Enhancing the diagnostic yield of monogenic diabetes in unresolved cases with early-onset hyperglycemia

To improve the precision of molecular diagnosis by means of a comprehensive bidirectional phenotypic and genotypic reanalysis in cases of unresolved monogenic diabetes previously investigated using a targeted next-generation sequencing (tNGS) panel. Molecular and clinical data from 128 unresolved cases referred between 2011 and 2019 were analyzed. These included 92 cases of suspected maturity-onset diabetes of the young (MODY), 12 of neonatal diabetes, 16 of familial partial lipodystrophy (FPLD), 7 of mitochondrial diabetes, and 1 of Wolfram syndrome. All cases were initially investigated using a tNGS panel consisting of 51 nuclear genes and the complete mitochondrial genome. This extensive reanalysis process increases molecular diagnosis from 9 to 22%. Phenotypic reevaluation, entailing in-depth phenotyping, is instrumental in excluding 62 atypical cases (48.4%). Genotypic reanalysis identifies 5 previously overlooked molecular defects: two mutations in regulatory regions (one in the HNF1A promoter and another in the PTF1A enhancer); one in the MTTK mitochondrial gene; one in the MFN2 gene; and one in the GCK gene. Our findings indicate that a combined approach of genotypic and, mainly, phenotypic reanalysis is an effective strategy for improving the accuracy of molecular diagnosis in individuals with suspected monogenic diabetes. Some people develop diabetes early in life due to inherited genetic conditions. However, identifying the exact cause can be difficult, and many people remain without a diagnosis after initial testing. In this study, researchers revisited the medical and genetic data of 128 individuals who were previously suspected to have a genetic form of diabetes but remained undiagnosed. By combining updated genetic tools with detailed clinical review, they were able to provide new diagnoses for some and rule out inherited diabetes in others. Because knowledge in genetics evolves rapidly, this study highlights the importance of reanalyzing past test results over time. Doing so can lead to more accurate diagnoses and better care for individuals and families affected by early-onset diabetes. Franco et al. perform a combined phenotypic and genotypic reanalysis of unresolved 128 monogenic diabetes cases. Their approach increases diagnostic yield and highlights the key role of deep phenotyping in previously overlooked cases, and provides a diagnosis for suspected cases.