Variability in Cochlear Implantation Outcomes in a Large German Cohort With a Genetic Etiology of Hearing Loss

Abstract

Objectives: The variability in outcomes of cochlear implantation is largely unexplained, and clinical factors are not sufficient for predicting performance. Genetic factors have been suggested to impact outcomes, but the clinical and genetic heterogeneity of hereditary hearing loss makes it difficult to determine and interpret postoperative performance. It is hypothesized that genetic mutations that affect the neuronal components of the cochlea and auditory pathway, targeted by the cochlear implant (CI), may lead to poor performance. A large cohort of CI recipients was studied to verify this hypothesis.

Design: This study included a large German cohort of CI recipients (n = 123 implanted ears; n = 76 probands) with a definitive genetic etiology of hearing loss according to the American College of Medical Genetics (ACMG)/Association for Molecular Pathology (AMP) guidelines and documented postoperative audiological outcomes. All patients underwent preoperative clinical and audiological examinations. Postoperative CI outcome measures were based on at least 1 year of postoperative audiological follow-up for patients with postlingual hearing loss onset (>6 years) and 5 years for children with congenital or pre/perilingual hearing loss onset (≤6 years). Genetic analysis was performed based on three different methods that included single-gene screening, custom-designed hearing loss gene panel sequencing, targeting known syndromic and nonsyndromic hearing loss genes, and whole-genome sequencing.

Results: The genetic diagnosis of the 76 probands in the genetic cohort involved 35 genes and 61 different clinically relevant (pathogenic, likely pathogenic) variants. With regard to implanted ears (n = 123), the six most frequently affected genes affecting nearly one-half of implanted ears were GJB2 (21%; n = 26), TMPRSS3 (7%; n = 9), MYO15A (7%; n = 8), SLC26A4 (5%; n = 6), and LOXHD1 and USH2A (each 4%; n = 5). CI recipients with pathogenic variants that influence the sensory nonneural structures performed at or above the median level of speech performance of all ears at 70% [monosyllable word recognition score in quiet at 65 decibels sound pressure level (SPL)]. When gene expression categories were compared to demographic and clinical categories (total number of compared categories: n = 30), mutations in genes expressed in the spiral ganglion emerged as a significant factor more negatively affecting cochlear implantation outcomes than all clinical parameters. An ANOVA of a reduced set of genetic and clinical categories (n = 10) identified five detrimental factors leading to poorer performance with highly significant effects ( p < 0.001), accounting for a total of 11.8% of the observed variance. The single strongest category was neural gene expression accounting for 3.1% of the variance.

Conclusions: The analysis of the relationship between the molecular genetic diagnoses of a hereditary etiology of hearing loss and cochlear implantation outcomes in a large German cohort of CI recipients revealed significant variabilities. Poor performance was observed with genetic mutations that affected the neural components of the cochlea, supporting the "spiral ganglion hypothesis."

Fig. 1.

Demographic and phenotypic characteristics of the genetic cochlear implant cohort. A, Age distribution of the study population (SP) (n = 76) across all age groups in decades (blue bars). The percentage for each decade is shown below the bar. The age distribution of the cohort (2021) was compared to the age distribution of the population in southwest Germany (BW) for similar reference years (2019) and decades (data from State Statistical Office Baden-Württemberg 2021) (orange bars). B, Age-related distribution of hearing loss onset in the genetic cochlear implant cohort. The phases of congenital onset and prelingual (0–2 years) and perilingual (3–6 years) hearing loss onset are shown in the first three bars (≤6 years). Postlingual hearing loss onset (>6 years) starts at the second bar (7–9 years) and continues through subsequent decades. The percentage for each time window is shown below the bar. C, Overview of the modes of inheritance in the total patient cohort. Pie chart showing the respective proportions of patients with autosomal-dominant, autosomal-recessive, and X-linked inheritance patterns, as well as patients with sporadic hearing impairment.

Fig. 2.

Distribution of hearing loss grades in the genetic cochlear implant cohort. A, Distribution of preoperative hearing loss grades for all implanted ears (n= 123). B, Distribution of preoperative hearing loss grades for all nonimplanted ears (n=29). NH indicates normal hearing (−10.0 to 19.9 dB HL), MHL mild hearing loss (20.0 to 34.9 dB HL), MOHL moderate hearing loss (35.0 to 49.9 dB HL), MSHL moderately severe hearing loss (50.0 to 64.9 dB HL), SHL severe hearing loss (65.0 to 79.9 dB HL), PHL profound hearing loss (80.0 to 94.9 dB HL), and CHL complete or total hearing loss (≥95.0 dB HL). Classification follows the recommendations of the Global Burden of Disease (GBD) Expert Group on Hearing Loss (Global Burden of Disease Hearing Loss Expert Group et al. 2013; Olusanya et al. 2019). Percentage values for different hearing loss grades are shown below bars.

Fig. 3.

Distribution of age at implantation and time delay between hearing loss onset and age at cochlear implantation. A, Distribution of age at cochlear implantation of all implanted ears (n = 123). Phases of early implantation at prelingual age are shown in the first two bars (0–1 and 1–2 years). Implantation at perilingual age is shown in the third bar (3–5 years). Implantation in late childhood (6–9 years) is shown in the fourth bar. Further distribution of age at implantation is shown in decades. Impacts of phenotypic characteristics on diagnostic solution rates. B, Time delay between hearing loss onset and age at cochlear implantation for all implanted ears (n = 123). C, Time delay between hearing loss onset and age at cochlear implantation for all unilateral implanted ears, first implanted ears in sequential bilateral implantations and simultaneous bilateral implantations (n = 95). D, Time delay between hearing loss onset and age at cochlear implantation for second implanted ears in sequential bilateral implantations (n = 28).

Fig. 4.

Cochlear implant performance for single genes according to the word recognition scores in the Freiburger monosyllabic speech intelligibility test at 65 dB SPL (WRS₆₅). A, Performance ranking for all single genes (n = 35). B, Performance ranking of single genes within five different gene expression groups according to the localization gene expression within the cochlea designated (1) Neural, (2) Hair Cell, (3) Cochlear Duct and Tectorial Membrane, (4) Stria Vascularis, and (5) Mitochondria. The black solid line shows the median of the overall cohort at 70%, the gray solid line shows the upper (80%) quartile, and the gray dashed line shows the lower quartile (45%).

Fig. 5.

Cochlear implant performance including gene expression and demographic and clinical parameters according to the word recognition scores in the Freiburger monosyllabic speech intelligibility test at 65 dB SPL (WRS₆₅) for 123 implanted ears. A, Cochlear implant performance for 30 categories. Demographic and clinical parameters consisted of inheritance based on the family history, onset of hearing loss, delay of implantation between the onset of hearing loss and cochlear implantation, grades of hearing loss, laterality of hearing loss and sequence of hearing loss. Statistical significance was determined with Fisher’s exact test (*p < 0.05, **p < 0.005, ***p < 0.0005). B, Cochlear implant performance for 10 broader genetic and clinical categories. Median value, interquartile range (IQR) and min/max estimates based on 1.5 IQR of word recognition scores. These represent five groups designated as (1) Gene expression: neural versus other nonneural genes; (2) age at implantation: 0–6 years (0-6y) of age versus age >6 years (gt 6y); (3) onset of hearing loss: congenital versus non-congenital (pre/peri/postlingual; pp_lingual); (4) implantation delay (gap): 0–5 years (0-5y) versus >5 years (gt 5y); (5) sequence of implantation: simultaneous bilateral implantation (simul_ears) versus subsequent bilateral or monaural only implantation (1 and 2 ears).