Diverse and rare candidate MODY gene variants were identified in one-fifth of a Bangladeshi cohort with nonobese, nonautoimmune youth-onset diabetes

Abstract The global distribution and frequency of maturity onset diabetes of the young (MODY) vary, necessitating investigation across diverse ethnic groups. This study aimed to investigate MODY gene variants and phenotypic characteristics among young Bangladeshi individuals with nonobese, nonautoimmune youth-onset diabetes. Fifty participants with diabetes (onset < 35 years, BMI < 25 kg/m², negative for islet autoantibodies, detectable C-peptide, and a family history of DM) and 50 young individuals with normoglycemia were enrolled. Targeted next-generation sequencing (NGS) was performed on a panel of 14 known MODY genes. Candidate MODY-gene variants were identified in 20% (10/50) of the diabetes cohort. There were 11 heterozygous missense variants across eight genes: HNF1A, PDX1, NEUROD1, KLF11, PAX4 (three variants), BLK, ABCC8 (two variants), and KCNJ11. No variants met the ACMG/AMP criteria for ‘Pathogenic’ or ‘Likely Pathogenic’ classification; all identified variants were categorized as variants of uncertain significance (VUS). No significant phenotypic differences were observed between individuals with diabetes who carried identified variants and those who did not. In conclusion, this study identified candidate MODY variants (all classified as VUS) in one-fifth of the Bangladeshi nonobese, nonautoimmune youth-onset diabetes cohort. These findings provide a preliminary indication of a distinct genetic pattern characterized by a low frequency of common variants and a relative abundance of variants in rare MODY-associated genes. These findings are hypothesis-generating and highlight potential genetic targets for future functional validation to confirm pathogenicity and to support definitive MODY diagnoses.