Maturity-Onset Diabetes of the Young Associated With a Pathogenic ABCC8 Variant: Expanding the Phenotypic Spectrum

Monogenic diabetes results from single-gene sequence variants affecting β-cell function. While ABCC8 sequence variants are linked to congenital hyperinsulinism (CHI) and neonatal diabetes, their role in maturity-onset diabetes of the young (MODY) is less defined. The objective of this report is to describe a patient with MODY caused by a heterozygous ABCC8 c.4613G>A (p.Arg1538Gln) sequence variant, highlighting its phenotypic variability and implications for diagnosis and management.

A 9-year-old boy presented with progressive weight gain and obesity (body mass index 25.25 kg/m², +2.32 SD). Fasting glucose was 94 mg/dL (reference: 70-100 mg/dL). Lifestyle modifications were recommended, but follow-up was not conducted.At age 11, he returned with fatigue and daytime sleepiness. Laboratory results showed a fasting glucose level of 343 mg/dL, a β-hydroxybutyrate level of 1.0 mmol/L (reference: <0.6 mmol/L), and a hemoglobin A1C level of 8% (64 mmol/mol) (reference: <5.7% [<39 mmol/mol]). Diabetes autoantibodies were negative. C-peptide was 0.53 ng/mL (reference: 0.93-3.73 ng/mL), and postprandial insulin was 100.1 μIU/mL (reference: <60 μIU/mL). Insulin therapy was initiated.Genetic testing confirmed a pathogenic ABCC8 c.4613G>A (p.Arg1538Gln) variant. At follow-up, hemoglobin A1C improved to 6% (42 mmol/mol), and fasting glucose was 136.5 mg/dL.

ABCC8 sequence variants exhibit a broad phenotypic spectrum, ranging from CHI to MODY. While the c.4613G>A (p.Arg1538Gln) variant has been previously associated with CHI, this case presents with MODY, highlighting its phenotypic variability.

This case expands the phenotypic spectrum of ABCC8-related diabetes, demonstrating that the c.4613G>A (p.Arg1538Gln) variant can present as MODY without prior CHI. Genetic testing is essential for accurate diagnosis and treatment strategies in monogenic diabetes.