Efficacy of Biomarker Screening Pathway in Monogenic Diabetes Diagnosis

pediatric blood test
pediatric blood test
Patients with assumed monogenic diabetes were examined using a novel 3-part biomarker screening pathway to detect incorrectly diagnosed cases of type 1 diabetes.

A 3-part biomarker screening pathway is safe, effective, and affordable for diagnosing monogenic diabetes in young-onset patients, according to research published in Diabetes Care.

“Monogenic diabetes, a young-onset form of diabetes, is often misdiagnosed as type 1 diabetes, resulting in unnecessary treatment with insulin,” wrote Andrew T. Hattersley, FRCP, FMedSci, FRS, from the Institute of Biomedical and Clinical Science at the University of Exeter Medical School and the National Institute for Health Research Exeter Clinical Research Facility at the Royal Devon and Exeter National Health System Foundation Trust in the United Kingdom, and colleagues. “A screening approach for monogenic diabetes is needed to accurately select suitable patients for expensive diagnostic genetic testing.”

Study investigators examined a group of patients (n=1407) diagnosed with monogenic diabetes before 30 years of age; 1365 patients had no known genetic cause for their condition, 34 patients had confirmed monogenic diabetes, and 8 patients had cystic fibrosis-related diabetes. Using a 3-part biomarker screening pathway, researchers assessed the sensitivity of each pathway component to determine its efficacy. 

The 3-part biomarker screening pathway is as follows:

  1. Assessment of endogenous insulin secretion, using urinary C-peptide/creatinine ratio (UCPCR);
  2. If UCPCR is ≥0.2 nmol/mmoL, measurement of glutamic acid decarboxylase (GAD) and islet antigen 2 (IA2) autoantibodies is taken; and
  3. If the patient is negative for both antibodies, molecular genetic diagnostic testing is performed for 35 monogenic diabetes subtypes. 

More than 1200 (n=1281; 94%) patients with no known genetic cause who were treated with insulin provided a sample for UCPCR testing. In total, 76% had minimal endogenous insulin secretion (UCPCR <0.2 nmol/mmoL) indicative of type 1 diabetes. These patients required no further testing.

IA2 and GAD autoantibodies were tested in a further 84 patients who were not treated with insulin, as well as 300 patients who tested positive for UCPCR and 2 patients with anuria. In total, 44% of patients tested positive for GAD and/or IA2 autoantibodies. These results also confirmed type 1 diabetes, requiring no further testing.

In 16% of the cohort, researchers performed Sanger sequencing for the 3 most common MODY (Maturity Onset Diabetes of the Young) genes; 8 patients tested positive (5 for hepatic nuclear factor 1 alpha [HNF1A], 2 for hepatic nuclear factor 4 alpha [HNF4A], and 1 for glucokinase [GCK]). These patients required no further testing.

Negative test results for MODY genes were identified in 208 patients requiring additional testing via targeted, next-generation sequencing. Mutations associated with monogenic diabetes were identified in 8 patients. POLD1 mutations were found in 9 patients, a “rarer” cause of monogenic diabetes, identified via next-generation exome sequencing.

When combined with the 34 previously known cases of monogenic diabetes, estimated disease prevalence was 3.6% (95% CI, 2.7%-4.7%). Positive predictive value for the sequencing pathway was 20% (a 1-in-5 detection rate), and negative predictive value was 99.9%.

“The biomarker screening pathway for monogenic diabetes is a systematic, cheap…and easily implemented approach to screening all patients with young-onset diabetes,” the researchers wrote. “The pathway picked up new cases of monogenic diabetes, even in areas of existing high detection…. In areas in which no cases have been identified, we estimate that 1 in 5 patients referred for genetic testing because of the pathway will have monogenic diabetes, which is a 5.6-fold higher detection rate than if all patients…received genetic testing.”

“Further studies are needed to determine whether the pickup rate could be further improved by integrating the pathway with clinical features…or whether this would result in more missed patients because of reduced testing,” they concluded. 

Study Limitations

  • Only a small number of patients with monogenic diabetes were available to evaluate the pathway sensitivity.
  • Despite C-peptide and antibody screening, positive predictive value is still low, at 20%.
  • The study population was 98% white, and patients were assessed a median of 14 years after their diagnosis; results may not be generalizable to other groups, and further study in other racial groups and in patients closer to diagnosis age is needed. 

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Shields BM, Shepherd M, Hudson M, et al; on behalf of the UNITED study team. Population-based assessment of a biomarker-based screening pathway to aid diagnosis of monogenic diabetes in young-onset patients [published online July 12, 2017]. Diabetes Care. doi: 10.2337/dc17-0224