MODY

Abstract

Maturity-Onset Diabetes of the Young (MODY) is the most common form of monogenic diabetes, accounting for approximately 1–5% of all diabetes cases. Despite remarkable advances in molecular genetics, MODY remains substantially underdiagnosed, with more than half of affected individuals estimated to be either undiagnosed or misclassified as having type 1 or type 2 diabetes. In recent years, the implementation of next-generation sequencing (NGS), the identification of novel diabetes-associated genes, and a deeper understanding of phenotypic heterogeneity have profoundly changed the diagnostic paradigm.

Clinical suspicion remains the cornerstone of MODY diagnosis, although traditional diagnostic criteria have evolved considerably. While early-onset diabetes, an autosomal dominant family history, absence of pancreatic autoimmunity, and preserved endogenous insulin secretion continue to be key diagnostic features, it is now recognized that incomplete penetrance, variable expressivity, obesity, and insulin resistance may obscure the diagnosis. Consequently, integrating clinical, biochemical, immunological, and genetic data has become essential to optimize patient selection for molecular testing and improve diagnostic accuracy.

Genetic testing has evolved from a confirmatory tool into a key component of clinical decision-making. Identifying the underlying genetic defect enables gene-specific treatment selection, prevents unnecessary therapies, improves prognostic assessment, identifies extrapancreatic manifestations, and facilitates genetic counseling and cascade screening of family members. Individuals with GCK variants generally do not require pharmacological treatment, whereas patients with HNF1A or HNF4A variants typically exhibit marked sensitivity to sulfonylureas. In contrast, HNF1B-related diabetes frequently requires comprehensive evaluation because of its associated renal and multisystem involvement. Furthermore, the continuous discovery of novel monogenic diabetes genes and the ongoing reinterpretation of genetic variants present new challenges for clinical practice.

This lecture will review current evidence regarding when to suspect MODY, which patients should undergo genetic testing, how molecular findings should be interpreted, and how precision medicine is transforming the diagnosis, treatment, and long-term management of individuals with monogenic diabetes. Finally, current barriers to genetic testing in Latin America and future opportunities to implement more effective screening and diagnostic strategies in routine clinical practice will be discussed.