Molecular and clinical profiles of pediatric monogenic diabetes subtypes: comprehensive genetic analysis of 138 patients

Abstract Background Single gene variants that give rise to neonatal diabetes mellitus (NDM), maturity onset diabetes of the young (MODY), and syndromic forms of diabetes mellitus (SDM) are responsible for 3.1% to 4.2% of all diabetes cases. This single-center study with a relatively larger sample size aimed to evaluate the clinical and genetic characteristics of Chinese children with suspected monogenic diabetes (MD) using next-generation sequencing (NGS) methods. Materials and Methods Data were collected from 1550 consecutive children diagnosed with diabetes/hyperglycemia at the Endocrinology Department of Children's Hospital of Nanjing Medical University from 2012 to 2023. The genotype and phenotype of 138 children with suspected MD were retrospectively analyzed. Results Among 138 children, 16, 97, and 25 patients with NDM, suspected MODY, and SDM, respectively, were assessed by NGS, with a pick-up rate of 87.5%, 57.8%, and 56%, respectively. In total, there was a high pick-up rate of MD, with 58% (80 of 138) among antibody-negative pediatric patients. Pathogenic variants were found in GCK, HNF1A, INS, KCNJ11, INSR, HNF4A, ABCC8, WFS1, ALMS1, HNF1B, BLK, and ZFP57 genes with 13 novel variants in addition to 4 patients with copy number variants. In this cohort, GCK-MODY was the leading cause and the mildest type of MODY. GCK-MODY displayed favorable lipid profile when compared to non-GCK-MODY and MODYX, which might be cardioprotective. Following an accurate genetic diagnosis of diabetes, 19 patients switched from insulin therapy to oral agents or lifestyle interventions. Conclusion NGS tests helped to identify the precise etiology of monogenic diabetic patients, which has implications for better individualized management.