The Clinical Spectrum and Significance of ABCC8 Gene Variants in the Diagnosis of Monogenic Diabetes

Abstract

Background: ABCC8 gene variants have been linked to a range of conditions that affect insulin secretion, such as congenital hyperinsulinism, neonatal diabetes and maturity-onset diabetes of the young (MODY). This study aimed to characterise ABCC8 variants and to assess their relationship with clinical phenotypes and family segregation. Methods: Between 2017 and May 2026, tNGS (targeted next-generation sequencing) analysis was performed on the DNA of 1202 patients who were referred for suspected monogenic diabetes. The exons and flanking intronic regions of the ABCC8 gene were assessed for single nucleotide variants (SNVs) and small insertions and deletions (indels). Rare variants were prioritised based on population frequency, in silico predictions and clinical classification. Selected variants were confirmed, and segregation analysis was performed using Sanger sequencing. Results: We identified five patients carrying pathogenic or likely pathogenic ABCC8 variants. A frameshift ABCC8 variant had not been previously reported. All patients had diabetes, with some also presenting with a history of hypoglycaemia. Family studies also revealed intra-familial variability and enabled the identification of previously unrecognized affected relatives. Conclusions: Our findings support the broad clinical spectrum associated with ABCC8 variants and highlight the importance of family segregation analysis. Comprehensive molecular and clinical evaluation may improve the detection of patients with ABCC8-related diabetes and distinguish this condition from other forms of monogenic diabetes.