Maturity-onset diabetes of the young (MODY) is a phenotypically and genetically heterogeneous group of diabetes caused by single defects in at least thirteen genes, characterised by autosomal dominant inheritance, a young age of onset and pancreatic β-cell dysfunction. Genetic testing for MODY has become a routine procedure allowing to set up proper treatment and discriminate from type 2 diabetes (T2D) whose symptoms are often overlapping. We analysed, in the last 5 years, more than 300 Italian families with MODY/T2D diagnosis by direct sequencing of genes GCK, HNF1α, HNF4α, IPF1 and HNF1β, and only about 40% of the cases resulted positive. Mutations in GCK gene account for up to 80% for all Italian MODY cases according to literature data. We then reanalysed the negative subjects through Next Generation Sequencing technology. We excluded common, non-coding and synonymous gene variants, and performed in-depth analysis on filtered sequence variants in a pre-defined set of 102 genes implicated in glucose metabolism. We found, in association with known heterozygous SNPs associated with diabetes, rare and pathogenetic variants, demonstrating that this approach leads to a genetic diagnosis in most of patients. For example, we identified new variants in the RFX6 gene and in two of these cases we also detected rare variants in WFS1 and ABCC8. All patients showed a good therapeutic response to dipeptidyl peptidase-4 (DPP4) inhibitors. This approach may help in understanding the molecular aetiology of diabetes and in providing a more personalised treatment for each genetic subtype.

MODY/Type 2 Diabetes: molecular analysis of a large cohort of patients by Next Generation Sequencing / R. Artuso; A. Provenzano; L. Giunti; B. Mazzinghi; E. Andreucci; L. Lenzi; B. Piccini; P. Mandich; A. Blasetti; E. Mannucci; S. Toni; S. Giglio. - ELETTRONICO. - 22:(2014), pp. 92-92. (Intervento presentato al convegno European Human Genetics Conference).

MODY/Type 2 Diabetes: molecular analysis of a large cohort of patients by Next Generation Sequencing

PROVENZANO, ALDESIA;MANNUCCI, EDOARDO;S. Giglio
2014

Abstract

Maturity-onset diabetes of the young (MODY) is a phenotypically and genetically heterogeneous group of diabetes caused by single defects in at least thirteen genes, characterised by autosomal dominant inheritance, a young age of onset and pancreatic β-cell dysfunction. Genetic testing for MODY has become a routine procedure allowing to set up proper treatment and discriminate from type 2 diabetes (T2D) whose symptoms are often overlapping. We analysed, in the last 5 years, more than 300 Italian families with MODY/T2D diagnosis by direct sequencing of genes GCK, HNF1α, HNF4α, IPF1 and HNF1β, and only about 40% of the cases resulted positive. Mutations in GCK gene account for up to 80% for all Italian MODY cases according to literature data. We then reanalysed the negative subjects through Next Generation Sequencing technology. We excluded common, non-coding and synonymous gene variants, and performed in-depth analysis on filtered sequence variants in a pre-defined set of 102 genes implicated in glucose metabolism. We found, in association with known heterozygous SNPs associated with diabetes, rare and pathogenetic variants, demonstrating that this approach leads to a genetic diagnosis in most of patients. For example, we identified new variants in the RFX6 gene and in two of these cases we also detected rare variants in WFS1 and ABCC8. All patients showed a good therapeutic response to dipeptidyl peptidase-4 (DPP4) inhibitors. This approach may help in understanding the molecular aetiology of diabetes and in providing a more personalised treatment for each genetic subtype.
2014
European Journal of Human Genetics
European Human Genetics Conference
R. Artuso; A. Provenzano; L. Giunti; B. Mazzinghi; E. Andreucci; L. Lenzi; B. Piccini; P. Mandich; A. Blasetti; E. Mannucci; S. Toni; S. Giglio
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/919730
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