A DNA resequencing array for genes involved in MODY/Type 2 Diabetes: a new era in clinical and molecular diagnosis

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. Common variants implicated in risk of diabetes explain only a minor proportion of the familial clustering observed in sporadic cases. We apply targeted resequencing technology to detect both known and novel mutations on a single high-throughput platform. We until now resequenced 12 cases with clinical diagnosis of MODY/T2D for 46 genes involved in this disorder. All the detected variations were confirmed by direct sequencing and potential pathogenicity was assessed by functional predictions and frequency in controls. We identified modest associations with common variants and a trend suggestive of an overrepresentation of rare variants in cases compared to controls for several genes, although it is plausible that combinations of rare and/or common variants in genes already implicated might explain the genetic basis of the disease. Between detected variants, we focus on 11, of which 2 are double heterozygous and plausibly pathogenic. In addition, our data show that, at least in the Italian population, mutations in the PDX1 are likely the second cause of MODY/T2D, and that many patients resistant to traditional therapies are double heterozygous for some genes individually associated with diabetes/hyperglycemia.Nextgeneration sequencing technologies are becoming the first tier for an immediate understanding of the molecular basis of most diseases. Altogether, these efforts should allow to better understand the disease pathogenesis, find new targets for clinical therapy, and allow prediction of disease.