Many patients with suspected monogenic diabetes remain undiagnosed despite next-generation sequencing. A study published in Communications Medicine demonstrates that combining genotypic reanalysis with detailed clinical phenotyping can substantially improve diagnostic precision.

The analysis included 128 unresolved cases referred between 2011 and 2019, encompassing suspected maturity-onset diabetes of the young (MODY), neonatal diabetes, familial partial lipodystrophy (FPLD), mitochondrial diabetes, and Wolfram syndrome. Each case had previously undergone targeted next-generation sequencing of 51 nuclear genes and the complete mitochondrial genome.

Reevaluation increased the molecular diagnosis rate from 9% to 22%. Five overlooked molecular defects were detected, including promoter, enhancer, and mitochondrial gene mutations. Importantly, in-depth phenotypic review excluded 48% of atypical cases that initially mimicked monogenic diabetes.

These findings emphasize that integrating clinical and genomic reanalysis refines molecular diagnosis, helping identify the underlying genetic cause of monogenic diabetes and enabling more precise, individualized management.