Case Report: A novel likely pathogenic GCK variant in a young Chinese girl with severe insulin resistance

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Abstract
Objective: To report a novel GCK variant (c.263T>C) identified in a patient with glucokinase-maturity-onset diabetes of the young (GCK-MODY) and to evaluate its pathogenicity and potential structural impact using in silico analyses. The proband had a paternal history of type 2 diabetes mellitus (T2DM) and was overweight with marked insulin resistance, presenting with clinical features suggestive of T2DM. She also exhibited transient glutamic acid decarboxylase antibody (GADA) positivity. Clinical characteristics were further evaluated to facilitate the differential diagnosis. Case presentation: A novel GCK missense variant was identified in a Chinese family, with the daughter as the proband. At 6 years of age, she presented with mild fasting hyperglycemia and initial GADA positivity and was misdiagnosed with type 1 diabetes mellitus (T1DM). However, her clinical features and family history were suggestive of MODY. Whole-exome sequencing revealed a heterozygous GCK c.263T>C variant, confirmed by Sanger sequencing in her mother, maternal grandmother, and maternal grandaunt. The variant was classified as likely pathogenic, establishing a diagnosis of GCK-MODY. Notably, she also exhibited obesity and a paternal family history of T2DM. During follow-up, GADA seroconverted to negative, with no evidence of persistent autoimmune diabetes. Conclusion: This case identifies a novel likely pathogenic GCK variant (c.263T>C) in a Chinese family and highlights the coexistence of GCK-MODY with insulin resistance within the same pedigree. The proband’s severe insulin resistance may be attributable to the combined effects of obesity and a paternal history of T2DM, contributing to a complex clinical phenotype. Transient GADA positivity was not associated with persistent autoimmune diabetes, suggesting it may reflect metabolic stress rather than true autoimmune pathogenesis.
Funding Information
  • National Natural Science Foundation of China (82570971, 82170854, 81870579, 81870545)
  • Peking Union Medical College Hospital (2025-PUMCH-C-021, 2022-PUMCH-C-019, UBJ06088)
  • Peking Union Medical College (3332025117, 3332024127)
  • Chinese Academy of Medical Sciences (CIFMS2021-1-I2M-002)
  • Natural Science Foundation of Beijing Municipality (7202163)
  • Beijing Municipal Science and Technology Commission, Adminitrative Commission of Zhongguancun Science Park (Z201100005520011)

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