High Throughput Sequencing Approach Identify MAFA as the fourteenth MODY gene

Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes mellitus characterised by autosomal dominant inheritance, a young age of onset and pancreatic β-cell dysfunction. It is both clinically and genetically heterogeneous with mutations at the moment in at least thirteen genes. 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. Although more than 40 loci associated with T2D or glycemic traits have been reported and reproduced, only a minor part of the genetic component of the disease has been explained, and the causative variants and affected genes are unknown for many of the loci. To determine the role of low-frequency coding variants in traits reflecting pancreatic β-cell function, insulin sensitivity and glycemia, we performed targeted resequencing technology by high-throughput sequencing in 27 patients with suspected MODY/T2D. They were Sanger sequencing-negative for mutations in the GCK, HNF1A, HNF4A, HNF1B genes. We excluded common, non-coding and synonymous gene variants, and performed in-depth analysis on filtered sequence variants in a pre-defined set of 103 genes implicated in glucose metabolism. We found, in association with known heterozygous SNPs already described in diabetes, rare and pathogenetic variants, demonstrating that this approach led to a genetic diagnosis in most of patients. Interestingly two novel possible causative variations in MAFA gene, implicated in diabetes in animal models, in t