Endocrine Abstracts

Congenital Hyperinsulinism is the most common cause of persistent hypoglycaemia in childhood. The condition is clinically and genetically heterogeneous with over 35 different disease genes identified. Routine screening of these genes in individuals living with congenital hyperinsulinism identifies a pathogenic variant in ~50% of cases. Understanding the genetic cause of an individual’s hyperinsulinism is critical as it will help to guide medical management. In recent years, genetic discovery efforts in congenital hyperinsulinism have focussed on screening for germline coding variants within genes known to have an important role in the pancreatic beta-cell. Much less attention has been afforded to the non-coding genome. This is largely because of the difficulties in interpreting the impact of non-coding variants on gene regulation. The Exeter Genomics Laboratory is an international referral centre for congenital hyperinsulinism, having received samples from over 4000 individuals living with this condition for genetic testing. Using state-of-the-art technology, we are improving our understanding of the genetics of this condition, which is leading to new knowledge of the pathways governing insulin secretion and importantly is providing more families with a genetic diagnosis. During this lecture I will show how we have developed methods to identify somatic variants in the known hyperinsulinism genes that are present in the pancreas but have remained undetected in leukocyte DNA. Results will also be presented from our genome sequencing studies which show how non-coding variants that disrupt the regulation of genes not normally expressed within the beta-cells, are a common cause of hyperinsulinism. These findings demonstrate, that for some, hyperinsulinism can present for the first time in adulthood- broadening the phenotypic spectrum associated with some monogenic forms of hyperinsulinism.