A clinical practice review of monogenic diabetes: a paradigm for precision medicine in endocrinology

Monogenic diabetes represents a diverse group of disorders caused by distinct genetic defects that impair pancreatic beta-cell development and function resulting in the young-age onset diabetes. The most common subtypes of monogenic diabetes are HNF1A-diabetes, GCK-related hyperglycaemia and HNF4A-diabetes; or syndromic diabetes such as HNF1B-diabetes and mitochondrial diabetes. Monogenic diabetes can also present as neonatal diabetes most commonly caused by pathogenic variants in KCNJ11 and ABCC8 genes. Advances in next generation sequencing have led to gene-based classification, elevating diagnosis and management from traditional clinical categories to precision medicine. Despite diagnostic advancements, monogenic diabetes is still frequently misdiagnosed as type 1 or type 2 diabetes, particularly in resource-limited settings. The use of calculators and algorithms for the likelihood of monogenic diabetes should be more readily utilised by healthcare professionals to aid in diagnosis. Genotype-phenotype correlations underpin targeted therapy; for instance, GCK-related hyperglycaemia is generally non-progressive and does not require pharmacological intervention, while HNF1A- or HNF4A-diabetes are successfully managed with sulfonylureas. Recognition of extra-pancreatic features is essential and requires multidisciplinary collaboration between endocrinologists, geneticists, and relevant specialists. This review synthesizes contemporary evidence, addresses diagnostic challenges, and advocates for proactive clinical assessment and equitable access to genomic testing to fully realise precision medicine benefits for all patients.