Clinical, Laboratory and Genetic Characteristics of Children with GCK-MODY (MODY2): Report of Four Novel Variants in GCK Gene

Abstract

Objective: Maturity-Onset Diabetes of the Young (MODY) is the most common type of monogenic diabetes. Heterozygous inactivating variants in glucokinase (GCK) gene are related to MODY2 (GCK-MODY). In this study, we aimed to investigate the phenotype and genotype characteristics of patients with GCK-MODY. Methods: Anthropometric and clinical characteristics (age, gender, weight, height and body mass index, complaints, family history), laboratory data (glucose, insulin, glycated hemoglobin, lipid levels) and molecular analysis of the GCK gene were collected from the hospital records. Results: The median age was 9.50 y (1.0-16.0), weight SDS -0.27 (-1.50-2.50), height SDS -0.09 (-2.20-1.60), and body mass index SDS -0.10 (-1.30-2.40). The median level of fasting blood glucose was 121 mg/dL (101-143), insulin was 9.50 mIU/mL (1.80-21.0), and HbA1c was 6.35% (6.20-6.60) at the time of diagnosis. Fourteen patients (78%) were diagnosed incidentally with asymptomatic hyperglycemia, while 4 patients (22%) had symptoms of polyuria and polydipsia. Ten different variants were detected in the GCK gene of 18 cases; one variant was nonsense, one variant was deletion, and the rest of the variants were missense mutations. Exon 7 was the most common location in coding regions and missense was the primary mutation type. The most common variant was c.802G>T (p.Glu268Ter) and detected in 5 (28%) patients. Four (22%) of the variants were novel; seven missense (p. Asp132Gly, p.Arg191Gln, p.Met238Thr, p.Met238Ile, p.Leu243Pro, p.Arg250Cys, p.Arg275Cys), one deletion (p.Pro153del) and one splice site mutation (c.863+3A>G). Conclusion: Since there is no specific treatment for GCK–MODY, GCK gene mutation screening should be considered in cases with early onset mild hyperglycemia, family history of impaired fasting glycemia and negative beta-cell antibodies to avoid unnecessary use of insulin or oral antidiabetic drugs. In this study, ten different variants were detected in the GCK gene of the 18 cases, four of which were novel.