Recognition of GCK Homozygote missense (His424Tyr) variant in a female patient with neonatal hyperglycemia.

Introduction: Heterozygous mutations in the GCK gene result in mildly elevated glucose levels from birth, and the homozygous loss-of-function mutations leads to permanent neonatal diabetes. In the present study we aim to investigate the cause of diabetes in an adult female patient with unusual course of diabetes.

Case presentation: We evaluate a female patient who previously encountered significant hyperglycemia during the infancy and subsequently experienced a relatively uneventful childhood. In later years, she faced significant hyperglycemia and retinopathy that required laser photocoagulation. Her treatment history included periods of oral hypoglycemic agents or insulin, which occasionally led to hypoglycemia, as well as extended intervals without treatment. However, she never required hospitalization for diabetic ketoacidosis. The patient's family history was significant, with her parents being cousins and having a history of prediabetes and gestational diabetes in several family members. Autoantibody tests for type 1 diabetes were negative. Next-generation sequencing analysis of the coding regions and conserved splice sites of several genes identified a homozygous GCK (T/T) missense (His424Tyr) variant, which was validated by Sanger sequencing. Heterozygous C/T mutations were revealed in the parents.

Discussion and conclusion: This case highlights the importance of considering homozygous GCK mutations as a potential cause of persistent neonatal diabetes, especially in patients with a history of elevated glucose levels from infancy, a family history of early-onset non-progressive diabetes and gestational diabetes, and parental consanguinity. Genetic testing can help identify the underlying genetic etiology in such cases. Early diagnosis is crucial to guide appropriate treatment and management strategies.