Childhood-onset mild diabetes caused by a homozygous novel variant in the glucokinase gene

Purpose Heterozygous loss-of-function mutations in the glucokinase (GCK) gene cause MODY 2, which is characterized by asymptomatic fasting hyperglycemia and does not require insulin treatment. Conversely, homozygous loss-of-function mutations in the same gene give rise to permanent neonatal diabetes mellitus (DM) that appears in the first 6-9 months of life and necessitates lifelong insulin treatment. We aimed to present the genotypic and phenotypic features of a 13-year-old patient diagnosed with DM at the age of 3 years due to a homozygous variant in the GCK gene. Methods The patient's clinical and laboratory findings at follow-up were not consistent with the initial diagnosis of type 1 DM; thus, next-generation sequencing of MODY genes (GCK, HNF1A, HNF1B, and HNF4A genes) was performed to identify monogenic causes of DM. Results A novel homozygous variant c.1222 G > T in the GCK gene was revealed. In silico analysis identified it as a pathogenic variant. His mother, father, and brother had the same heterozygous variant in the GCK gene and were diagnosed with MODY 2 (mild fasting hyperglycemia and elevated HbA1c) after genetic counseling. Conclusion In this case report, a patient with a homozygous variant in the GCK gene, who was diagnosed with DM after the infantile period, was presented, highlighting the fact that cases with homozygous variants in the GCK gene can, though rarely, present at a later age with a milder phenotype.

Automated summary

Heterozygous loss-of-function mutations in the glucokinase gene cause MODY 2 characterized by asymptomatic fasting hyperglycemia, while homozygous mutations lead to permanent neonatal diabetes mellitus. A 13-year-old patient diagnosed with diabetes mellitus at age 3 due to a homozygous variant in the GCK gene exemplifies the possibility of homozygous variants in GCK gene presenting with a milder phenotype at a later age.