Insights into INS Gene Variation from Seven Years of Monogenic Diabetes Testing—Novel Genetic Variants and Their Clinical Implications

Monogenic diabetes (MD) is a rare and heterogeneous group of disorders caused by genetic variants in genes involved in glucose metabolism. Among many MD genes, the insulin gene (INS) deserves special attention, as its variants are responsible for both permanent neonatal diabetes mellitus (PNDM) and transient neonatal diabetes mellitus (TNDM), as well as a form of MODY (maturity-onset diabetes of the young)—INS-MODY. The aim of the study was to perform a clinical and molecular analysis of patients focused on the evaluation of INS gene variants identified during molecular testing in patients referred with suspected MD, and to assess the prediction of their impact on protein structure using in silico methods. Between 2017 and 2024, 1043 unrelated probands were tested using targeted next-generation sequencing (tNGS) panels. Three pathogenic or likely pathogenic variants in the INS gene were identified in three unrelated families, indicating that this gene accounts for 0.38% of MD cases. This allowed for the diagnosis of PNDM in two patients with diabetes diagnosed within the first four months of life and INS-MODY in a patient with diabetes since the age of 16. Moreover, in the patient with PNDM and the INS:c.T104C variant, additional disorders were identified in the form of intrauterine growth restriction (IUGR) and neurological disorders. Importantly, two of the identified genetic variants, c.C103G and c.G3C, have not previously been described in the literature. Furthermore, in silico analysis of the variants at the protein level, i.e., investigation of mutations at the 35th residue, indicated that symptom severity correlates with the extent of structural changes in insulin. The results obtained broaden the spectrum of causative variants of the INS gene, but also emphasize the clinical significance of these variants in patients with various forms of diabetes, pointing to the key role of comprehensive genetic testing in enabling accurate diagnosis and targeted treatment of patients.