Systematic Genetic Study of Diabetic Youth in a Single Country Reveals the Prevalence of Diabetes Subtypes, Novel Candidate Genes, and Response to Precision Therapy.

Identifying gene variants causing monogenic diabetes increases understanding of disease etiology and allows for implementation of precision therapy to improve metabolic control and quality of life. Here, we aimed to assess the prevalence of monogenic diabetes in diabetic youth in Lithuania, uncover potential diabetes-related gene variants, and prospectively introduce precision treatment. First, we assessed all pediatric and most young adult diabetic patients in Lithuania (n = 1209) for diabetes-related autoimmune antibodies. We then screened all antibody-negative patients using targeted high-throughput sequencing of more than 300 potential candidate genes. In this group, 40.7% had monogenic diabetes, with the highest percentage (100%) in infants (diagnosis at ages 0-12 months), followed by those diagnosed at ages >1-18 years (40.3%) and at >18-25 years (22.2%). The overall prevalence of monogenic diabetes in diabetic youth in Lithuania was 3.5% (1.9% for GCK diabetes, 0.7% for HNF1A, 0.2% for HNF4A and ABCC8, 0.3% for KCNJ11, and 0.1% for INS). Furthermore, we identified likely pathogenic variants in 11 additional genes. Microvascular complications were present in 26% of those with monogenic diabetes. Prospective treatment change was successful in over 50% of eligible candidates, with C-peptide over 252 pmol/L emerging as the best prognostic factor.