GCK Mutation Analysis and Clinical Profiles of Chinese Pediatric Patients with MODY2: Insights into Screening and Diagnosis

Chang Su,1,* Yurong Piao,2,* Congli Chen,1 Yuqi Miao,1 Di Wu,1 Yanmei Sang1 1Department of Pediatric Endocrinology, Genetic and Metabolism, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China; 2Department of Rheumatology and Immunology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China*These authors contributed equally to this workCorrespondence: Yanmei Sang, Email [email protected]: To investigate the clinical and genetic features of maturity onset diabetes of the young type 2 (MODY 2) in Chinese pediatric patients and optimize the screening strategy.Methods: A total of 11 Chinese pediatric patients diagnosed with MODY2 were enrolled in this study. Detailed clinical data and follow-up outcomes were retrospectively collected and summarized. Genetic testing was conducted using next-generation sequencing (NGS), and all identified variations were verified by Sanger sequencing.Results: All cases carried heterozygous mutations in the GCK gene. 9 pathogenic variations were identified, including 8 missense mutations, 1 frameshift mutation, and 1 splice-site mutation. Among these, the mutation c.456T>G was novel. The mean age at diagnosis was 8.1± 2.7 (years). 10 of 11 cases had a family history of hyperglycemia or diabetes. 2 cases were overweight. Patients exhibited mild hyperglycemia. The median HbA1c was 6.3% (interquartile range [IQR]: 6.3%– 6.4%). Glucose increment in OGTT was 1.68± 0.95 mmol/L. Mean triglyceride level was 0.62± 0.15 mmol/L. Two cases were positive for insulin antibodies. All cases were treated with a balanced diet after diagnosis. The follow-up period was 1.5– 7 years, and the median HbA1c was 6.3% (IQR: 6.2%– 6.4%).Conclusion: MODY2 typically manifests with mild, stable fasting hyperglycemia and is predominantly caused by missense mutations in the GCK gene. Our findings support the inclusion of triglyceride levels as a screening marker and highlight that features like overweight status and autoantibody positivity may coexist in MODY2, warranting comprehensive evaluation to prevent misdiagnosis.Keywords: maturity onset diabetes of the young type 2, monogenic diabetes, GCK gene, gene mutation