From biology to genes and back again: Gene discovery for monogenic forms of beta cell dysfunction in diabetes

This review focusses on gene discovery strategies used to identify monogenic forms of diabetes caused by reduced pancreatic beta cell number (due to destruction or defective development) or impaired beta cell function. Gene discovery efforts in monogenic diabetes have identifi ed 36 genes so far. These genetic causes have been identified using four main approaches: linkage analysis, candidate gene sequencing and most recently, exome and genome sequencing. The advent of next-generation sequencing has allowed researchers to move away from linkage analysis (relying on large pedigrees and/or multiple families with the same genetic condition) and candidate gene (relying on previous knowledge on the gene’s role) strategies to use a gene agnostic approach, utilising genetic evidence (such as variant frequency, predicted variant effect on protein function, and predicted mode of inheritance) to identify the causative mutation. This approach led to the identification of 7 novel genetic causes of monogenic diabetes, 6 by exome sequencing and one by genome sequencing. In many of these cases, the disease-causing gene was not known to be important for beta cell function prior of the gene discovery study. These novel findings highlight a new role for gene discovery studies in furthering our understanding of beta cell function and dysfunction in diabetes. Whilst many gene discovery studies in the past were led by knowledge in the field (through the candidate gene strategy) now they often lead the scientific advances in the field by identifying new important biological players to be further characterised by in vitro and in vivo studies.