Endocrine Abstracts

Background

Maturity Onset Diabetes of the Young (MODY) constitutes a genetically and clinically heterogeneous type of Monogenic Diabetes (MD), characterized by early onset of hyperglycemia, autosomal dominant inheritance and defect in β-cell insulin secretion. To date, various MODY subtypes have been reported, each one of a distinct genetic etiology.

Materials and methods

A total of 114 patients of Greek origin fulfilling MODY criteria are reported. Twenty-four patients with GCK-MODY phenotype were tested by Sanger sequencing. Ninety patients were tested employing a Next Generation Sequencing Targeted Gene Panel of seven MODY genes (GCK, HNF1A, HNF4A, HNF1B, INS, ABCC8 and KCNJ11), 40 of which had been previously tested by Sanger sequencing for GCK, HNF1A and HNF4A, according to patients’ phenotypes. Patients, with no pathogenic variant detected, were tested by Multiplex Ligation-dependent Probe Amplification (MLPA) for CNVs.

Results

GCK-MODY was found to be the most frequent MODY subtype (18.4%), followed by ABCC8-MODY (9.6%) and HNF1A-MODY (6.1%), whereas HNF4A-MODY is rare (0.8%). Two patients were identified with HNF1B variants and another 3 with whole HNF1B gene deletion, making a total of 4.4% of HNF1B-MODY. The ABCC8 MODY patients (9.6%) presented with a wide spectrum of clinical and biochemical characteristics: fasting blood glucose ranging from 103 to 365 mg/dl (5.7–20.3 mmol/l), HbA1c 5.4% to 11.9% (35.5–107 mmol/mol), age of onset of diabetes from 9 yrs to 42 yrs, BMI from 17.2 to 27.7 kg/m² and birth weight from 2700 g to 4100 g.

Conclusions

Overall in our cohort a diagnostic rate of 45% was achieved. The majority of the patients were GCK-MODY (18.4%), followed by ABCC8-MODY 9.6%, indicating that ABCC8 gene variants are frequently related to MD. The phenotypic characteristics of the patients carrying ABCC8 variants, exhibit genetic heterogeneity, ranging from a mild phenotype, similar to the mild GCK phenotype, to a more severe phenotype, similar to that of HNF1A and HNF4A defects. Molecular genetic diagnosis of the MODY subtype is of outmost importance for clinical diagnosis, disease progression prognosis and family counseling. Furthermore, it specifies pharmacologic treatment, since different MODY subtypes require different therapeutic approaches, constituting an example of personalized medicine.