Non-coding mutations in congenital hyperinsulinism: deciphering the role of gene dysregulation in human disease

Hyperinsulinism is a life-threatening genetic condition where babies produce too much insulin leading to low glucose. Despite extensive efforts to screen the coding regions of the genome the aetiology remains unknown in 50% of patients suggesting that non-coding mutations are a key cause of disease. My preliminary studies have identified regulatory mutations leading to inappropriate expression of a beta-cell 'disallowed' gene as a major cause of hyperinsulinism. This contradicts the received wisdom that non-coding mutations would most likely disrupt genes involved in normal beta-cell function. To exploit this new knowledge, I will use state-of-the-art genomics to study >2000 genetically-unsolved patients to discover further mutations disrupting beta-cell 'disallowed' genes and identify the mechanism(s) by which they cause disease. These studies provide an unrivalled opportunity to determine the regulatory networks critical for tissue-specific gene suppression and to improve understanding of the non-coding genome which will be key for many genetic diseases