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Objective: Maturity onset diabetes of the young (MODY) occurs due to mutations in genes involved in pancreatic beta cell function and insulin secretion, has heterogeneous clinical and laboratory features, and account for 1-5% of all diabetes cases. The prevalence and distribution of MODY subtypes vary between countries. The aim of this study was to evaluate the clinical and laboratory characteristics, mutation distribution, and phenotype-genotype relationship in a large case series of pediatric Turkish patients genetically diagnosed with MODY. Methods: MODY cases from 14 different pediatric endocrinology departments were included. Diagnosis, treatment, follow-up data, and results of genetic analysis were evaluated. Results: A total of 224 patients were included, of whom 101 (45%) were female, and the mean age at diagnosis was 9.4±4.1 years. Gene variant distribution was: 146 (65%) GCK; 43 (19%) HNF1A; 8 (3.6%) HNF4A, 8 (3.6%) KLF11 and 7 (3.1%) HNF1B. The remaining 12 variants were: PDX (n=1), NEUROD1 (n=3), CEL (n=1), INS (n=3), ABCC8 (n= 3) and KJNC11 (n=1). Of the cases, 197 (87.9%) were diagnosed with incidental hyperglycemia, 16 with ketosis (7%) and 7 (3%) with diabetic ketoacidosis (DKA), while 30% presented with classical symptoms of diabetes. Two-hundred (89%) had a family history of diabetes. Anti-GAD antibody was detected in 13 cases, anti-islet antibody in eight and anti-insulin antibody in four. Obesity was present in 16. Distribution of therapy was: 158 (71%) diet only; 23 (11%) intensive insulin treatment; 17 (7.6%) sulfonylureas; 10 (4.5%) metformin; and 6 (2.7%) insulin and oral anti-diabetic treatment. Conclusion: This was the largest genetically diagnosed series from Turkey. The most common gene variants were GCK and HNF1A with much lower proportions for other MODY types. Hyperglycemia was the most common presenting symptom while 11% of patients had diabetes-associated autoantibodies and 7% were obese. The majority of patients received dietary management only. [ABSTRACT FROM AUTHOR]

Objective: Maturity-onset diabetes of the young (MODY) is the most common type of monogenic diabetes. To date, mutations have been identified in 14 different genes of patients with a clinical diagnosis of MODY. This study screened mutations in 14 MODY-related genes and the regulator factor X6 (RFX6) gene in children Methods: The presence of clinical features of MODY and negative results for three autoantibody markers of type 1 diabetes mellitus (T1DM) in children and adolescents were used as inclusion criteria for genetic testing. The screening panel for next-generation sequencing included 14 MODY-related genes (GCK, HNF4A, HNF1A, HNF1B, PDX1, NEUROD1, KLF11, CEL, PAX4, INS, BLK, ABCC8, KCNJ11, and APPL1) and the RFX6 gene. Results: Twenty-four different variants in MODY-related genes were identified in 49 children diagnosed with autoantibody-negative T1DM. Twelve variants were classified as pathogenic/likely pathogenic (P/LP) while 12 were interpreted as variant of unknown significance. Nine of the P/LP variants were found in GCK, two in HNF1B, and one in ABCC8. Three variants were novel, and one was a de novo variant. All but one of the variants exhibited heterozygotic inheritance. Conclusion: The frequencies of the MODY subtypes differed from previous reports. Although GCK-MODY was the most frequent mutation in Turkish children, similar to previous studies, the second most prevalent MODY subtype was HNF1B-MODY. This study also established three additional novel mutations in different MODY genes. [ABSTRACT FROM AUTHOR]

Background: Although monogenic diabetes accounts for a small proportion of diabetes cases, accurate diagnosis may significantly change treatment. This study aimed to contribute to knowledge about the genotype-phenotype relationship in monogenic diabetes. Methods: This study used data from a tertiary centre in Turkey. Genetic analysis outcomes for 36 patients were evaluated. The panel included 23 genes related to maturity-onset diabetes of the young (MODY), neonatal diabetes, and some genes related to hyperglycemic hypoglycemia. The next-generation sequencing method was used after DNA isolation from the peripheral blood. Results: Mutations were identified in 19 (52.8%) of 36 patients. Of the 19 mutations, 7 (36.8%) were new mutations. A total of 20 cases met the MODY clinical criteria, and mutations were identified in 11 (55%) of them. In total, nine patients had more than one mutation. Mutations were identified on the ABCC8 (n = 7), PDX1 (n = 6), GLIS3 (n = 6), ZFP57 (n = 5), GCK (n = 4), HNF1A (n = 3), GLUD (n = 3), and HNF4A, KLF11, NKX2-2, and INSR genes (n = 1 each). Conclusion: Our findings highlight a broad clinical and genetic spectrum of MODY, and genetic analysis may provide a better understanding of diabetes and improve the individualised treatment approach. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to investigate the molecular basis of maturity-onset diabetes of the young (MODY) by targeted-gene sequencing of 20 genes related to monogenic diabetes, estimate the frequency and describe the clinical characteristics of monogenic diabetes and MODY in the Trakya Region of Turkey. Methods: A panel of 20 monogenic diabetes related genes were screened in 61 cases. Illumina NextSeq550 system was used for sequencing. Pathogenicity of the variants were assessed by bioinformatics prediction software programs and segregation analyses. Results: In 29 (47.5%) cases, 31 pathogenic/likely pathogenic variants in the GCK, ABCC8, KCNJ11, HNF1A, HNF4A genes and in 11 (18%) cases, 14 variants of uncertain significance (VUS) in the GCK, RFX6, CEL, PDX1, KCNJ11, HNF1A, G6PC2, GLIS3 and KLF11 genes were identified. There were six different pathogenic/likely pathogenic variants and six different VUS which were novel. Conclusion: This is the first study including molecular studies of twenty monogenic diabetes genes in Turkish cases in the Trakya Region. The results showed that pathogenic variants in the GCK gene are the leading cause of MODY in our population. A high frequency of novel variants (32.4%-12/37) in the current study, suggests that multiple gene analysis provides accurate genetic diagnosis in MODY. [ABSTRACT FROM AUTHOR]

Objective: Type 1 diabetes (T1D) is the most common cause of diabetes in childhood but type 2 diabetes (T2D) and maturity onset diabetes of the young (MODY) are emerging as noteworthy causes of diabetes at young ages. The aim is to determine the distribution, trends and clinical features of the different types of diabetes in childhood in one tertiary center. Methods: The records of children and adolescents aged 0-18 years who were diagnosed as "diabetes/persistent hyperglycemia" between January 1999 and December 2016, were reviewed. Clinical and laboratory characteristics of the patients at diagnosis and type of diabetes were recorded. Results: The mean ± standard deviation age of 835 patients (48.7% females) at diagnosis was 8.8±4.4 years. Eighty-four percent of the patients were diagnosed as T1D, 5.7% as T2D, 5.3% as clinical MODY and 5% as being cases of other types of diabetes. The frequency of diabetic ketoacidosis (DKA) and severe DKA in T1D were 48.4% and 11.6%, respectively. Fourteen patients (29.2%) with T2D presented with ketosis and two of them (4.2%) had DKA at diagnosis. Antibody positivity was 83.1% in T1D and 14.8% in T2D. A statistically significant increase in the frequency of T2D has clearly been demonstrated in recent years with a frequency of 1.9%, 2.4% and 7.9% in 1999-2004, 2005-2010 and 2011-2016, respectively (p<0.001). In MODY, genetic analysis was performed in 26 (59%) patients and HNF1A and GCK gene mutations were detected in 3 (11.5%) and 14 (53.8%) patients, respectively. Conclusion: Although the most frequent cause of DM is T1D in childhood, a trend towards increase in the frequency of T2D in recent years is notable in our population. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Current clinical guidelines for childhood-onset monogenic diabetes outside infancy are mainly focused on identifying and testing for dominantly inherited, predominantly MODY genes. There are no systematic studies of the recessively inherited causes of monogenic diabetes that are likely to be more common in populations with high rates of consanguinity. We aimed to determine the contribution of recessive causes of monogenic diabetes in paediatric diabetes clinics and to identify clinical criteria by which to select individuals for recessive monogenic diabetes testing., Methods: We conducted a cross-sectional study of 1093 children from seven paediatric diabetes clinics across Turkey (a population with high rates of consanguinity). We undertook genetic testing of 50 known dominant and recessive causes of monogenic diabetes for 236 children at low risk of type 1 diabetes. As a comparison, we used monogenic diabetes cases from UK paediatric diabetes clinics (a population with low rates of consanguinity)., Results: Thirty-four children in the Turkish cohort had monogenic diabetes, equating to a minimal prevalence of 3.1%, similar to that in the UK cohort (p = 0.40). Forty-one per cent (14/34) had autosomal recessive causes in contrast to 1.6% (2/122) in the UK monogenic diabetes cohort (p < 0.0001). All conventional criteria for identifying monogenic diabetes (parental diabetes, not requiring insulin treatment, HbA 1c  ≤ 58 mmol/mol [≤7.5%] and a composite clinical probability of MODY >10%) assisted the identification of the dominant (all p ≤ 0.0003) but not recessive cases (all p ≥ 0.2) in Turkey. The presence of certain non-autoimmune extra-pancreatic features greatly assisted the identification of recessive (p < 0.0001, OR 66.9) but not dominant cases., Conclusions/interpretation: Recessively inherited mutations are a common cause of monogenic diabetes in populations with high rates of consanguinity. Present MODY-focused genetic testing strategies do not identify affected individuals. To detect all cases of monogenic paediatric diabetes, it is crucial that recessive genes are included in genetic panels and that children are selected for testing if they have certain non-autoimmune extra-pancreatic features in addition to current criteria., (© 2021. The Author(s).)

Maturity onset diabetes is a genetic form of diabetes mellitus characterized by an early age at onset and several etiologic genes for this form of diabetes have been identified in many patients. Maturity onset diabetes type 2 [MODY2 (#125851)] caused by mutations in the glucokinase gene (GCK). Although its prevalence is not clear, it is estimated that 1%-2% of patients with diabetes have the monogenic form. The aim of this study was to evaluate the molecular spectrum of GCK gene mutations in 177 Turkish MODY type 2 patients. Mutations in the GCK gene were identified in 79 out of 177. All mutant alleles were identified, including 45 different GCK mutations, 20 of which were novel., (Copyright © 2017. Published by Elsevier B.V.)