Revealing Monogenic Diabetes: Clinical and Genetic Features of Pediatric MODY Cases in Türkiye: Single Center...

Maturity-onset diabetes of the young (MODY) represents a genetically and clinically heterogeneous form of monogenic diabetes caused by defects in pancreatic β-cell function. Accurate molecular diagnosis is essential for distinguishing MODY from type 1 and type 2 diabetes, enabling precision-based management and targeted therapy. This study aimed to evaluate the genetic and clinical features of pediatric patients with MODY, to assess the prevalence of common and rare subtypes, and to report novel pathogenic variants identified in a Turkish cohort.

This single-center, retrospective cohort study evaluated 81 pediatric patients with suspected MODY followed between 2022 and 2025. Genetic analysis was performed using targeted next-generation sequencing (NGS) panels, including HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, INS, ABCC8, KCNJ11, APPL1, and CEL. Patients were selected based on the presence of at least two clinical features suggestive of MODY, as defined by the 2022 International Society for Pediatric and Adolescent Diabetes (ISPAD) Clinical Practice Consensus Guidelines. Demographic, biochemical, and clinical data were extracted from hospital records and analyzed descriptively.

Genetic variants were identified in 25 of 81 patients (30.9%), including pathogenic, likely pathogenic, and variants of uncertain significance (VUS). Of these, 22 variants were classified as pathogenic or likely pathogenic, corresponding to a diagnostic yield of 27.2%. The most frequently affected gene was GCK (72.0%), followed by HNF1A (8.0%), with single cases identified in HNF1B, INS, PDX1, CEL, and KCNJ11. Rare MODY subtypes collectively accounted for 20.0%. Three novel GCK variants c.1055T >C, c.1229A >C, and c.185_186insA were identified. One patient with syndromic features harbored a heterozygous 17q12 microdeletion encompassing HNF1B, approximately 1.5 Mb in size, and presented with global developmental delay, intellectual disability, epilepsy, dysmorphic facial features, persistent hypomagnesemia, and a bicornuate uterus with normal renal structure. Following genetic analysis, two patients had therapy adjustments based on the identified variants.

This study underscores the clinical and genetic heterogeneity of MODY in the pediatric population and reinforces the value of comprehensive NGS panels for accurate diagnosis, even in patients who do not fully meet classical MODY criteria. The identification of novel GCK variants and the detection of rare subtypes further expand the mutational and phenotypic spectrum of pediatric monogenic diabetes. These findings highlight the importance of incorporating population-specific genomic data into clinical practice and of periodically re-evaluating gene-disease associations as new molecular and functional evidence emerges. Ultimately, the integration of molecular diagnostics into routine pediatric diabetes care will enhance diagnostic yield, optimize management, and improve long-term outcomes for affected families.