Defining genotype/phenotype relationships in known and novel causes of hyperinsulinaemic hypoglycaemia (360G-Wellcome-081188_A_06_Z)

Hyperinsulinaemic hypoglycaemia (HI) is a clinically and genetically heterogeneous disorder with mutations in five genes reported to date. We have recently found a new cause of transient hypoglycaemia due to mutations in the HNF4A gene encoding the transcription factor HNF-4 . The aim of this project is to characterise this novel cause of hypoglycaemia and to compare with the previously described types of hyperinsulinism. A large cohort ( > 200) of patients with hyperinsulinaemic hypoglycaemia is already available for this purpose and this resource will be expanded with further recruitment of patients with both severe HI (referred to KH at GOS) and milder, sometimes transient HI (national recruitment programme co-ordinated by JPS in Bristol). Mutations in known genes will be identified by a combination of high throughput sequencing, mRNA analysis and gene dosage studies. New genetic aetiologies will be sought by candidate gene analysis and homozygosity mappingin consanguineous families not linked to known loci. These studies will provide new insights into the physiology of the human beta cell and may have potential treatment implications for both hypoglycaemia and diabetes.