Advancing precision medicine: the case for monogenic diabetes mellitus in Singapore

As Singapore moves towards greater integration of precision medicine into clinical practice,[1] its potential to reshape the management of major public health challenges, such as diabetes mellitus (DM), is far-reaching. Diabetes mellitus poses a significant public health challenge — both in Singapore and globally — driven by a rising prevalence, increased healthcare utilisation, and the substantial human capital costs associated with the disease and its complications.[2] Renal and cardiovascular diseases are major contributors to the morbidity and mortality linked to DM.[2] Moreover, individuals are diagnosed with DM at a younger age, with an attendant increase in complications.[3] While obesity and lifestyle changes are major contributors to this alarming trend, local data suggest that monogenic DM may be underdiagnosed as a cause of young-onset DM.[4] This underdiagnosis is attributed to the perception that maturity-onset diabetes of the young (MODY) is rare, as well as the lack of clinical suspicion for genetic causes of DM. In Maturity onset diabetes of the young, the clinical features often overlap with those of type 1 DM (diagnosed before age 25) and type 2 DM (characterised by negative autoantibody testing), making accurate diagnosis more challenging. Maturity onset diabetes of the young is genetically heterogeneous, implicating more than 20 genes and accounting for 1%–2% of all cases of DM. In addition, even when the diagnosis is suspected in the presence of these features in a young individual with a strong family history, the lack of awareness of or access to genetic testing for monogenic causes of DM often delays diagnosis, especially in Asian populations where the prevalence of MODY has not been formally established.[4] Accurate and timely identification of the gene responsible for causing MODY enables treatment to be appropriately tailored to individual patients and facilitates screening of family members. For instance, the majority (95%) of MODY cases are associated with mutations in hepatocyte nuclear factor 1A (HNF1A), hepatocyte nuclear factor 4A (HNF4A) and glucokinase (GCK), but their natural history and management differ greatly. HNF1A- and HNF4A-associated MODY respond well to low-dose sulphonylureas and are more susceptible to vascular complications and mortality, while GCK-MODY is managed with lifestyle modification and has a low prevalence of vascular complications.[5] As described by Tan et al.,[6] the National Healthcare Group–Khoo Teck Puat Hospital Monogenic Diabetes Registry aims to determine the prevalence and spectrum of MODY, describe its natural history in secondary care institutions in Singapore, and develop an algorithm for genetic testing based on clinical parameters and biomarkers. As the study aptly highlights, existing clinical tools for identifying individuals with MODY are not sufficiently sensitive for diverse populations, especially in Asian-dominant cohorts like Singapore. It provides valuable insights not only into the genetic landscape, but also the biochemical profiles of MODY in Singapore, thereby enhancing our understanding of population-specific patterns and underscoring the need for cohort studies — such as Tan et al’s study[6] — in the development of population-specific diagnostic algorithms. This study reinforces the value of local data in guiding policies and clinical practices best suited for our population. Looking ahead, it also highlights the critical need for incorporating genetic testing into DM care and its significant impact on improving patient outcomes. Importantly, the study also emphasises that genetic conditions such as monogenic DM have implications that extend beyond the affected individual to their relatives, who may share the same genetic variants and could similarly benefit from early diagnosis and treatment. In conclusion, Tan et al’s study represents a major advancement in the understanding and management of MODY — a hitherto underappreciated cause of DM — and its complications in young patients, who face the highest risk of morbidity during their most productive years and the greatest impact on life expectancy. This study also provides timely evidence of the prevalence and genetic diversity of monogenic DM in Singapore, illustrating another milestone in our journey towards precision medicine. Building on this foundation, continued research and clinical implementation are crucial in reducing disease burden and improving patient outcomes in Singapore.