Molecular genetic diagnosis of clinical suspected mody(maturity-onset diabetes of the young) in Turkish children using targeted next generation sequencing

Diabetes is a severe chronic disease especially in childhood with clinical and etiopathogenetic heterogeneity. Maturity Onset Diabetes of the Young (MODY) is a type of diabetes with an autosomal dominant inheritance pattern and marked genetic heterogeneity. Molecular genetic diagnosis of MODY is necessary for optimal treatment, prognosis and genetic counseling. For the diseases with genetic heterogeneity, NGS method (new generation sequence analysis) is themost ideal method to apply the confusion. In this study, we aimed to establish genetic etiology with NGS andevaluate the genotype-phenotype association in our patients clinically diagnosed with MODY diabetes. Thirty-five patients with clinical suspicion of MODY diabetes were included in the study. Candidate patients wereselected from among the most appropriate from the Duzce University, Medical Faculty, Division of Pediatric Endocrinology database according to their family history, body weight, ketose susceptibility, insulin, C-peptide and autoantibody presence DNA was isolated from peripheral blood samples and 13 genes named GCK, HNF1A, HNF4A, HNF1B, PDX1, NEUROD1, KLF11, CEL, PAX4, INS, BLK, ABCC8 and KCNJ11 in MODY etiology were studied by NGS method. The variants were verified with NGS. Pathogenicity was determined by evaluating together with the bioinformatics-in-silico analysis of thedetectedvariants, segregationstudies, andtheclinicalandlaboratoryfindings of thepatients. Mutations were detected in MODY genes in 11 patients (31%). 2 mutations in GCK, 2 mutations in CEL, 1 mutation in HNF1A, KLF11, BLK, NEUROD1, ABCC8 and 1 mutation in HNF1A, HNF4A and WFS1 genes were detected. Nine of the patients were in heterozygous form, 1 patient had a compound heterozygote and 1 patient had a complex genotype. In our study, we identified two new variants that were not previously described, named c.537delG in Exon 5 of GCK gene and IVS5-1G>A in Exon 6 of CEL gene. Because it may be clinically difficult to distinguish MODY diabetes from type 1 and type 2 diabetes, we can say that many patients with monogenic form of diabetes are misclassified. Although MODY accounts for 1-2% of all diabetic cases, the molecular genetic diagnosis of MODY is necessary for optimal treatment, prognosis and genetic counseling. Molecular studies including more people with MODY diabetes in theTurkish population will reveal specific changes in our country, new mutations will be identified and genotype-phenotype associations will be made more accurate.