Population-Based Assessment of a Biomarker-Based Screening Pathway to Aid Diagnosis of Monogenic Diabetes in Young-Onset Patients

Abstract

OBJECTIVEMonogenic diabetes, a young-onset form of diabetes, is often misdiagnosed as type 1 diabetes, resulting in unnecessary treatment with insulin. A screening approach for monogenic diabetes is needed to accurately select suitable patients for expensive diagnostic genetic testing. We used C-peptide and islet autoantibodies, highly sensitive and specific biomarkers for discriminating type 1 from non-type 1 diabetes, in a biomarker screening pathway for monogenic diabetes. RESEARCH DESIGN AND METHODSWe studied patients diagnosed at age 30 years or younger, currently younger than 50 years, in two U.K. regions with existing high detection of monogenic diabetes. The biomarker screening pathway comprised three stages: 1) assessment of endogenous insulin secretion using urinary C-peptide/creatinine ratio (UCPCR); 2) if UCPCR was ‡0.2 nmol/mmol, measurement of GAD and IA2 islet autoantibodies; and 3) if negative for both autoantibodies, molecular genetic diagnostic testing for 35 monogenic diabetes subtypes. RESULTSA total of 1,407 patients participated (1,365 with no known genetic cause, 34 with monogenic diabetes, and 8 with cystic fibrosis-related diabetes). A total of 386 out of 1,365 (28%) patients had a UCPCR ‡0.2 nmol/mmol, and 216 out of 386 (56%) were negative for GAD and IA2 and underwent molecular genetic testing. Seventeen new cases of monogenic diabetes were diagnosed (8 common Maturity Onset Diabetes of the Young [Sanger sequencing] and 9 rarer causes [next-generation sequencing]) in addition to the 34 known cases (estimated prevalence of 3.6% [51/1,407] [95% CI 2.7-4.7%]). The positive predictive value was 20%, suggesting a 1-in-5 detection rate for the pathway. The negative predictive value was 99.9%. CONCLUSIONSThe biomarker screening pathway for monogenic diabetes is an effective, cheap, and easily implemented approach to systematically screening all young-onset patients. The minimum prevalence of monogenic diabetes is 3.6% of patients diagnosed at age 30 years or younger.

Plasma Fucosylated Glycans and C-Reactive Protein as Biomarkers of HNF1A-MODY in Young Adult–Onset Nonautoimmune Diabetes

“…The MODY calculator could be used to assess 14 of 16 of the probands with damaging MODY variants, and 9 of these had an estimated probability of .20%, thus a sensitivity of 56% for detecting HNF1A-MODY ( Table 2). This is similar to the classic criteria and also to performance in the Using pharmacoge-Netics to Improve Treatment in Earlyonset Diabetes (UNITED) study, where 55% of cases were missed by the calculator (,25% risk) (35). The calculator would also lead to selection of a higher proportion of the cases (37% compared with 22-27%).…”

Phenotype, genotype and glycaemic variability in people with activating mutations in the ABCC8 gene: response to appropriate therapy

“…Making the correct diagnosis and choosing the correct treatment from diagnosis can be challenging for clinicians, but is crucial to prevent long‐term morbidity and mortality . In the UK, MODY accounts for 3.6% of diabetes cases in individuals diagnosed at age <30 years . Factors that raise the suspicion of monogenic diabetes include the diagnosis of diabetes before age 25 years in at least one and ideally two family members, with absence of ketones at presentation , the lack of insulin treatment or the presence of measurable C‐peptide in serum at least 3 to 5 years after diagnosis of early onset diabetes, and the presence of diabetes in one parent (two generations) and ideally a grandparent or child (3 generations).…”

Update of variants identified in the pancreatic β‐cell K ATP channel genes KCNJ11 and ABCC8 in individuals with congenital hyperinsulinism and diabetes

“…Diabetes is the opposing disorder to CHI and results from hyper‐ rather than hypoglycemia. Current estimates suggest that approximately 0.4% of all diabetes (and up to 3.5% of those diagnosed under 30 years of age) has a monogenic cause (Shepherd et al, 2016; Shields et al, 2017). Individuals diagnosed with monogenic diabetes outside of infancy are generally classified as having maturity onset diabetes of the young, whereas neonatal diabetes (NDM) describes congenital diabetes.…”