From Biology to Genes and Back Again: Gene Discovery for Monogenic Forms of Beta-Cell Dysfunction in Diabetes

Abstract

This review focuses 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 identified 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, utilizing 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 seven novel genetic causes of monogenic diabetes, six 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 to 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. While 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 characterized by in vitro and in vivo studies.

Keywords: MODY; gene discovery; neonatal diabetes; next-generation sequencing.