Next-Generation Sequencing for the Diagnosis of Monogenic Diabetes and Discovery of Novel Aetiologies

Monogenic diabetes describes a genetically heterogeneous set of disorders which are caused by a mutation in a single gene. For both major subtypes, maturity-onset diabetes of the young and neonatal diabetes, making a genetic diagnosis is important for clinical management because the genetic subtype defines the treatment. Mutations in at least 26 genes have been identified through studies using genetic linkage, candidate gene sequencing and most recently, exome sequencing. With the advent of next-generation sequencing technology, it is now possible to do a single test to identify mutations in any of the known genes, either for the purposes of a clinical diagnostic test or as a pre-screen in the search for novel disease genes. Exome sequencing focuses on the protein-coding regions of the genome and has been applied in a small number of monogenic diabetes studies. It requires a strategy for selecting those patients likely to have a monogenic aetiology, defining the likely mode of inheritance and filtering variants to identify possible deleterious variants for further investigation. The identification through exome sequencing of GATA6 mutations as the most common cause of pancreatic agenesis is likely to be the first of many new discoveries enabled by exome or genome sequencing.