The FINNMODY study : clinical characterization of maturity-onset diabetes of the young (MODY) in Finland

The most common form of monogenic diabetes is called Maturity-onset Diabetes of the Young (MODY), which accounts for 1–3% of all cases of diabetes. Initially, MODY was a diagnosis for a familial form of diabetes that occurred in the lean and the young, demonstrated no dependence on exogenous insulin, and followed a dominant pattern of inheritance. Today, the clinical manifestation is more heterogeneous, and MODY has increasingly become a genetic diagnosis. More than 90% of the pathogenic gene variants responsible for MODY reside in GCK, HNF1A, HNF4A, or HNF1B.

Although classical Mendelian diseases involve fully penetrant and distinctive phenotypes, heterogeneity in patients with MODY is pronounced. Even those with the same gene variant manifest with diverse clinical presentations. The characterization of gene–disease associations and heterogeneity in patients with MODY have inspired the three studies included in this thesis.



In Study I, our aim was to systematically assess hepatobiliary and pancreatic manifestations in 14 Finnish patients affected by pathogenic gene variants of HNF1B. The patients underwent magnetic resonance imaging and magnetic resonance cholangiopancreatography. In conclusion, half of the patients (7 of 14) had an anomalous finding of the biliary system, and 6 of them had bile duct cysts (BDCs). Although untreated BDCs have generally been associated with a substantial risk of malignant transformation, it is not known whether the BDCs of genetic origin are similarly premalignant.



In Study II, the aim of the international effort was to establish whether heterozygous protein-truncating variants (PTVs) in RFX6 are a novel genetic aetiology for MODY. Comparing between independent patient and control cohorts, we found that the RFX6 PTVs were enriched among the patients, whose clinical presentation was strongly suggestive of MODY, and among those routinely referred to genetic testing for MODY. In addition, the individuals heterozygous for the RFX6 PTVs demonstrated dysglycaemia and lower levels of serum glucose–dependent insulinotropic polypeptide (a.k.a. gastric inhibitory polypeptide, GIP).



Study III was a multigenerational, longitudinal and cross-sectional family-based characterization study with a specific focus on the clinical and metabolic presentation of HNF1A p.(Gly292fs), the most common pathogenic variant responsible for HNF1A-MODY. The 12 families studied included 145 heterozygous carriers of the variant and their 139 first-degree relatives without the variant. Three of the 12 families were large multigenerational families who have continued their extensive follow-up ever since they were first identified and reported by our group in the 1990s. In conclusion, the carriers were leaner than the non-carriers, and they demonstrated enhanced lipolytic activity. Plasma glucose levels were higher in carriers than in non-carriers throughout the OGTT, and suggestive of insulin deficiency, serum insulin levels were lower in carriers than in noncarriers during the OGTT response. Although most carriers developed diabetes at a young age, one-third remained free of diabetes at 33 years. The polygenic risk score for type 2 diabetes also modified the age at onset of diabetes in patients with HNF1A-MODY.



Studies I–III and numerous previous studies have indicated that patients with MODY are vastly heterogeneous. National efforts, including the studies conducted in Finland, might play a major role due to possible population differences. Personalized tailoring of medical therapy (e.g. a switch from insulin treatment to oral agents) is often possible regardless of the clinical presentation and origin of a patient, but further research is essential to explore individual predictors of the treatment response. Although the response has only rarely been assessed in engineered human cell line models, in vitro studies could provide novel mechanistic insights concerning MODY and other monogenic forms of diabetes.



To summarize, systematic studies on individuals with a pathogenic gene variant can uncover profound heterogeneity associated with monogenic diabetes. These studies provide a valuable source for genetic laboratories to produce high-quality gene reports. Precision medicine in monogenic diabetes is progressively becoming a reality.