Who Should Have Genetic Testing for Maturity-onset Diabetes of the Young?

Rochelle Naylor; Louis H. Philipson


Clin Endocrinol. 2011;75(4):422-426. 

In This Article

Abstract and Introduction


Maturity-onset diabetes of the young (MODY) is a clinically heterogeneous group of monogenic disorders characterized by autosomal dominant inheritance of young-onset, non-insulin-dependent diabetes. The genes involved are important in beta cell development, function and regulation and lead to disorders in glucose sensing and insulin secretion. Heterozygous GCK mutations cause impaired glucokinase activity resulting in stable, mild hyperglycaemia that rarely requires treatment. HNF1A mutations cause a progressive insulin secretory defect that is sensitive to sulphonylureas, most often resulting in improved glycaemic control compared with other diabetes treatment. MODY owing to mutations in the HNF4A gene results in a similar phenotype, including sensitivity to sulphonylurea treatment. HNF1B mutations most frequently cause developmental renal disease (particularly renal cysts) but may also cause MODY in isolation or may cause the renal cysts and diabetes syndrome (RCAD syndrome). Mutations in NEUROD1, PDX1 (IPF1), CEL and INS are rare causes of MODY. MODY is often misdiagnosed as type 1 or type 2 diabetes. However, a correct genetic diagnosis impacts treatment and identifies at-risk family members. Thus, it is important to consider a diagnosis of MODY in appropriate individuals and to pursue genetic testing to establish a molecular diagnosis.


Monogenic diabetes, caused by single gene mutations, accounts for approximately 2% of all diabetes cases.[1] The most prevalent phenotype is maturity-onset diabetes of the young (MODY). MODY is characterized by dominant inheritance of early-onset (typically before 25 years of age), non-insulin dependent diabetes. The term MODY describes a heterogeneous group of disorders caused by mutations in genes important to beta cell development, function and regulation, glucose sensing, and in the insulin gene itself. Mutations in at least eight different genes can cause MODY.[2] The expected clinical course, complications and associated extra-pancreatic features vary based upon the underlying molecular genetic defect (Table 1).[3] The majority of MODY cases go undiagnosed owing to frequent misclassification as either type 1 or type 2 diabetes.[4] Correctly identifying MODY has important implications for treatment, surveillance of complications and associated extra-pancreatic disorders, and identification of affected and at-risk family members. Thus, it is important that clinicians appreciate the impact of a correct molecular diagnosis of monogenic diabetes.


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