Variable presentations of GCK gene mutation in a family

Area of Science:

• Genetics
• Endocrinology
• Pediatrics

Background:

• The GCK gene encodes glucokinase, a key regulator of glucose metabolism.
• Mutations in GCK are associated with monogenic forms of diabetes, including MODY and PNDM.

Observation:

• A family with two siblings presenting with distinct hyperglycemic phenotypes.
• Older sibling: asymptomatic hyperglycemia, heterozygous for a paternally inherited GCK pathogenic variant.
• Younger sibling: low birth weight, persistent hyperglycemia from infancy, compound heterozygous for novel GCK mutations.

Findings:

• Heterozygous inactivating GCK mutations result in maturity-onset diabetes of the young type 2 (MODY 2), characterized by mild fasting hyperglycemia.
• Compound heterozygous inactivating GCK mutations cause permanent neonatal diabetes mellitus (PNDM).

Implications:

• Establishes a genotype-phenotype correlation for GCK mutations.
• Highlights the importance of GCK gene sequencing for diagnosing neonatal and young-onset diabetes.
• Informs genetic counseling and potential therapeutic strategies for affected families.