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

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.