Applying the power of genetics to increase knowledge of underlying mechanisms of recessively inherited congenital hyperinsulinism. (360G-Wellcome-105636_Z_14_Z)

This project will search for novel genetic causes of recessively inherited congenital hyperinsulinism in patients born to consanguineous parents in whom all the known genetic causes of HI have been excluded 1. Using genetic approaches to localise the genetic location of the aetiological gene I will use genome-wide SNP analysis to identify large ( > 3cM) homozygous segments, which are identical by descent in all 187 subjects. To refine gene localisation I will: a. Genotype additional affecte d and unaffected family members b. Search for shared haplotypes across families in ethnically matched apparently unrelated individuals c. Combine analysis of unrelated individuals with shared extra- pancreatic features d. Combine analysis of multiple families with isolated hyperinsulinism to identify shared regions of homozygosity. 2. Next generation sequencing to identify potential variants Potential aetiological variants in coding and non-coding regions will be detected within the refin ed regions of linkage by genome sequencing in key family members. 3. Confirming aetiological role of variants To define a novel aetiological gene needs replication in multiple families and finding different variants in the same gene. Therefore potential aetiological genes will be sequenced in the larger cohort. When there is clear genetic evidence we will go on perform appropriate functional studies to investigate disease mechanism(s).