Next generation sequencing targeted gene panel in Greek MODY patients increases diagnostic accuracy

Background Maturity Onset Diabetes of the Young (MODY) constitutes a genetically and clinically heterogeneous type of monogenic diabetes. It is characterized by early onset, autosomal dominant inheritance and a defect in pancreatic β-cell insulin secretion. To date, various MODY subtypes have been reported, each one of a distinct genetic etiology. Objective The aim of this study was to identify the molecular defects of 50 patients with MODY employing the methodology of next generation sequencing (NGS) targeted gene panel. Methods A panel of seven MODY genes was designed and employed to screen 50 patients fulfilling the MODY diagnostic criteria. Patients with no pathogenic, likely pathogenic or uncertain significance variants detected, were further tested by multiplex ligation-dependent probe amplification (MLPA) for copy number variations (CNVs). Results Eight different pathogenic or likely pathogenic variants were identified in eight MODY patients (diagnostic rate 16%). Five variants of uncertain significance were also detected in seven MODY patients. Five novel pathogenic and likely pathogenic variants were detected in the genes GCK; p.Cys371X, HNF1A; p.Asn402Tyr, HNF4A; p.Glu285Lys, and ABCC8; p.Met1514Thr and p.Ser1386Phe. Two de novo heterozygous deletions of the entire HNF1B gene were detected in two patients, raising the diagnostic rate to 20%. Conclusions Although many MODY patients still remain without exact MODY type identification, the application of NGS methodology provided rapid results, increased diagnostic accuracy, and was cost-effective compared to Sanger sequencing. Accurate genetic diagnosis of the MODY subtype is important for treatment selection, disease prognosis, and family counseling.