What question did this study set out to answer?

To report the first instance of the GCK c.781G>A variant presenting as neonatal hyperinsulinaemic hypoglycaemia.

May 21, 2026QJM0 citations

A Novel Phenotype of GCK c.781GA Variant Causing Neonatal Refractory Hyperinsulinaemic Hypoglycaemia

Key Points

To report the first instance of the GCK c.781G>A variant presenting as neonatal hyperinsulinaemic hypoglycaemia.
Genetic analysis identified a heterozygous GCK c.781G>A variant.
Protein modelling confirmed a gain-of-function effect.
The infant was treated with diazoxide and monitored post-discharge.
The infant exhibited severe refractory neonatal hypoglycaemia with elevated insulin levels.
Successful management with diazoxide led to discontinuation of treatment two weeks after discharge.
This case expands the phenotypic spectrum of the GCK c.781G>A variant.

Abstract

Abstract Glucokinase (GCK) mutations are well-known causes of maturity-onset diabetes of the young type 2 (MODY2) and hyperinsulinaemic hypoglycaemia type 3 (HH3). The GCK c.781GA (p.Gly261Arg) variant has been exclusively reported in MODY2. We describe a term male infant with severe refractory neonatal hypoglycaemia and inappropriately elevated insulin. Genetic analysis identified a heterozygous GCK c.781GA variant inherited from his father. Protein modelling supported a gain-of-function effect. The infant responded well to diazoxide and discontinued treatment two weeks after discharge. This is the first report of GCK c.781GA presenting as neonatal HH3, expanding the known phenotypic spectrum of this variant.

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