{
  "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.\n\nMethods: 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.\n\nResults: 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).\n\nConclusion: 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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Endocrinology, Genetics, and Metabolism, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health",
    "School of Medicine, Tsinghua University",
    "Peking Union Medical College Hospital",
    "Department of Endocrinology, Baoding Children’s Hospital",
    "Department of Rheumatology and Immunology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health",
    "Department of General Surgery, Peking Union Medical College Hospital",
    "State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Jiahui Chen"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Xingwu Zhang"
    },
    {
      "affs": [
        3
      ],
      "name": "Rongmin Li"
    },
    {
      "affs": [
        0
      ],
      "name": "Rui Ma"
    },
    {
      "affs": [
        4
      ],
      "name": "Yurong Piao"
    },
    {
      "affs": [
        0
      ],
      "name": "Yanmei Sang"
    },
    {
      "affs": [
        5,
        6
      ],
      "name": "Xianze Wang"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/fdn5t7rq70xds.bib",
  "cited_by": 0,
  "doi": "10.3389/fendo.2026.1991026",
  "fulltext_url": null,
  "id": "fdn5t7rq70xds",
  "issns": [
    "1664-2392"
  ],
  "landing_url": "https://www.frontiersin.org/articles/10.3389/fendo.2026.1991026/full",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1311|Genomics and Rare Diseases"
    ]
  ],
  "openalex": "W7223050034",
  "pdf_url": "https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2026.1991026/pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-20",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/fdn5t7rq70xds.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:20Z",
      "native_id": "10.3389/fendo.2026.1991026",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fendo.2026.1991026/full"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:1311|Genomics and Rare Diseases",
      "subfield": "genetics-genomics"
    }
  ],
  "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",
  "title_text": "Case Report: ABCC8 variants in Chinese youth: a nine-family case series and a pragmatic three-pillar framework for adjudicating variants of uncertain significance",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:20:20Z",
  "url": "https://research.draconitic.com/paper/fdn5t7rq70xds",
  "venue": "Frontiers in Endocrinology",
  "versions": []
}