A new biomarker screening pathway for diagnosing monogenic diabetes
medwireNews: Researchers have developed a new biomarker screening pathway to systematically screen all patients with young-onset diabetes for monogenic diabetes.
The researchers describe the pathway as “a simple, cheap, effective screening pathway that could be implemented at a population level to help correctly diagnose patients with monogenic diabetes.”
They highlight the importance of such a screening test, given that monogenic diabetes is often misdiagnosed as type 1 diabetes, resulting in individuals undergoing unnecessary insulin therapy.
The study included 1407 participants who were diagnosed with diabetes at the age of 30 years or younger and who were younger than 50 years at enrolment. Of these, 42 had a known genetic cause for their diabetes, with monogenic diabetes confirmed in 34, while eight had cystic fibrosis-related diabetes and 1365 had no known genetic cause for their diabetes.
The 1365 patients with no known genetic cause completed a three-stage screening pathway. Only the 1281 patients receiving insulin treatment underwent the first phase, involving urinary C-peptide/creatinine ratio (UCPCR) assessment to determine endogenous insulin secretion. Of these, 979 had minimal endogenous insulin secretion, based on a cutoff of 0.20 nmol/mmol, and were diagnosed with type 1 diabetes and not screened further.
The 302 patients who tested positive due to a UCPCR of 0.2 nmol/mmol or above and the remaining 84 patients not receiving insulin treatment then entered phase two and were screened for glutamic acid decarboxylase (GAD) and islet antigen-2 (IA2) islet autoantibodies.
A type 1 diabetes diagnosis was confirmed for 170 patients who tested positive for GAD and IA2 antibodies, indicative of islet autoimmunity.
The remaining 216 patients who tested negative for both antibodies entered the third phase of screening, completing molecular genetic diagnostic testing for 35 monogenic diabetes subtypes.
Eight patients received a new diagnosis of monogenic diabetes based on the presence of maturity-onset diabetes of the young (MODY) genes (five HNF1A, two HNF4A, and one GCK), as did nine patients who tested negative for these genes, but positive for genes associated with monogenic diabetes on targeted next-generation sequencing.
Andrew Hattersley (University of Exeter Medical School and Royal Devon and Exeter NHS Foundation Trust, UK) and the UNITED study researchers therefore identified 17 new cases of monogenic diabetes using the pathway, which is described in full in Diabetes Care.
The pathway was found to have 85% specificity. The positive predictive value was 20%, suggesting a one-in-five detection rate, while the negative predictive value was 99.9%. This extremely high negative predictive value “indicates [this] is an extremely effective approach for ruling out monogenic diabetes,” say the researchers.
And a separate health economic evaluation of the pathway for detecting the three common forms of MODY has been carried out as a separate project, and has shown the pathway to be cost-saving.
The strength of the pathway, say the researchers, “is the integration of two biomarkers (C-peptide and islet autoantibodies [both GAD and IA2]), rather than relying on clinical features.”
They explain: “This offers a simple approach that does not require specific clinician interpretation or complex algorithms of different combinations of features.”
By Catherine Booth
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