The genetics of Cholesteatoma

Prinsley, Peter (2018) The genetics of Cholesteatoma. Doctoral thesis, University of East Anglia.

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    Abstract

    Introduction
    A cholesteatoma is a mass of keratinizing epithelium in the middle ear. It is a rare disorder, associated with significant morbidity, especially deafness. There is little evidence for Mendelian inheritance, but an original observation by the author of affected families in Norfolk, including individuals with bilateral disease, suggests a genetic component for its aetiology.

    Methods
    A systematic literature review to identify studies about the genetics of cholesteatoma has been performed and a biobank for subsequent whole exome sequencing studies of familial disease has been established. A pilot sequencing study to identify candidate variants that segregate with the disease phenotype, using NimbleGen library construction and exome capture and the Illumina HiSeq4000 platform, has been completed.

    Results
    The literature review identified several case-series with multiply-affected families and associations with congenital malformation syndromes.

    DNA and clinical data has been collected from 66 participants from 13 multiply affected Norfolk families. The pilot whole exome sequencing [WES] study of 16 participants from four families identified 95,437 variants. In one family all five recruited individuals have been sequenced. Variant filtering, using pedigree analysis, has identified several mutations of potential significance.

    Conclusion
    A systematic review has been completed and a unique biobank to explore the genetics of cholesteatoma is established A WES strategy and bioinformatics pipeline have been developed in the pilot study and preliminary filtering has identified candidate variants that could have an impact on relevant biological pathways. There are no other published descriptions of a WES strategy to investigate the genetics of familial cholesteatoma. The potential impact of an understanding of the genetic basis of cholesteatoma is discussed.

    Item Type: Thesis (Doctoral)
    Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
    Depositing User: Gillian Aldus
    Date Deposited: 10 Jan 2019 12:07
    Last Modified: 10 Jan 2019 12:07
    URI: https://ueaeprints.uea.ac.uk/id/eprint/69528
    DOI:

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