Systematic Assessment of Etiology in Adults With a Clinical Diagnosis of Young-Onset Type 2 Diabetes Is a Successful Strategy for Identifying Maturity-Onset Diabetes of the Young

Abstract

OBJECTIVEMisdiagnosis of maturity-onset diabetes of the young (MODY) remains widespread, despite the benefits of optimized management. This cross-sectional study examined diagnostic misclassification of MODY in subjects with clinically labeled young adult-onset type 1 and type 2 diabetes by extending genetic testing beyond current guidelines.RESEARCH DESIGN AND METHODSIndividuals were selected for diagnostic sequencing if they displayed features atypical for their diagnostic label. From 247 case subjects with clinically labeled type 1 diabetes, we sequenced hepatocyte nuclear factor 1 α (HNF1A) and hepatocyte nuclear factor 4 α (HNF4A) in 20 with residual β-cell function ≥3 years from diagnosis (random or glucagon-stimulated C-peptide ≥0.2 nmol/L). From 322 with clinically labeled type 2 diabetes, we sequenced HNF1A and HNF4A in 80 with diabetes diagnosed ≤30 years and/or diabetes diagnosed ≤45 years without metabolic syndrome. We also sequenced the glucokinase (GCK) in 40 subjects with mild fasting hyperglycemia.RESULTSIn the type 1 diabetic group, two HNF1A mutations were found (0.8% prevalence). In type 2 diabetic subjects, 10 HNF1A, two HNF4A, and one GCK mutation were identified (4.0%). Only 47% of MODY case subjects identified met current guidelines for diagnostic sequencing. Follow-up revealed a further 12 mutation carriers among relatives. Twenty-seven percent of newly identified MODY subjects changed treatment, all with improved glycemic control (HbA1c 8.8 vs. 7.3% at 3 months; P = 0.02).CONCLUSIONSThe systematic use of widened diagnostic testing criteria doubled the numbers of MODY case subjects identified compared with current clinical practice. The yield was greatest in young adult-onset type 2 diabetes. We recommend that all patients diagnosed before age 30 and with presence of C-peptide at 3 years' duration are considered for molecular diagnostic analysis.

Monogenic diabetes: old and new approaches to diagnosis

“…In our study in Oxford, about one-quarter of the patients diagnosed with MODY had a treatment change as a consequence of their diagnosis. 5 We are also able to give people information about the likely course and prognosis of their diabetes, which is particularly helpful for those with GCK-MODY. Finally, follow up and screening of family members is very important for a monogenic condition, as firstdegree relatives will have a 50% risk of carrying the same mutation and should have diabetes screening with or without genetic testing.…”

“…From the areas of maximum prevalence (about 100 cases per million population), it was calculated that at least 80% of cases are being missed across the UK, 7 and there are long delays averaging >10 years from onset of diabetes until correct molecular diagnosis. 5,7 Misdiagnosis of MODY arises because the phenotype of monogenic diabetes is not sufficiently distinctive to allow easy clinical differentiation from common forms of diabetes. For example, patients tend to be young and lean, as is the case in type 1 diabetes, but do not require insulin and are β-cell antibody negative, as is the case in type 2 diabetes.…”

“…5 We chose characteristic features to distinguish MODY from common forms of diabetes: residual endogenous insulin secretion for at least 3 years after diagnosis in those labelled clinically as having type 1 diabetes and young age of onset and absence of metabolic syndrome in those assumed to have type 2 diabetes. Within these selected groups, 10-20% had MODY, showing that it is possible to select cases on the basis of simple clinical features and achieve reasonable rates of positive tests.…”

Targeted next-generation sequencing reveals MODY in up to 6.5% of antibody-negative diabetes cases listed in the Norwegian Childhood Diabetes Registry

“…A molecular diagnosis of monogenic diabetes is essential for optimal treatment, prognosis and genetic counselling. Patients with MODY caused by a mutation in the HNF1A or HNF4A genes are sensitive to sulfonylurea treatment, which is associated with improved glycaemic control and quality of life [5][6][7][8][9]. Moreover, patients with a mutation in GCK typically do not require pharmacological intervention [10].…”

Developing a framework for implementation of genetic services: learning from examples of testing for monogenic forms of common diseases

“…Genes involved in sudden cardiac death were identified later and clinical cardiogenetic services began to be implemented by early 2000; however, systematic clinical testing and accompanying services are still lacking or not fully effective in many places. Key genes causing monogenic subtypes of diabetes were identified in the late 1990s but only few specialist centers currently aim at detection and follow-up of maturity-onset diabetes of the young (MODY) patients (Thanabalasingham et al 2012).…”