0.007, P=0.001, and P=0.012, respectively). CONCLUSIONS: Using targeted panel sequencing followed by pathogenicity evaluation, we were able to make molecular genetic diagnoses for 23 (21.1%) suspected monogenic diabetes patients. Lower BMI, higher MODY probability, and lower C-peptide levels were characteristics of these participants.