Loss of function variants and locus heterogeneity in familial cholesteatoma

Ryan Cardenas, Peter Prinsley, Carl Philpott, Mahmood F. Bhutta, Emma Wilson, Daniel Brewer, Barbara Jennings

Research output: Contribution to conferenceAbstract


Background: Cholesteatoma is a rare progressive disease of the middle ear. Most cases are sporadic, but some patients report a positive and extensive family history of cholesteatoma.

Methods: We performed an observational study of 21 individuals treated for cholesteatoma who were recruited from ten multiply-affected families. We used whole exome sequencing (WES) to identify functionally important gene variants segregating with cholesteatoma in the most distantly related participants from each family. These family studies were complemented with gene-level mutational burden analysis.

Results: Filtered data from pairs and trios of participants in each family revealed 398 rare, loss of function (LOF) variants co-segregating with cholesteatoma. We found LOF variants common to two (or more) families for six genes: DENND2C, DNAH7, NBEAL1, NEB, PRRC2C, and SHC2. The gene-level analysis of mutation-burden identified a significant burden for the genes in the DNAH gene family, which encode products involved in ciliary structure. Common pathways for the candidate genes included GTPase regulator activity, calcium ion binding, and degradation of the extracellular matrix.

Discussion and Conclusion: The number of candidate genes identified and the locus heterogeneity that we describe within and between affected families, suggest that the genetic architecture for familial cholesteatoma is complex. We are now conducting a WES genome-wide association study of 1114 sporadic cases and matched controls from the UK Biobank cohort to follow up on these findings. We will apply machine learning and pathway analysis to further elucidate the mechanisms of disease.

Grant Reference: Bernice Bibby Grant number A1136 and Rosetrees Trust R203056

Conflict of Interest: Ryan Cardenas: None declared, Peter Prinsley: None declared, Carl Philpott Grants from NIHR, grants from ESPRC, & grants from ENT, UK, Personal fees from Stryker, personal fees from Abbott, personal fees from Olympus, and Trustee of Fifth Sense., Mahmood Bhutta: None declared, Emma Wilson: None declared, Dan Brewer: None declared, Barbara Jennings: None declared
Original languageEnglish
Publication statusPublished - 4 Jan 2024
Event56th European Society of Human Genetics (ESHG) Conference - Glasgow
Duration: 10 Jun 202313 Jun 2023


Conference56th European Society of Human Genetics (ESHG) Conference

Cite this