Whole exome sequencing in early-onset non-autoimmune diabetes in Malta : spectrum of monogenic variants and performance of the Exeter MODY probability calculator

Abstract

Early-onset non-autoimmune diabetes mellitus (EONADM) is defined as diabetes diagnosed before or at the age of 35 in the absence of pancreatic autoantibodies. Earlyonset type 2 diabetes mellitus (EOT2DM) and maturity-onset diabetes of the young (MODY) are two types of EONADM, with MODY often being misdiagnosed as EOT2DM. MODY presents a diagnostic challenge due to phenotypic overlap and the requirement of genetic testing. In Malta, the high prevalence of type 2 diabetes and obesity further increases the chances of misdiagnosis, potentially affecting patient outcomes. This retrospective study analyses the spectrum of monogenic EONADM variants and evaluates the performance of the MODY Probability Calculator (MPC) in a Maltese cohort. Participant and genetic data from a cohort of 205 Maltese individuals diagnosed with atypical EONADM was obtained from a previous study. All participants underwent clinical evaluation and whole exome sequencing. MODY classification was based on a ten-gene panel and MPC scores were calculated to estimate MODY risk. Variant impacts were predicted using in silico tools and molecular modelling. Genotype-phenotype associations were analysed statistically, and receiver operating characteristic (ROC) analysis was employed to evaluate the predictive performance of the MPC and other clinical variables. This study identified 19 MODY-positive participants harbouring 15 unique pathogenic/likely pathogenic variants, including five novel variants, in eight MODY genes. Variants were predominantly found in GCK and HNF1A, with two unrelated participants having a novel CEL variant worthy of further research. ROC analysis revealed that the MPC, despite being the best-performing variable, showed subpar discriminative ability. These findings highlight the importance of genetic testing for atypical diabetes cases and suggest the need for population-specific screening strategies, directly impacting the future of precision medicine in Malta.