Investigation of novel genetic variations by whole exome sequencing in patients without mutations in genes associated with maturi̇ty-onset diabetes of the young (MODY) and their families

Background: Maturity-onset diabetes of the young (MODY) is the most common form of monogenic diabetes. MODY is a heterogeneous genetic disease. Until now, 14 different subtypes associated with 14 different genes have been identified. Today, next-generation sequencing technologies have been increasingly used in recent years for its molecular diagnosis. In the first step, targeted panels for known genes are applied, but the genetic etiology remains unexplained in approximately 20-30% of patients (MODY-X). In this study, we aimed to identify the genes and pathways that play a role in the pathogenesis of Diabetes Mellitus (DM) in the MODY-X group. Material and Method: In this study, whole exome sequencing of peripheral blood was performed in 5 patients and their affected first-degree relatives (5 families, n=10) who were followed up between 2020 and 2023 at Istanbul University-Cerrahpaşa, Cerrahpaşa Faculty of Medicine, Department of Medical Genetics with a prediagnosis of MODY, who had at least 3 generations of relatives with DM and whose genetic diagnosis could not be established by targeted panels for the etiology of MODY. Results: Two novel variants of unknown clinical significance were detected in the GIGYF1 gene in 2 different families. Variants thought to be significant in GCKR, SLC30A8, MAPK8IP1, ITPR3, ONECUT1 genes, which were previously mentioned as candidate genes in the etiology of diabetes. In addition, RFX7, RAP1GAP, EXOC7 genes, which have not been previously demonstrated in diabetic patients, were thought to be associated with DM pathogenesis as a result of this study. Conclusion: Whole exome sequencing method targets coding regions in the genome. WES provides an important contribution to deepen genetic research and identify new genes and variants that may cause the disease, especially in the MODY-X patient group where targeted panels are insufficient to make a diagnosis. Keywords: Diabetes Mellitus, MODY, MODY-X, Whole exome sequencing