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

Abstract

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.

Functional studies of deafness-associated pendrin and prestin variants

“…Thus, it is conceivable that conserved residues between pendrin and prestin are of similar functional importance in these structurally similar proteins. Interestingly, however, the number of prestin missense variants reported to date is only 13, of which 6 are associated with autism with unknown pathophysiological relevance to hearing (Cardenas et al, 2023; Han et al, 2019; Koire et al, 2021; Morgan et al, 2018; Mutai et al, 2013; Sloan-Heggen et al, 2016; Toth et al, 2007; Zhou et al, 2022). In this study, we characterized p.A100T (c.298G>A), p.P119S (c.355C>T), and p.S441L (c.1322C>T) prestin variants that are all associated with hearing loss.…”

Functional Studies of Deafness-Associated Pendrin and Prestin Variants

“…Thus, it is conceivable that conserved residues between pendrin and prestin are of similar functional importance in these structurally similar proteins. Interestingly, however, the number of prestin missense variants reported to date is only 13, six of which are associated with autism with unknown pathophysiological relevance to hearing [ 54 , 62 , 63 , 64 , 65 , 66 , 67 , 68 ]. In this study, we characterized p.A100T (c.298G>A), p.P119S (c.355C>T), and p.S441L (c.1322C>T) prestin variants that are all associated with hearing loss.…”

Editorial: Otitis media susceptibility due to genetic variants

“…Previous DNA exome and genome-wide association studies in humans have mostly focused on the common forms of OM, including acute OM, recurrent acute OM, chronic OM with effusion, and chronic suppurative OM ( Santos-Cortez et al, 2019 ; Jamieson et al, 2021 ). Before this study, only two exome sequencing studies on families with cholesteatoma were published by the same group ( Prinsley et al, 2019 ; Cardenas et al, 2023 ), with none of the candidate genes and pathways overlapping with those identified by Lee et al These studies suggest that at least a subset of cholesteatoma patients has a potential genetic basis in their disease etiology. Of note, unlike acute OM, cholesteatoma is not as easily modeled in animals ( Park and Lee, 2013 ), which makes the molecular characterization of human cholesteatoma an effective path to a better understanding of long-standing OM pathology.…”