Introduction: Monogenic diabetes (also known as maturity-onset diabetes of the young or MODY) is a rare genetic disorder with an undetermined prevalence in Singapore. The NHG-KTPH Monogenic Diabetes Registry was set up in mid-2017 to capture longitudinal data of individuals genetically diagnosed with monogenic diabetes to study their prevalence and disease trajectories.
Methods: Patients with clinical phenotype suggestive of monogenic diabetes i.e., diabetes onset =<45 years old, BMI <32.5 kg/m2 and GAD autoantibody-negative were recruited and subjected to genetic testing comprising of next-generation 16-MODY gene panel sequencing, mt.3242A>G TaqMan genotyping and multiplex ligation-dependent probe amplification (MLPA) for 4 common MODY genes. Genetic variants annotated as likely pathogenic/pathogenic according to ACMG guidelines were validated using Sanger sequencing. Individuals with such variant(s) were included in the Registry. EQ-5D-5L instrument was also administered for quality of life assessment.
Results: Among 171 patients who were subjected to MODY genetic testing, 26 (15%) were found to harbor likely pathogenic/pathogenic variants. 93% of these variants were found in common MODY genes (HNF1A, HNF4A, GCK, HNF1B, MT-TL1) that had important clinical implications. Biomarkers such as C-peptide, hs-CRP and HDL were significantly different in those with likely pathogenic/pathogenic variants than those without.
Discussion: Monogenic diabetes is present in 15% of our study participants with young-onset diabetes, which is greater than the reported 5% in UK. Clinical demographics and biomarkers can be further evaluated to improve the pick-up rate of monogenic diabetes among young-onset diabetes, with specific calibration applied to different subtypes of monogenic diabetes. This will improve cost-effectiveness of genetic testing and facilitate implementation of precision medicine for individuals with monogenic diabetes.
S. Ang: None. C. Tan: None. Y. Kon: None. L. Xia: None. S. Lim: None.