A study of the genetics of cholesteatoma through systematic review and whole exome sequencing

Barbara Jennings, Carl Philpott, Mahmood Bhutta, Gavin Willis, Daniel Swan, Jane Woods, Peter Prinsley

Research output: Contribution to conferenceAbstractpeer-review


Introduction: A cholesteatoma is a mass of keratinising epithelium in the middle ear. It is a rare disorder, associated with significant morbidity. Its OMIM entry (#604183) cites minimal evidence for Mendelian inheritance, but we have observed 31 multiply affected families in Norfolk; including individuals with bilateral disease, suggesting a genetic component for its aetiology.

Methods: We conducted a systematic literature review (SR) to identify any published studies about the genetics of cholesteatoma and established a national biobank for subsequent whole exome sequencing (WES) studies of familial disease. We have also completed a pilot sequencing study to identify candidate variants that segregate with the disease phenotype (using NimbleGen exome capture; and the Illumina HiSeq4000 platform).

Results: In our SR, we identified 8 case-series with multiply-affected families and associations with congenital malformation syndromes. DNA and clinical data have been collected from 42 participants (from 9 multiply affected Norfolk families) to date. In 2018, participants will also be recruited from 10 additional UK centres.

Our pilot: WES study of 16 participants from 4 families identified 95,437 variants. Variant filtering, using pedigree analysis, has identified 430 candidate genes for further filtering using the Ensembl Variant Effect Predictor.

Conclusion: We have completed our SR (see PROSPERO register CRD42015023579) and established the first biobank to explore the genetics-of-cholesteatoma. 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 TGF β signalling and inflammatory processes.
Original languageEnglish
Publication statusAccepted/In press - 12 Mar 2018
EventEuropean Conference of Human Genetics 2018 - Milan, Italy
Duration: 16 Jun 201819 Jun 2018


ConferenceEuropean Conference of Human Genetics 2018

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