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

Abstract

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.