Utility of next-generation sequencing for the genetic study of MODY diabetes

Next-generation sequencing (NGS) is increasingly used for diagnosing monogenic forms of diabetes, including maturity-onset diabetes of the young (MODY). We aimed to evaluate the utility of NGS in patients with clinical suspicion of MODY, analyzing genotype-phenotype correlations. A total of 150 unrelated patients from the Region of Murcia (Spain) with suspected MODY were included. Whole-exome sequencing was performed and validated with Sanger and multiplex ligation-dependent probe amplification (MLPA). Variants were classified according to the American College of Medical Genetics and Genomics (ACMG) criteria. Relevant clinical data were collected per the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) criteria and analyzed using SPSS v.27.0.2.0. The diagnostic yield was 16.67% (25/150). Pathogenic or likely pathogenic variants were mainly identified in GCK (38.89%) and HNF1A (33.33%). Significant differences were found between patients with and without genetic diagnosis in family history, age of onset, and body mass index (P < 0.05). Variants of uncertain significance (VUS) were identified in 22 families (14.66%). One VUS was reclassified as likely pathogenic, and three were prioritized for further evaluation. NGS is a valuable tool for the genetic diagnosis of MODY. Integration of clinical data and systematic re-evaluation and prioritization of VUS can enhance diagnostic accuracy and inform clinical decision-making.