An Asian monogenic diabetes registry: prevalence, long-term renal trajectory and development of a diagnostic algorithm for selection of candidates for genetic testing.

Introduction: Through the National Healthcare Group-Khoo Teck Puat Hospital Monogenic Diabetes Registry, we aimed to determine the prevalence and spectrum of maturity-onset diabetes of the young (MODY), describe the long-term renal trajectory of major MODY subtypes, and develop a diagnostic algorithm based on a combination of clinical parameters and biomarkers to refine selection of candidates for genetic testing.

Methods: A total of 373 study participants attending secondary care diabetes centres in Singapore were referred for genetic testing. Key inclusion criteria for genetic testing included onset age ≤35 years, body mass index <32.5 kg/m2 and absence of glutamic acid decarboxylase autoantibody.

Results: Analysis of 16 genes and one mitochondrial variant led to a molecular diagnosis in 49 participants, with pathogenic variants present mostly in HNF1A (29%), HNF4A (23%) and GCK (15%). Long-term renal trajectory data observed between these major MODY subtypes were not significantly different, but some key observations were typical for each subgroup. For instance, patients with HNF4A-MODY were predisposed to the risk of microvascular complications (i.e., diabetic kidney disease), while patients with GCK-MODY had mild and non-progressive hyperglycaemia. A structured diagnostic algorithm, including readily available biomarkers such as high-sensitive C-reactive protein (hs-CRP) and high-density lipoprotein-cholesterol (HDL-c), provided 71% diagnostic accuracy, achieving a negative predictive value of 0.94 and a sensitivity of 0.68.

Conclusion: The prevalence of MODY (13%) is non-trivial among young-onset diabetes referred for genetic testing based on clinical classifiers suggestive of MODY. Current clinical assessment tools may include hs-CRP and HDL-c to refine selection of candidates for genetic testing.