ABCC8 encodes a regulatory subunit of the sulfonylurea receptor 1, or SUR1, which helps control the ATP-sensitive potassium channel in pancreatic beta cells. Pathogenic changes can impair glucose-stimulated insulin secretion, producing disorders that range from neonatal hyperinsulinism, in which excess insulin causes dangerously low blood glucose, to neonatal or youth-onset diabetes. The gene has also proved unusually difficult to interpret. Among nine unrelated families assessed at Beijing Children’s Hospital, three carried variants classified as likely pathogenic and six carried variants of uncertain significance, or VUS. A VUS is a sequence change for which available evidence does not yet establish whether it causes disease.

The cohort illustrates how differently ABCC8-related disease can appear. One 2-year-9-month-old boy carrying the nonsense variant p.Arg248Ter developed neonatal hyperinsulinism, severe perinatal asphyxia, developmental delay, infantile spasms and difficulty chewing. A 9-year-old girl with p.Ala1457Thr had fasting glucose of 16.8 mmol/L and an HbA1c of 11.3%, yet retained measurable C-peptide, a marker of endogenous insulin production, and was treated with insulin before switching to gliclazide. By contrast, a 15-year-old boy carrying p.Gly1255Ser was obese, had acanthosis nigricans, hyperuricemia and dyslipidemia, but also showed preserved C-peptide and satisfactory control with gliclazide 20 mg once daily. Even among likely pathogenic variants, therefore, the phenotypes ranged from a severe neonatal syndrome to subtle adolescent hyperglycemia and an obesity-associated metabolic presentation.

To structure the more difficult VUS cases, the investigators proposed three pillars: whether the patient’s phenotype fits ABCC8-related disease, whether the variant tracks with dysglycemia through a family, and whether functional or treatment-response evidence supports an effect on insulin secretion. The first pillar considered body habitus, C-peptide, islet autoantibodies, ketosis and age at onset. The second required segregation analysis, including careful identification of relatives who carried the variant but had no documented phenotype. The third drew on assays such as minigene splicing experiments and CGM measurements taken before and after treatment changes. Concordant positive evidence was labeled as supporting pathogenicity, concordant negative evidence as refuting it, and conflicting or missing evidence as inconclusive.

The clearest example of support came from a 13-year-old lean girl with the missense variant c.824G>A, or p.Arg275Gln. She was evaluated after asymptomatic hyperglycemia, with a fasting glucose of 6.67 mmol/L, a random glucose of 17.3 mmol/L and an HbA1c of 10.3%. Her C-peptide rose from 0.96 ng/mL when fasting to 4.12 and 4.56 ng/mL after meals, while tests for five types of islet autoantibodies were negative. Across sequential 14-day CGM periods, her time in the target glucose range of 3.9 to 10.0 mmol/L was 75.8% on metformin and 81.7% after metformin was withdrawn, but reached 85.2% when she received gliclazide 20 mg per day. Her mean glucose fell from 8.52 mmol/L on metformin to 6.85 mmol/L on gliclazide. The team treated this therapeutic gradient as orthogonal evidence that the variant mattered, rather than relying on the variant label alone.

That interpretation came with an important limitation. Time below range rose to 5.0% on gliclazide, above the international target of less than 4%, and coefficient of variation increased to 34.6% after metformin withdrawal, indicating greater glucose instability despite a higher time in range. The case therefore did not establish that sulfonylurea treatment was risk-free or that the variant was definitively proven pathogenic. It showed how standardized CGM can expose differences among treatments that might otherwise be obscured by a single HbA1c value. The girl’s mother carried the same variant and had gestational diabetes at 31, and her CGM profile on metformin showed 96.5% time in range.

Not every ABCC8 variant behaved as expected. A 13-year-old lean boy carried the deep-intronic variant c.3651-11C>A. Although the variant was absent from population databases and received supporting evidence for rarity, it remained a VUS, with its ACMG score increasing from zero to one. It was present in his mother, who had insulin-treated gestational diabetes, and in his 61-year-old maternal grandfather, whose glycemic status was not documented. That pattern was not informative enough to establish segregation. A laboratory minigene assay also found identical wild-type and mutant transcripts containing the complete exons 29 through 31, with no exon skipping or activation of a cryptic splice site. Most decisively, his CGM profile showed no time in range on either metformin or gliclazide: mean glucose was 19.05 mmol/L on metformin and 17.00 mmol/L after the switch, while the time in range remained 0%. The investigators therefore judged the evidence to refute pathogenicity for this patient.

The six VUS cases also demonstrated why one variant cannot automatically define one disease in every carrier. The same p.Arg275Gln substitution found in the lean, sulfonylurea-responsive girl also appeared in an obese 11-year-old boy whose fasting insulin was 8.6 μU/mL and whose homeostatic model assessment of insulin resistance was approximately 3.4. He also carried a second ABCC8 VUS inherited from his father. His clinical picture was more consistent with obesity-related insulin resistance than with the pattern observed in Case 1, and his family was managed with metformin and lifestyle measures. The researchers left his classification inconclusive, explicitly contrasting him with the supportive evidence in the other carrier of the same substitution.

Three further variants remained inconclusive. A boy with p.V560M presented at 4 years and 9 months with polyuria, polydipsia, weight loss and ketosis, while his fasting C-peptide was only 40 pmol/L. The variant had a population frequency of 0.0109 and was annotated as benign or likely benign in ClinVar, so the team considered it unlikely to explain the phenotype. In a 14-year-old with p.Ala464Glu, preserved C-peptide and a non-ketotic presentation suggested some ABCC8 compatibility, but a weakly positive glutamic acid decarboxylase antibody and a strong family history of type 2 diabetes created phenocopy risk. A 9-year-old with p.Gln369Arg was lean and had asymptomatic hyperglycemia, a low fasting but preserved meal-stimulated C-peptide response and a borderline antibody result. Her father had type 2 diabetes, and a family-based glimepiride trial was planned before any change in her treatment.

The findings are promising but remain provisional. This was a retrospective, single-center case series, and the cohort was small because ABCC8-related diabetes is rare. Only two families underwent longitudinal CGM across sequential treatment phases; the other seven were recruited through differing clinical routes. Some relatives had not been tested or had incomplete glycemic documentation, and follow-up was short. The investigators did not perform electrophysiological or Rb+/Tl+ flux assays for p.Arg275Gln, while the minigene result for the intronic variant applied only to the conditions tested. The authors also noted that BMI z-scores would need verification against Chinese national growth standards. Prospective, multicenter studies would be needed to validate both the three-pillar framework and a standardized CGM sulfonylurea challenge across larger and more ancestrally diverse populations.

Subject of Research: A retrospective nine-family case series evaluating a three-pillar framework for adjudicating ABCC8 variants of uncertain significance in Chinese youth with dysglycemia.

Article Title: Case Report: ABCC8 variants in Chinese youth: a nine-family case series and a pragmatic three-pillar framework for adjudicating variants of uncertain significance

Article References: Chen, J., Zhang, X., Li, R., Ma, R., Piao, Y., Sang, Y., & Wang, X. (2026). Case Report: ABCC8 variants in Chinese youth: a nine-family case series and a pragmatic three-pillar framework for adjudicating variants of uncertain significance. Frontiers in Endocrinology, 17, Article 1991026. https://doi.org/10.3389/fendo.2026.1991026

Image Credits: AI Generated

DOI: 10.3389/fendo.2026.1991026

Keywords: ABCC8-MODY, youth-onset diabetes, variants of uncertain significance, continuous glucose monitoring, sulfonylurea therapy, monogenic diabetes, genetic diagnosis, beta-cell function, case series, Case, Report, ABCC8