Glucokinase-Related Maturity-Onset Diabetes of the Young in India and the Clinical Utility of the MODY Probability Calculator for Identifying Underdiagnosed and Rare Forms

Abstract Aims/Introduction: Heterozygous inactivating mutations in the glucokinase (GCK) gene induce a fasting hyperglycaemic disorder known as GCK-MODY. Although considered rare in India, we describe eight patients representing the largest Indian case series and propose the utility of the MODY probability calculator (MPC)as a tool to identify GCK-MODY in individuals with a high positive predictive value. Materials and Methods Next-generation sequencing of 14 MODY/62 monogenic diabetes genes was performed in a cohort of 837 individuals with young-onset diabetes, identifying eight index cases with pathogenic or likely pathogenic GCK mutations. Two additional subjects carrying a novel GCK variant were detected through family screening for non-GCK MODY. Results Eight patients were identified with GCK gene variants, which include 4 previously reported variants and three novel variants. Interestingly, GCK-MODY patients had a positive predictive value (PPV) of ≥ 75.5% and were diagnosed under the age of 25 years. The mean fasting glucose and postprandial glucose levels were 6.7 mmol/L ± 0.69 and 8.16 mmol/L ± 1.96, with an average HbA1c of 47.25 mmol/mol ± 4.94(6.46% ± 0.44). Additionally, 2 subjects with fasting hyperglycemia who were screened as part of an extended MODY family testing positive for KLF11 and WFS1 mutations were also positive for a novel GCK variant. Conclusions This study contributes to the evidence of GCK-MODY in India and highlights the value of screening individuals diagnosed before 25 years with a high PPV, achieving a diagnostic yield of 4.8%. Despite its low prevalence, the mild clinical phenotype of GCK-MODY likely contributes to its underdiagnosis.