Learning Objectives: The support of BSO to identify affected families is sought.

Introduction: This research project seeks to identify genetic pathways predisposing to cholesteatoma. Familial clustering of cholesteatoma has been observed in East Anglia (Prinsley 2009). DNA sequencing has advanced so that whole exome sequencing of affected and unaffected individuals is now feasible.

Methods: A database of East Anglian families with cholesteatoma forms the core recruitment group for this study. However, the British Society of Otology (BSO) network could help identify other families. Pedigree charts and blood/saliva samples will be obtained from affected families for DNA extraction.

In the second stage, exome sequencing will be coupled to a linkage analysis in the families in which cholesteatoma is segregating. In conjunction with the pedigree mapping, we will have an opportunity to identify genetic polymorphisms predisposing to formation of cholesteatoma, and by using multiple affected families, to identify recurrent pathways or genes identified through this methodology.

Results: A research team of clinicians and scientists has been assembled and a systematic literature review has been carried out. Data extracted from the literature review will be used to identify pathways to focus on during the filtering steps to identify variants of interest that co- segregate with the disease phenotype. Funding has been secured from the Royal College of Surgeons of England and from the Rosetrees Foundation. The project will be adopted on to the NIHR Portfolio subject to Research Ethics Approval. The whole exome sequencing and analysis will be performed at The Genome Analysis Centre in Norwich.

Conclusions: A project has been created to identify genetic causes of cholesteatoma.

By selecting the right families, the project has potential to yield information that may widen our understanding of the disease pathophysiology.