Co-occurrence of Loss-of-Function GCK and ABCC8 Variants in a Pedigree With a Spectrum of Dysglycemia

Glucokinase and ATP-sensitive potassium (KATP) channels in pancreatic β-cells control insulin secretion in response to glucose stimulation to maintain glucose homeostasis. It is well established that loss-of-function (LOF) variants in GCK, which encodes glucokinase, are diabetogenic, whereas LOF variants in KATP channel genes lead to congenital hyperinsulinism (HI) and hypoglycemia. However, how the co-occurrence of GCK and KATP channel variants manifests in glycemic phenotypes is unknown. This study presents a multiplex pedigree with a heterozygous GCK deletion along with a heterozygous ABCC8 variant that results in the E1209K missense variant in the regulatory subunit of the KATP channel sulfonylurea receptor 1 (SUR1). The three-generation pedigree exhibits a complex spectrum of dysglycemia depending on genotype and age at referral. Individuals harboring the heterozygous GCK deletion alone present with maturity-onset diabetes; those harboring the heterozygous ABCC8 E1209K variant alone exhibit HI resulting from the LOF of KATP channels, with some developing diabetes later in life; and those harboring both GCK and ABCC8 variants escape HI but not diabetes. This unique pedigree offers insights into the complex interplay between LOF genetic variants of glucokinase and KATP channels in age-dependent dysglycemia. Article Highlights Genetic variants causing loss of function (LOF) of glucokinase or ATP-sensitive potassium (KATP) channels underlie diabetes or congenital hyperinsulinism, respectively, but how the co-occurrence of such variants affects glucose control is unknown. This study presents genotypes and clinical phenotypes in a pedigree with LOF variants in both GCK and the pancreatic KATP channel. Heterozygous glucokinase deletion masked infantile hyperinsulinemia and hypoglycemia caused by a heterozygous LOF KATP channel variant. Carriers of the LOF KATP variant exhibited a shift from hypoglycemia to diabetes, as has been reported previously in some carriers of KATP LOF variants.