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Peer-reviewedCC BY 4.0Frontiers in Endocrinology

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

  • Jiahui Chen1
  • Xingwu Zhang2,3
  • Rongmin Li4
  • Rui Ma1
  • Yurong Piao5
  • Yanmei Sang1
  • Xianze Wang6,7
7 affiliations
  1. 1Department of Endocrinology, Genetics, and Metabolism, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health
  2. 2School of Medicine, Tsinghua University
  3. 3Peking Union Medical College Hospital
  4. 4Department of Endocrinology, Baoding Children’s Hospital
  5. 5Department of Rheumatology and Immunology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health
  6. 6Department of General Surgery, Peking Union Medical College Hospital
  7. 7State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital
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Abstract

Background: ABCC8-maturity-onset diabetes of the young (ABCC8-MODY) is a rare monogenic diabetes with elusive genotype–phenotype correlations and frequent misdiagnosis as type 1 or type 2 diabetes. Adjudicating ABCC8 variants of uncertain significance (VUS) remains a major clinical challenge, particularly in youth.

Methods: We conducted a single-center retrospective case series of nine unrelated Chinese families with ABCC8 variants (nine probands; none previously reported). Inclusion required dysglycemia before 18 years, an ABCC8 variant identified by whole-exome sequencing (WES), and detailed clinical records. Two families (Cases 1 and 2) underwent deeper phenotyping with continuous glucose monitoring (CGM) across sequential treatment phases, Sanger segregation, and, for the intronic variant of Case 2, a minigene splicing assay. We defined and applied a pragmatic three-pillar framework for VUS adjudication: (i) phenotype congruence, (ii) familial segregation, and (iii) functional–pharmacological evidence.

Results: Three families carried likely pathogenic (LP) variants (p.Arg248Ter, p.Ala1457Thr, p.Gly1255Ser) with coherent phenotypes ranging from neonatal hyperinsulinism with neurodevelopmental sequelae to sulfonylurea-responsive youth-onset diabetes. Six families carried VUS with marked heterogeneity. In Case 1 (c.824G>A, p.Arg275Gln; ACMG score 2), a lean phenotype, preserved C-peptide, negative islet autoantibodies, and a CGM-documented response to gliclazide (time-in-range [TIR] 85.2% vs 75.8% on metformin) supported pathogenicity. In Case 2 (c.3651-11C>A; score 1 after adding PM2_supporting), a splicing-neutral minigene assay, a non-informative segregation pattern (a variant-carrying 61-year-old maternal grandfather without a documented diabetic phenotype), and absent glycemic response to gliclazide (TIR 0.0%) argued against pathogenicity. The evidence matrix classified two VUS as supported (Case 1), one as refuted (Case 2), and three as inconclusive (Cases 5, 8, 9).

Conclusion: This nine-family case series illustrates that ABCC8 VUS interpretation requires an integrative strategy combining phenotype, segregation, functional data, and CGM-derived treatment response. The proposed three-pillar framework provides a practical structure for this adjudication and may reduce misdiagnosis and guide precision therapy in youth-onset monogenic diabetes.

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Cite

BibTeXRIS
BibTeX
@article{chen2026case,
  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}},
  author = {Jiahui Chen and Xingwu Zhang and Rongmin Li and Rui Ma and Yurong Piao and Yanmei Sang and Xianze Wang},
  journal = {Frontiers in Endocrinology},
  year = {2026},
  month = oct,
  doi = {10.3389/fendo.2026.1991026},
  url = {https://www.frontiersin.org/articles/10.3389/fendo.2026.1991026/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Case Report: ABCC8 variants in Chinese youth: a nine-family case series and a pragmatic three-pillar framework for adjudicating variants of uncertain significance
AU  - Jiahui Chen
AU  - Xingwu Zhang
AU  - Rongmin Li
AU  - Rui Ma
AU  - Yurong Piao
AU  - Yanmei Sang
AU  - Xianze Wang
PY  - 2026
DA  - 2026/10/20
JO  - Frontiers in Endocrinology
DO  - 10.3389/fendo.2026.1991026
UR  - https://www.frontiersin.org/articles/10.3389/fendo.2026.1991026/full
AB  - Background: ABCC8-maturity-onset diabetes of the young (ABCC8-MODY) is a rare monogenic diabetes with elusive genotype–phenotype correlations and frequent misdiagnosis as type 1 or type 2 diabetes. Adjudicating ABCC8 variants of uncertain significance (VUS) remains a major clinical challenge, particularly in youth.  Methods: We conducted a single-center retrospective case series of nine unrelated Chinese families with ABCC8 variants (nine probands; none previously reported). Inclusion required dysglycemia before 18 years, an ABCC8 variant identified by whole-exome sequencing (WES), and detailed clinical records. Two families (Cases 1 and 2) underwent deeper phenotyping with continuous glucose monitoring (CGM) across sequential treatment phases, Sanger segregation, and, for the intronic variant of Case 2, a minigene splicing assay. We defined and applied a pragmatic three-pillar framework for VUS adjudication: (i) phenotype congruence, (ii) familial segregation, and (iii) functional–pharmacological evidence.  Results: Three families carried likely pathogenic (LP) variants (p.Arg248Ter, p.Ala1457Thr, p.Gly1255Ser) with coherent phenotypes ranging from neonatal hyperinsulinism with neurodevelopmental sequelae to sulfonylurea-responsive youth-onset diabetes. Six families carried VUS with marked heterogeneity. In Case 1 (c.824G>A, p.Arg275Gln; ACMG score 2), a lean phenotype, preserved C-peptide, negative islet autoantibodies, and a CGM-documented response to gliclazide (time-in-range [TIR] 85.2% vs 75.8% on metformin) supported pathogenicity. In Case 2 (c.3651-11C>A; score 1 after adding PM2_supporting), a splicing-neutral minigene assay, a non-informative segregation pattern (a variant-carrying 61-year-old maternal grandfather without a documented diabetic phenotype), and absent glycemic response to gliclazide (TIR 0.0%) argued against pathogenicity. The evidence matrix classified two VUS as supported (Case 1), one as refuted (Case 2), and three as inconclusive (Cases 5, 8, 9).  Conclusion: This nine-family case series illustrates that ABCC8 VUS interpretation requires an integrative strategy combining phenotype, segregation, functional data, and CGM-derived treatment response. The proposed three-pillar framework provides a practical structure for this adjudication and may reduce misdiagnosis and guide precision therapy in youth-onset monogenic diabetes.
SN  - 1664-2392
ER  -