Diabetes mellitus – analysis of gene variants associated with subtypes of Maturity-Onset Diabetes of the Young (MODY)

Background: MODY (Maturity-Onset Diabetes of the Young) is an inherited form of non-insulin dependent diabetes mellitus, caused by a pathogenic gene variant in one of many MODY genes. The purpose of this article is to highlight the importance of functional studies for the evaluation of consequence of such gene variants, for precise diagnosis and personalized treatment of MODY. Material and methods: The article is based on a review of the literature, and the authors’ own research within this field and experience with the patient group. Results: Based on the American College of Medical Genetics and Genomics (ACMG) recommendations concerning the evaluation and classification of gene variants, including functional studies of gene variants, tailored functional assays for MODY gene variants have been developed over the years. Such functional assays include evaluating the effect of gene variants on the ability of MODY proteins to effectively dimerize, bind DNA, transactivate target genes, and localize to the cell nucleus, as well as effect on the MODY protein level. Conclusion: Data gathered from the genetic classification of a MODY gene variant, with data from the functional assays, clinical patient data/family history, and previous reports on gene variant from the literature, have shown to collectively be important in the evaluation of the severity of gene variants, as well as relevant for treatment recommendations. Further research and optimalization of assays will be important for the evaluation of gene variants associated with more subtypes of MODY.