Case Report: A novel 1, 171 bp GCK promoter/exon 1 deletion in a Chinese pedigree: correcting a misdiagnosis of MODY10 based on an incidental INS variant.

Background: Maturity-onset diabetes of the young (MODY) comprises a heterogeneous group of autosomal dominant monogenic diabetes disorders; accurate molecular diagnosis is essential, as different subtypes require fundamentally distinct management strategies. Objective: In a Chinese pedigree initially misdiagnosed as MODY10 based on an incidental INS variant, we aimed to identify the true genetic etiology through comprehensive genetic analysis (including copy number variation [CNV] detection) and continuous glucose monitoring (CGM), and to illustrate the clinical consequences of rigorous variant interpretation. Methods: Detailed clinical evaluation, whole-exome sequencing (WES), whole-genome sequencing (WGS), multiplex ligation-dependent probe amplification (MLPA), segregation analysis, and CGM monitoring were performed across three generations of the pedigree. Results: We identified a 1, 171 bp GCK deletion (chr7:44, 228, 224-44, 229, 394 [GRCh37], encompassing the β-cell promoter, exon 1, and part of intron 1) that co-segregated with diabetes across three generations. This deletion removes the β-cell promoter while leaving the hepatic promoter intact, predicting selective loss of the pancreatic glucokinase isoform. The deletion was classified as pathogenic under ACMG/AMP criteria using the ClinGen Monogenic Diabetes Expert Panel specifications. Segregation analysis revealed that an INS variant (NM_000207.3:c.4G>A, p.Ala2Thr; rs535989053) did not co-segregate with diabetes: it was inherited from the euglycaemic maternal grandfather (fasting glucose 5.0 mmol/L, HbA1c 5.2%) and was absent in the proband. Under ACMG/AMP criteria, the INS variant meets criteria for a benign allele (BS1, BP2). The proband (isolated MODY2) exhibited a characteristic "plateau-like" stable mild hyperglycemia (coefficient of variation [CV] 14.35%). The elder brother, who carries both variants, showed a similar stable pattern (CV 13.41%). The mother, who also carries both variants, had been treated with insulin for ten years under the erroneous MODY10 diagnosis; upon discontinuation of insulin, her glycemic control remained stable, with CGM metrics comparable to those of her children. Conclusion: This case underscores the critical importance of CNV analysis and segregation studies in monogenic diabetes diagnostics. The identification of a large GCK deletion corrected the initial misdiagnosis of MODY10-based on an incidental INS variant-and enabled appropriate genetic counseling and discontinuation of unnecessary insulin therapy. CGM emerges as a valuable ancillary tool for distinguishing MODY2 from MODY10 and for reassuring patients that pharmacological treatment is not required.