ESPE Abstracts

Introduction: Maturity Onset Diabetes of the Young (MODY) is clinically and genetically heterogeneous type of Monogenic Diabetes (MD) and to date 14 genes have been associated with different MODY subtypes. It is a rare disease characterized by early onset hyperglycemia, autosomal dominant inheritance, and defect in β cell insulin secretion, often misclassified as T1DM or T2DM.

Materials and Methods: Genetic analysis was performed in 323 Greek unrelated patients, fulfilling MODY criteria over a period of 4 years. 279/323 patients underwent targeted Next Generation Sequencing (tNGS) with a custom panel for: GCK, HNF1A, HNF4A, HNF1B, INS, ABCC8, KCNJ11, NEUROD1, CEL, PDX1, APPL1, WFS1, INSR. Copy Number Variation Analysis (CNVs) was performed by MLPA. Confirmation of the detected variants and segregation analysis was performed employing Sanger Sequencing. 44/323 patients with mild fasting hyperglycemia phenotype, suggestive of GCK-MODY, underwent Sanger Sequencing of GCK gene.

Results: By tNGs genetic diagnosis was achieved in 30% (83/279) of the patients, while by Sanger sequencing the GCK gene genetic diagnosis reached 45.5% (20/44). MLPA analysis revealed 2 heterozygous deletions: GCK gene exon 1 and whole HNF1B gene. Furthermore, we identified 3 digenic cases (GCK-ABCC8, HNF4A-KCNJ11, HNF1A-HNF1B), in which each variant was of paternal and maternal origin. Overall, the frequency of the different MODY subtypes were: GCK (17.6%), HNF1A (8.2%) followed by ABCC8 (4%), HNF4A (1.43%) and HNF1B (1.43%). Rare MODY subtypes such as KCNJ11 (1.07%) and INS (1.07%) were also detected. Five patients, who presented with diabetes without any syndromic clinical features were carrying heterozygous variants in syndromic monogenic diabetes genes: three patients carried a variant in WFS1 (1 LP, 2 VUS), one patient two variants in cis in WFS1 (1 LP, 1 VUS) and one patient a variant in INSR (VUS).

Conclusions: Genetic diagnosis was achieved in 32% of tested patients. The most frequent MODY subtypes in this study were found to be GCK, HNF1A and ABCC8, while rarer subtypes and patients with variants in syndromic genes were also detected. Genetic diagnosis is important since different MODY subtypes require different treatment. The application of NGS increases molecular diagnosis rates in MODY patients, reduces diagnostic time and cost and allows identification of rarer subtypes. Multiple gene screening in MD patients, through expanded panels of MODY and syndromic diabetes genes, provides early diagnosis of atypical presentations, disease progression prognosis and family genetic counseling.