Data from: Diagnosis of monogenic diabetes in adults: lessons from genetic testing by next-generation sequencing in 1564 patients

Context: In adults, monogenic diabetes (MgD) are difficult to distinguish from common diabetes causes. Objective: We assessed the diagnostic rate and genetic spectrum of MgD using next-generation sequencing in patients with adult-onset diabetes referred for genetic testing. Design: Cross-sectional analysis. Setting: 116 Endocrinology departments. Participants: 1564 adult probands with a suspicion of MgD, based on the absence of diabetes autoantibodies, an age ≤40 years and a body-mass index (BMI) <30 kg/m² at diagnosis, and a family history of diabetes in ≥2 generations. Measurements: 7 genes (GCK, HNF1A, HNF4A, HNF1B, ABCC8, KCNJ11 and INS) were analyzed. Variant pathogenicity was assessed using current guidelines. Results: Pathogenic variants were identified in 254 patients (16.2%), and in 23.2% of EuroCaucasian patients. HNF1B, ABCC8/KCNJ11, and INS variants accounted for 13% of the cases. As compared to non-monogenic cases, a younger age, a lower BMI and the absence of diabetes symptoms at diagnosis, an EuroCaucasian origin, and a family history of diabetes in ≥3 generations were associated with MgD, but with wide phenotypic overlaps. In the total population, two clusters were identified, that differed by the severity of diabetes. MgD cases were more prevalent in the milder phenotypic cluster. The phenotypes of the patients with variants of uncertain significance (n=59) were closer to that of non-monogenic patients. Conclusion: Variants of HNF1B and the K-ATP channel genes were more frequently involved in MgD than expected. Phenotype overlapping makes the diagnosis of MgD difficult in adults, and underlies the benefit of NGS in clinically selected patients.