Outcome evaluation in genetically characterised populations and auditory profiling

Cochlear Implantation & Auditory Outcomes

6 min read

Not all patients benefit equally from cochlear implantation, and one of the most important unsolved questions is how the underlying genetics of hearing loss influences implant outcomes. Our approach combines careful audiological phenotyping — using objective measures of cochlear function, electrophysiology, and psychophysics — with genotypic characterisation to identify predictors of implant success.

Cochlear site-of-lesion was long thought to be a key determinant of outcome: genes disrupting synaptic transmission (OTOF) or auditory nerve integrity (OPA1) were expected to yield worse results than those affecting outer hair cells. The data from our genotyped cohort tell a more nuanced story. In the largest single-centre genotyped CI cohort published to date (Fehrmann et al., 2025) — 220 subjects (299 ears) carrying pathogenic variants in 31 nuclear and mitochondrial genes — the median phoneme score was 90%, and outcome variability was not explained by cochlear site-of-lesion but by subject-specific factors: age at implantation, duration of hearing loss, pre-implantation hearing aid use, and CI experience. Collectively these factors accounted for 19% of outcome variance, with poorer outcomes (phoneme score <70%) concentrated in subjects with prolonged auditory deprivation or late implantation.

Main findings

Gene / syndrome Phenotype CI outcomes Key finding Reference
Overall genotyped cohort (31 genes) Severe-to-profound SNHL Median phoneme 90%, IQR not reported Site-of-lesion not predictive; age at implantation, SNHL duration, and HA use are the dominant predictors (Fehrmann et al., 2025)
TMPRSS3 / DFNB8/DFNB10 AR progressive SNHL Phoneme 89% at 5 yr, stable to 10 yr; word recognition 76% (international cohort) No difference vs. non-SGN-gene controls; contradicts spiral ganglion hypothesis; older age at implantation associated with worse outcomes (Fehrmann et al., 2023; Colbert et al., 2024)
COCH / DFNA9 Progressive ADSNHL + vestibular 35% pre-CI → 84% at 1 yr post-CI Fazekas score (cerebral WML) not predictive; SCC signal loss in 97.7% on MRI (missing reference)
COCH / DFNA9 (p.Pro51Ser) Progressive ADSNHL + vestibular (LCCL domain) Noninferior vs. matched controls; stable to 5 yr; QoL improved Higher pre-CI aided speech perception predicts better outcomes; residual hearing post-CI predicts 1-yr score; supports earlier implantation before further decline (Robijn et al., 2026)
WFS1 (mono-allelic) DFNA6/14/38 + Wolfram-like syndrome (Velde et al., 2023) Mean phoneme 90 ± 9% at 1 yr; 94 ± 6% at 10 yr Good and stable long-term outcomes; contradicts suggested link with auditory neuropathy (Fehrmann et al., 2025)
Usher syndrome type 1 — early (≤ 7 yr) Congenital profound SNHL + RP Phoneme 100% (IQR 95–100) Simultaneous bilateral implantation outperforms sequential; early CI is critical (Fehrmann et al., 2024)
Usher syndrome type 1 — late (≥ 8 yr) Congenital profound SNHL + RP Phoneme 12% (IQR 0–12) Sound detection only; insufficient for oral communication (Fehrmann et al., 2024)
Usher syndrome type 2 Moderate–severe progressive SNHL + RP Phoneme 85% (IQR 81–95) Younger age at CI and higher pre-implantation scores predict better outcomes (Fehrmann et al., 2024)
Usher syndrome type 3 Variable progressive SNHL + RP Phoneme 71% (IQR 45–91) High inter-subject variability; outcome prediction remains challenging (Fehrmann et al., 2024)

outcomes per group Figure. CI outcomes per gene, sorted by median phoneme score (high-to-low) and colour-coded by site-of-lesion. Dots represent individual ears.

Summary

Across diagnostic groups the picture is consistently encouraging: cochlear implantation is an effective rehabilitation option for the large majority of individuals with hereditary hearing loss, regardless of the specific gene involved. The clearest exception remains late implantation in USH1, where prolonged auditory deprivation without adequate residual hearing leaves too little neural substrate for speech recognition — sound detection remains, but oral communication does not (Fehrmann et al., 2024). At the other extreme, early-implanted USH1 subjects achieve ceiling-level performance, underscoring that the window for intervention is the most powerful modifiable variable in this group.

The TMPRSS3 results are instructive for a different reason. TMPRSS3 was long suspected to cause poor CI outcomes because of its expression in spiral ganglion neurons — the very cells that cochlear implants stimulate. Long-term follow-up in a multicentre DOOFNL cohort showed otherwise: phoneme scores of 89% at five years, stable to ten years, with no difference from non-SGN-gene controls (Fehrmann et al., 2023; Colbert et al., 2024). This directly challenges the spiral ganglion hypothesis as a simple predictor of CI performance.

Complementing the gene-specific outcome data, work on auditory profiling (Lanting et al., 2022) has shown that suprathreshold cochlear processing — assessed by loudness growth and spectral resolution — is shaped by genotype and provides better biomarkers for predicting speech-in-noise performance than audiometric threshold alone. This framework informs both CI candidate evaluation and the design of audiological endpoints for inner-ear gene therapy trials.

An IIR research grant (2022–2025, with Cochlear Ltd) supported the PhD project by Mirthe Fehrmann that generated much of the gene-specific outcome data above. A second IIR project (2025–2029, with MedEl) now addresses anatomy-based fitting and the neural correlates of listening effort, with pilot studies currently running.

Key references

Journal Articles

  1. Robijn, S. M. M., Van Nierop, J. W. I., Huinck, W. J., Mylanus, E. A. M., Kunst, H. P. M., Lanting, C. P., & Pennings, R. J. E. (2026). Performance Results and Timing of Cochlear Implantation in Patients With DFNA9 (p.Pro51Ser). Otology & Neurotology. https://doi.org/10.1097/MAO.0000000000004969
  2. Fehrmann, M. L. A., Haer-Wigman, L., Kremer, H., Yntema, H. G., Thijssen, M. E. G., Mylanus, E. a. M., Huinck, W. J., Lanting, C. P., & Pennings, R. J. E. (2025). Cochlear Implantation Outcomes in Genotyped Subjects with Sensorineural Hearing Loss. Journal of the Association for Research in Otolaryngology: JARO, 26(3), 331–348. https://doi.org/10.1007/s10162-025-00987-0
  3. Fehrmann, M. L. A., Lanting, C. P., Haer-Wigman, L., Mylanus, E. a. M., Huinck, W. J., & Pennings, R. J. E. (2025). Good Cochlear Implantation Outcomes in Subjects with Mono-Allelic WFS1-associated Sensorineural Hearing Loss - a Case Series. International Journal of Audiology, 64(8), 863–871. https://doi.org/10.1080/14992027.2024.2411579
  4. Fehrmann, M. L. A., Lanting, C. P., Haer-Wigman, L., Yntema, H. G., Mylanus, E. A. M., Huinck, W. J., & Pennings, R. J. E. (2024). Long-Term Outcomes of Cochlear Implantation in Usher Syndrome. Ear and Hearing, 45(6), 1542–1553. https://doi.org/10.1097/AUD.0000000000001544
  5. Colbert, B. M., Lanting, C., Smeal, M., Blanton, S., Dykxhoorn, D. M., Tang, P.-C., Getchell, R. L., Velde, H., Fehrmann, M., Thorpe, R., Chapagain, P., Elkhaligy, H., Kremer, H., Yntema, H., Haer-Wigman, L., Redfield, S., Sun, T., Bruijn, S., Plomp, A., … Liu, X. Z. (2024). The Natural History and Genotype–Phenotype Correlations of TMPRSS3 Hearing Loss: An International, Multi-Center, Cohort Analysis. Human Genetics, 143(5), 721–734. https://doi.org/10.1007/s00439-024-02648-3
  6. Velde, H. M., Huizenga, X. J. J., Yntema, H. G., Haer-Wigman, L., Beynon, A. J., Oostrik, J., Pegge, S. A. H., Kremer, H., Lanting, C. P., & Pennings, R. J. E. (2023). Genotype and Phenotype Analyses of a Novel WFS1 Variant (c.2512C>T p.(Pro838Ser)) Associated with DFNA6/14/38. Genes, 14(2), 457. https://doi.org/10.3390/genes14020457
  7. Fehrmann, M. L. A., Huinck, W. J., Thijssen, M. E. G., Haer-Wigman, L., Yntema, H. G., Rotteveel, L. J. C., Widdershoven, J. C. C., Goderie, T., van Dooren, M. F., Hoefsloot, E. H., van der Schroeff, M. P., Mylanus, E. a. M., DOOFNL consortium, Lanting, C. P., & Pennings, R. J. E. (2023). Stable Long-Term Outcomes after Cochlear Implantation in Subjects with TMPRSS3 Associated Hearing Loss: A Retrospective Multicentre Study. Journal of Otolaryngology - Head & Neck Surgery = Le Journal D’Oto-Rhino-Laryngologie Et De Chirurgie Cervico-Faciale, 52(1), 82. https://doi.org/10.1186/s40463-023-00680-3
  8. Lanting, C., Snik, A., Leijendeckers, J., Bosman, A., & Pennings, R. (2022). Genetic Hearing Loss Affects Cochlear Processing. Genes, 13(11), 1923. https://doi.org/10.3390/genes13111923

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