Abstract
Monogenic forms of diabetes mellitus, collectively classified as MODY (Maturity Onset Diabetes of the Young), represent rare, genetically determined variants of the disease with an autosomal dominant inheritance pattern, typically manifesting at a young age while maintaining preserved insulin secretion and the absence of autoimmune markers. One of the most well-characterized subtypes is glucokinase-associated diabetes (MODY 2), caused by mutations in the GCK gene encoding glucokinase – a key glucose sensor of pancreatic β-cells. Genetically verified cases of MODY 2 are characterized by a stable clinical course, mild hyperglycemia, and a low risk of vascular complications, which necessitates a differentiated therapeutic strategy.
Aim. To present the clinico-genomic characterization of a patient carrying a heterozygous pathogenic p.Thr228Met substitution in the GCK gene, determining the development of type 3 diabetes (MODY 2), and to analyze the phenotypic features in the context of metabolic and hereditary predisposition.
Materials and methods. A clinical case of a 20-year-old male with early-onset hyperglycemia, negative autoantibodies to β-cell antigens, and preserved C-peptide secretion was analyzed. Molecular genetic testing using the “Diabetes–Hyperinsulinism” gene panel was performed by next-generation sequencing (Illumina platform, >99% target coverage), revealing a pathogenic c.683C>T (p.Thr228Met) variant in a heterozygous state. The data were interpreted in accordance with ACMG standards and national guidelines.
Conclusions. The heterozygous p.Thr228Met mutation in the GCK gene defines a stable phenotype of moderate hyperglycemia with preserved β-cell function, consistent with the clinical variant of MODY 2. Molecular genetic verification of monogenic diabetes via sequencing is a key component of personalized medicine, allowing clinicians to avoid unwarranted therapy intensification and to optimize metabolic control.
Keywords: type 3 diabetes, MODY 2, GCK, glucokinase, p.Thr228Met, monogenic diabetes, molecular diagnostics, clinical case.
Aim. To present the clinico-genomic characterization of a patient carrying a heterozygous pathogenic p.Thr228Met substitution in the GCK gene, determining the development of type 3 diabetes (MODY 2), and to analyze the phenotypic features in the context of metabolic and hereditary predisposition.
Materials and methods. A clinical case of a 20-year-old male with early-onset hyperglycemia, negative autoantibodies to β-cell antigens, and preserved C-peptide secretion was analyzed. Molecular genetic testing using the “Diabetes–Hyperinsulinism” gene panel was performed by next-generation sequencing (Illumina platform, >99% target coverage), revealing a pathogenic c.683C>T (p.Thr228Met) variant in a heterozygous state. The data were interpreted in accordance with ACMG standards and national guidelines.
Conclusions. The heterozygous p.Thr228Met mutation in the GCK gene defines a stable phenotype of moderate hyperglycemia with preserved β-cell function, consistent with the clinical variant of MODY 2. Molecular genetic verification of monogenic diabetes via sequencing is a key component of personalized medicine, allowing clinicians to avoid unwarranted therapy intensification and to optimize metabolic control.
Keywords: type 3 diabetes, MODY 2, GCK, glucokinase, p.Thr228Met, monogenic diabetes, molecular diagnostics, clinical case.
For citation:Yurin S.M., Apalkov D.A., Minenkova T.A., Razinkova N.S., Serezhkina A.V. Integrative clinicogenomic analysis of the monoallelic pathogenic substitution p.Thr228Met in the GCK gene as a nosological marker of type 3 diabetes (MODY 2) with a phenotype of moderate stable hyperglycemia and preserved β-cell secretory capacity. Clinical review for general practice. 2025; 6 (10): 39–42 (In Russ.). DOI: 10.47407/kr2025.6.10.00691
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