Whole exome sequencing study identifies candidate loss of function variants and locus heterogeneity in familial cholesteatoma

Cardenas, Ryan, Prinsley, Peter, Philpott, Carl ORCID: https://orcid.org/0000-0002-1125-3236, Bhutta, Mahmood F., Wilson, Emma, Brewer, Daniel S. ORCID: https://orcid.org/0000-0003-4753-9794 and Jennings, Barbara A. ORCID: https://orcid.org/0000-0003-3792-9182 (2023) Whole exome sequencing study identifies candidate loss of function variants and locus heterogeneity in familial cholesteatoma. PLoS One, 18 (3). ISSN 1932-6203

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Cholesteatoma is a rare progressive disease of the middle ear. Most cases are sporadic, but some patients report a positive family history. Identifying functionally important gene variants associated with this disease has the potential to uncover the molecular basis of cholesteatoma pathology with implications for disease prevention, surveillance, or management. We performed an observational WES study of 21 individuals treated for cholesteatoma who were recruited from ten multiply affected families. These family studies were complemented with gene-level mutational burden analysis. We also applied functional enrichment analyses to identify shared properties and pathways for candidate genes and their products. Filtered data collected from pairs and trios of participants within the ten families revealed 398 rare, loss of function (LOF) variants co-segregating with cholesteatoma in 389 genes. We identified six genes DENND2C, DNAH7, NBEAL1, NEB, PRRC2C, and SHC2, for which we found LOF variants in two or more families. The parallel gene-level analysis of mutation burden identified a significant mutation burden for the genes in the DNAH gene family, which encode products involved in ciliary structure. Functional enrichment analyses identified common pathways for the candidate genes which included GTPase regulator activity, calcium ion binding, and degradation of the extracellular matrix. The number of candidate genes identified and the locus heterogeneity that we describe within and between multiply affected families suggest that the genetic architecture for familial cholesteatoma is complex.

Item Type: Article
Additional Information: Funding: PP CP BJ Bernice Bibby Grant number A1136 no PP CP BJ Rosetrees Trust Grant number R203056 (The Genetics of Cholesteatoma study) https://rosetreestrust.co.uk/project-grant-applications/ no PP Modi pump priming grant Royal College of Surgeons https://www.rcseng.ac.uk/dental-faculties/fds/research/fds-pump-priming-grants/ no The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. **** Data Availability: All raw exome sequencing data and the combined VCFs for SNPs and Indels detected using two pipelines (GATK HaplotypeCaller and Freebayes) are available at the European Genome-Phenome Archive (https://ega-archive.org/; Series accession ID: EGAS00001006147; Dataset accession ID: EGAD00001008671). The accession IDs for data from each sample are listed in Table 1 and are: EGAN00003527778, EGAN00003527779, EGAN00003527738, EGAN00003527740, EGAN00003527739, EGAN00003527754, EGAN00003527756, EGAN00003527737, EGAN00003527736, EGAN00003527741, EGAN00003527742, EGAN00003527743, EGAN00003527752, EGAN00003527751, EGAN00003527750, EGAN00003527762, EGAN00003527755, EGAN00003527753, EGAN00003527757, EGAN00003527759, EGAN00003527770, EGAN00003527774, EGAN00003527771, EGAN00003527773, EGAN00003527766, EGAN00003527747, EGAN00003527749, EGAN00003527748, EGAN00003527746, EGAN00003527745, EGAN00003527772, EGAN00003527744, EGAN00003527769, EGAN00003527768, EGAN00003527765, EGAN00003527767, EGAN00003527781, EGAN00003527780, EGAN00003527764, EGAN00003527763, EGAN00003527760, EGAN00003527761, EGAN00003527758, EGAN00003527775, EGAN00003527776, EGAN00003527777 The VCF IDs for each samples are listed in Table 1 and are: EGAZ00001862733, EGAZ00001862737, EGAZ00001862745, EGAZ00001862744, EGAZ00001862736, EGAZ00001862742, EGAZ00001862741, EGAZ00001862749, EGAZ00001862747, EGAZ00001862746, EGAZ00001862738, EGAZ00001862748, EGAZ00001862740, EGAZ00001862734, EGAZ00001862732, EGAZ00001862750, EGAZ00001862735, EGAZ00001862739, EGAZ00001862730, EGAZ00001862731, EGAZ00001862743 The metadata associated with each sample is available in Table 1. In combination this is the minimal data set needed to replicate all study findings reported in this article.
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups: Faculty of Medicine and Health Sciences > Research Groups > Respiratory and Airways Group
Faculty of Medicine and Health Sciences > Research Groups > Cancer Studies
Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health
Faculty of Medicine and Health Sciences > Research Centres > Lifespan Health
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Depositing User: LivePure Connector
Date Deposited: 16 Feb 2023 09:30
Last Modified: 19 Oct 2023 03:33
URI: https://ueaeprints.uea.ac.uk/id/eprint/91149
DOI: 10.1371/journal.pone.0272174

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