Prediction of cochlear implant performance by genetic mutation: the spiral ganglion hypothesis

Abstract

Background: Up to 7% of patients with severe-to-profound deafness do not benefit from cochlear implantation. Given the high surgical implantation and clinical management cost of cochlear implantation (>$1 million lifetime cost), prospective identification of the worst performers would reduce unnecessary procedures and healthcare costs. Because cochlear implants bypass the membranous labyrinth but rely on the spiral ganglion for functionality, we hypothesize that cochlear implant (CI) performance is dictated in part by the anatomic location of the cochlear pathology that underlies the hearing loss. As a corollary, we hypothesize that because genetic testing can identify sites of cochlear pathology, it may be useful in predicting CI performance.

Methods: 29 adult CI recipients with idiopathic adult-onset severe-to-profound hearing loss were studied. DNA samples were subjected to solution-based sequence capture and massively parallel sequencing using the OtoSCOPE(®) platform. The cohort was divided into three CI performance groups (good, intermediate, poor) and genetic causes of deafness were correlated with audiometric data to determine whether there was a gene-specific impact on CI performance.

Results: The genetic cause of deafness was determined in 3/29 (10%) individuals. The two poor performers segregated mutations in TMPRSS3, a gene expressed in the spiral ganglion, while the good performer segregated mutations in LOXHD1, a gene expressed in the membranous labyrinth. Comprehensive literature review identified other good performers with mutations in membranous labyrinth-expressed genes; poor performance was associated with spiral ganglion-expressed genes.

Conclusions: Our data support the underlying hypothesis that mutations in genes preferentially expressed in the spiral ganglion portend poor CI performance while mutations in genes expressed in the membranous labyrinth portend good CI performance. Although the low mutation rate in known deafness genes in this cohort likely relates to the ascertainment characteristics (postlingual hearing loss in adult CI recipients), these data suggest that genetic testing should be implemented as part of the CI evaluation to test this association prospectively.

Figure 1

Cochlear implant performance by patient. HINT, CNC, and combined scores are shown. Data is sorted by combined score. *indicates individuals for which the genetic cause of hearing loss was determined in this study. Poor, intermediate, and good performance groups are separated by dashed lines.

Figure 2

Expression pattern of hearing loss genes. Genes with established genotype-phenotype correlations are included. Genes expressed in the membranous labyrinth (labeled blue) include: GJB2, SLC26A4, OTOF, LOXHD1, KCNQ1, CDH23, MYO7A, POU3F4, MYH9, TMC1, and COCH. Genes expressed in the spiral ganglion (labeled red) include: TMPRSS3, CHD7, and DDP1/TIMM8a. (Adapted from the Hereditary Hearing Loss Homepage, hereditaryhearingloss.org, with permission from Van Camp G and Smith RJH)