Identifying Children With Poor Cochlear Implantation Outcomes Using Massively Parallel Sequencing

Abstract

Cochlear implantation is currently the treatment of choice for children with severe to profound hearing impairment. However, the outcomes with cochlear implants (CIs) vary significantly among recipients. The purpose of the present study is to identify the genetic determinants of poor CI outcomes. Twelve children with poor CI outcomes (the “cases”) and 30 “matched controls” with good CI outcomes were subjected to comprehensive genetic analyses using massively parallel sequencing, which targeted 129 known deafness genes. Audiological features, imaging findings, and auditory/speech performance with CIs were then correlated to the genetic diagnoses. We identified genetic variants which are associated with poor CI outcomes in 7 (58%) of the 12 cases; 4 cases had bi-allelic PCDH15 pathogenic mutations and 3 cases were homozygous for the DFNB59 p.G292R variant. Mutations in the WFS1, GJB3, ESRRB, LRTOMT, MYO3A, and POU3F4 genes were detected in 7 (23%) of the 30 matched controls. The allele frequencies of PCDH15 and DFNB59 variants were significantly higher in the cases than in the matched controls (both P < 0.001). In the 7 CI recipients with PCDH15 or DFNB59 variants, otoacoustic emissions were absent in both ears, and imaging findings were normal in all 7 implanted ears. PCDH15 or DFNB59 variants are associated with poor CI performance, yet children with PCDH15 or DFNB59 variants might show clinical features indistinguishable from those of other typical pediatric CI recipients. Accordingly, genetic examination is indicated in all CI candidates before operation.

Timing of cochlear implantation in auditory neuropathy patients with OTOF mutations: Our experience with 10 patients

“…However, this limitation could be overcome with the availability of high‐throughput DNA sequencing to address paediatric SNHI. By simultaneously screening 129 deafness genes using the massively parallel sequencing technique, our recent study demonstrated that mutations in DFNB59 and PCDH15 , two genes expressed in the spiral ganglion neurons and/or brainstem auditory nuclei, were associated with unfavourable CI outcomes . Second, as in most previous reports, all 10 patients with OTOF mutations in this study had stationary severe‐to‐profound hearing levels before surgery, and the decision to perform cochlear implantation in these patients at an earlier age is less controversial.…”

“…The decision to undertake cochlear implantation is further complicated by the fact that improvement of auditory phenotypes with age may be observed in approximately 20% of children with ANSD . Recent studies have shown that genetic testing is of great help in determining the site of pathology in paediatric sensorineural hearing impairment (SNHI) . Specifically, mutations in the OTOF gene, a common cause of clinical ANSD, are an indicator that the pathology is confined to the synapse; post‐synaptic neurons and nerve fibres are preserved for electrical stimulation of CI.…”

Genetic variants in the peripheral auditory system significantly affect adult cochlear implant performance

“…One study that included 81 subjects with post-lingual hearing loss showed that CI users with genetic mutations in the sensory partition performed well after cochlear implantation, but no statistical analysis was performed (Miyagawa et al, 2016). A case-control study examined pediatric patients with good performance (n=30) and poor performance (n=12) and showed that genetic mutations in the sensory partition were more common in the high performing group, and that a specific mutation in spiral ganglion neurons ( DFNB59 p.Gly292Arg) was significantly more common in the poor performing group (Wu et al, 2015). Our goal was to further examine this relationship using a large number of subjects and comprehensive genetic testing which incorporates examination of causative genetic mutations affecting the spiral ganglion but also deleterious genetic variants that may independently affect this structure.…”

A novel missense variant in the nuclear localization signal of POU4F3 causes autosomal dominant non-syndromic hearing loss

“…The sequencing methods and analysis pipelines have been previously reported 27, 28 . In brief, genomic DNA was fragmented into 800 bps.…”