Monogenic diabetes, a form of diabetes that occurs at a young age, is frequently misdiagnosed as type 1 diabetes. This misdiagnosis often leads to unnecessary insulin treatment. To improve diagnostic accuracy and streamline the identification process for monogenic diabetes, a robust screening approach is essential. Such an approach would enable the precise selection of patients who would benefit most from costly genetic testing. This study introduces a biomarker screening pathway for monogenic diabetes, utilizing C-peptide and islet autoantibodies, which are known for their high sensitivity and specificity in differentiating type 1 from non-type 1 diabetes. This method aims to refine diabetes care in 2017 diagnosis and beyond.
In this research, we examined patients diagnosed with diabetes at or before the age of 30 and who were under 50 years of age at the time of the study. The participants were drawn from two regions in the U.K. known for their high rates of monogenic diabetes detection. The biomarker screening pathway was structured in three stages. The first stage involved evaluating endogenous insulin secretion through the urinary C-peptide/creatinine ratio (UCPCR). If the UCPCR was found to be ≥0.2 nmol/mmol, the pathway progressed to the second stage: measuring GAD and IA2 islet autoantibodies. Finally, for patients who tested negative for both autoantibodies, the third stage was molecular genetic diagnostic testing for 35 different subtypes of monogenic diabetes.
Our study included a total of 1,407 patients, comprising 1,365 individuals without a known genetic cause for their diabetes, 34 with confirmed monogenic diabetes, and 8 with cystic fibrosis-related diabetes. Among the 1,365 patients, 386 (28%) exhibited a UCPCR ≥0.2 nmol/mmol. Of these 386 patients, 216 (56%) were negative for both GAD and IA2 autoantibodies and subsequently underwent molecular genetic testing. This testing led to the diagnosis of 17 new cases of monogenic diabetes. These included 8 cases of common Maturity Onset Diabetes of the Young (MODY), identified through Sanger sequencing, and 9 cases of rarer causes, detected using next-generation sequencing. These new diagnoses were in addition to the 34 previously known cases. The estimated prevalence of monogenic diabetes in this cohort was 3.6% (51 out of 1,407 patients) with a 95% confidence interval of 2.7-4.7%. The positive predictive value of this screening pathway was 20%, indicating a 1-in-5 detection rate. The negative predictive value was remarkably high at 99.9%.
In conclusion, the biomarker screening pathway for monogenic diabetes represents an effective, cost-efficient, and easily implementable strategy for the systematic screening of all young-onset diabetes patients. Our findings indicate that the minimum prevalence of monogenic diabetes is 3.6% among patients diagnosed at age 30 years or younger. This pathway offers a significant advancement in diabetes care, particularly in improving diagnostic accuracy and ensuring appropriate treatment strategies are applied from the point of 2017 diagnosis practices onwards.
