Monogenic diabetes is a rare form of diabetes which results from pathogenic/likely pathogenic variants (P/LP) in a single gene. Monogenic diabetes can be subdivided into three main groups: neonatal diabetes, maturity onset diabetes of the young (MODY) and syndromic diabetes (Zhang et al., 2021).

MODY is a rare, monogenic form of diabetes inherited in an autosomal dominant fashion. It is typically characterized by onset prior to 25 years of age and diabetes that does not always require insulin treatment. In addition, insulin levels can often be in the normal range and obesity is rarely associated. The incidence of MODY is approximately 1% to 4% of the diabetic population, and affected individuals are often misdiagnosed as having type I or type II diabetes (Rubio-Cabezas et al., 2014). It has been suggested that up to 2% of individuals diagnosed with early-onset type II diabetes may in fact have a monogenic cause (Bansel et al., 2017). It is important to distinguish MODY cases from other types of diabetes, given that the specific genetic change can impact ideal treatment strategy. In addition, people with MODY do not require regular screening for autoimmune conditions as is standard for those with type 1 diabetes (Johnson et al., 2018).

Several causative genes for MODY have been identified, with clinical presentation varying depending on underlying genetic etiology. HNF1A, GCK, and HNF4A are the most prevalent genes, accounting for more than 80% of all diagnoses. P/LP variants in the GCK gene cause mild, stable hyperglycemia that does not progress and typically does not require treatment (McDonald and Ellard, 2013; Firdous et al., 2018; American Diabetes Association Professional Practice Committee, 2025). P/LP variants in HNF1A and HNF4A, which provide code for transcription factor proteins, result in a progressive insulin secretory error and hyperglycemia that can cause vascular problems. While insulin treatment may be required in later life, sulphonylurea tablets often successfully control diabetes in individuals with this diagnosis (McDonald and Ellard, 2013; Kim, 2015). Less common causes of MODY include P/LP variants in ABCC8, APPL1, CEL, HNF1B, INS, KCNJ11, NEUROD1, and PDX1 (Greeley et al., 2022; Johnson et al., 2018; Bansal et al., 2017; Pollin et al., 2019). 

Neonatal diabetes is defined as diabetes diagnosed prior to age 6 months and can be permanent or transient. Approximately 80-85% of cases of neonatal diabetes have an underlying monogenic cause (American Diabetes Association Professional Practice Committee, 2025). Activating P/LP variants in KCNJ11 or ABCC8 are common causes of neonatal diabetes. Diabetes related to P/LP variants in these genes have important treatment implications as they can be managed well with oral sulfonylureas rather than insulin therapy (Letourneau and Greeley, 2018). Other causes of neonatal diabetes include imprinting anomalies at chromosome 6q24, as well P/LP variants in INS, GATA6, EIF2AK3, EIF2B1, and FOXP3, among others (Greeley et al., 2022; American Diabetes Association Professional Practice Committee, 2025).

Diabetes may also be a feature of certain rare genetic syndromes. A syndromic form of diabetes should be considered in individuals with diabetes and extra-pancreatic features such as deafness, congenital anomalies, immune problems, or renal involvement (Greeley et al., 2022; Maloney et al., 2023). When a syndromic form of monogenic diabetes is suspected, testing should be targeted to the condition highest on the differential, whenever possible. If targeted testing is not feasible, a broad panel approach could also be considered (Greeley et al., 2022; Maloney et al., 2023).

Given the impact of an accurate monogenic diabetes diagnosis on subsequent treatment and management, genetic testing is appropriate for suspicious patients. Multiple groups have published guidelines for determining the best candidates for genetic testing. The International Society for Pediatric and Adolescent Diabetes (ISPAD) Consensus Guidelines state that a diagnosis of type 1 diabetes prior to age 6 months is extremely rare, should prompt immediate testing for monogenic causes (Greeley et al., 2022). Additionally, when the accuracy of a type I or II diabetes diagnosis is in question, and a diagnosis of monogenic diabetes is suspected, genetic testing should also be considered (Greeley et al., 2022). The American Diabetes Association has included recommendations for genetic testing for monogenic diabetes as part of their “Standards of Care in Diabetes” (American Diabetes Association Professional Practice Committee, 2025). These guidelines recommend genetic testing for all individuals with diabetes diagnosed in the first 6 months of life, and for children/young adults who do not have the typical characteristics of type 1 or type 2 diabetes and who often have a family history of autosomal dominant diabetes. The guidelines also make recommendations for testing based on certain blood chemistry (ex. hemoglobin A1C levels and glucose levels) especially in the absence of obesity (American Diabetes Association Professional Practice Committee, 2025). Finally, the National Society of Genetic Counselors have issued a practice resource suggesting that genetic testing should be considered as part of the etiological workup for individuals exhibiting clinical features consistent with monogenic diabetes (Maloney et al., 2023).