Genotype–Phenotype Correlations & Natural History

Understanding how a specific genetic variant translates into an audiological phenotype — and how that phenotype evolves over time — matters first and foremost to patients and their clinicians. But it has a second, increasingly urgent purpose: without a quantitative natural history baseline, it is impossible to tell whether an intervention is actually working. In rare genetic disorders where randomised controlled trials are ethically or logistically impractical, prospective cohort data and meta-analysed progression curves serve as the external comparator arm against which a treated patient’s trajectory can be measured. This project documents that baseline for three genetic hearing loss models — DFNA9, TMPRSS3-related hearing loss, and Usher syndrome type 2A — each of which is now the subject of active therapeutic development.

Findings by disease model

Disease / gene	Phenotype	Study	Key finding	Reference
DFNA9 (COCH)	Progressive ADSNHL + vestibular	HuGE meta-analysis (n = 475)	Variant-specific audiometric progression rates quantified; vWFA2-domain variants progress more rapidly than vWFA1-domain variants; progression accelerates with age	(Robijn et al., 2022)
DFNA9 (COCH)	Progressive ADSNHL	Case series	Novel vWFA2 variant extends phenotypic spectrum toward a milder end; illustrates range of disease expression within DFNA9	(Smits et al., 2021)
DFNA9 (COCH)	End-stage SNHL	CI outcomes cohort	Good CI outcomes despite co-occurring cerebral white matter lesions and vestibular abnormalities; MRI findings alone do not predict speech perception post-implantation	(Fehrmann et al., 2024)
TMPRSS3	Recessive, post-lingual SNHL	International multi-centre cohort	Largest TMPRSS3 natural history study to date; genotype-specific progression rates characterised; age-of-onset and rate-of-progression vary substantially by variant class	(Colbert et al., 2024)
TMPRSS3	Post-implant	Retrospective multi-centre	Stable long-term CI outcomes across genotype groups over 10+ years of follow-up; establishes post-intervention benchmark	(Fehrmann et al., 2023)
USH2A / Usher type 2A	Syndromic HL + retinitis pigmentosa + vestibular	4-year prospective cohort (CRUSH study)	Age-related typical audiograms (ARTA) established for the first time in USH2A; hearing relatively stable with a mid-frequency-predominant pattern; vestibular phenotype characterised longitudinally	(Wijn et al., 2025)
Usher syndrome (pan-USH)	End-stage SNHL	Long-term CI outcomes	Good CI outcomes across USH subtypes and genotypes; trajectory to implantation candidacy described, relevant for intervention timing	(Fehrmann et al., 2024)

Summary

DFNA9 is caused by dominant-negative variants in COCH and is characterised by progressive, high-frequency sensorineural hearing loss accompanied by vestibular dysfunction. The HuGE systematic review and audiometric meta-analysis quantified variant-specific progression rates across 475 carriers, establishing for the first time that domain of mutation (vWFA1 vs. vWFA2) predicts trajectory (Robijn et al., 2022).

Figure. A phenotypic analysis of DFNA9; the calculated age of onset and annual threshold deterioration (ATD) across variants affecting cochlin within the LCCL, the Ivd1, and the vWFA2 domain. (A) ATD of the pure-tone average across PTA0,5-4kHz with increasing age. (B) Parameter estimates of the age-of-onset (HL >25 dB) and the ATD (dB/year) for the various variants.

Individual variant characterisations extend the phenotypic spectrum (Smits et al., 2021), and a dedicated CI outcomes study demonstrates that — even in the presence of white matter lesions and vestibular abnormalities — cochlear implantation yields reliable speech perception, informing late-stage management (Fehrmann et al., 2024).

TMPRSS3-associated hearing loss presents as a recessive, predominantly post-lingual sensorineural loss that can progress rapidly in some variant classes. A large international multi-centre cohort study characterised the natural history with genotype-specific resolution (Colbert et al., 2024), while retrospective multicentre follow-up confirmed that CI outcomes remain stable over more than ten years (Fehrmann et al., 2023). Together, these datasets define both the untreated disease trajectory and the post-intervention ceiling — exactly the paired data structure needed to evaluate a future therapy.

The CRUSH study in Usher syndrome type 2A followed a Dutch USH2A cohort prospectively over four years, capturing both audiometric and vestibular trajectories (Wijn et al., 2025). The resulting ARTA curves reveal a relatively stable, mid-frequency-predominant hearing loss pattern that diverges from the rapid progression often assumed for syndromic forms. Long-term CI outcomes across all Usher subtypes confirm a predictable post-implant plateau (Fehrmann et al., 2024). Knowing this natural rate of change — and its variance — is what will make a trial interpretable.

Towards intervention: why this baseline matters now

The clinical urgency behind this work has sharpened considerably. Proof-of-concept gene therapy trials for OTOF-related hearing loss — conducted in China, the United States, and Europe — have now demonstrated that substantial restoration of hearing is possible in children with otoferlin deficiency, validating the translational pathway from gene discovery to first-in-human therapy for hereditary hearing loss. Antisense oligonucleotide (AON) approaches, which modulate splicing rather than replacing a gene, extend this pipeline to dominant and autosomal recessive conditions that are less amenable to conventional gene addition.

Two programmes directly relevant to this natural history work are being developed at Radboudumc by colleagues Erwin van Wijk and Erik de Vrieze. Their AON-based splice modulation approach targets the common Dutch USH2A pseudoexon variant (c.7595-2144A>G, accounting for a substantial fraction of Dutch USH2A alleles) as well as COCH variants underlying DFNA9, with early-phase clinical work already underway. The CRUSH audiometric baselines and the DFNA9 meta-analysis progression curves produced by our group feed directly into the outcome measure design for those programmes — defining what change in threshold or word recognition score constitutes a meaningful treatment effect beyond expected natural history.

This intersection of natural history research and therapeutic development is also reflected in invited work on genetic therapies (missing reference) and on audiological biomarkers for clinical trials (missing reference).

Key references

Journal Articles

1. Wijn, D. H., Fehrmann, M. L. A., Robijn, S. M. M., Velde, H. M., Smits, J. J., van Wijk, E., Beynon, A. J., Cals, F. L. J., Hoyng, C. B., Yzer, S., Lanting, C. P., & Pennings, R. J. E. (2025). From Sound to Stability: Lessons Learned From the CRUSH Study on Hearing Loss Progression and Vestibular Phenotype in Usher Syndrome Type 2A. Otology & Neurotology, 10.1097/MAO.0000000000004851. https://doi.org/10.1097/MAO.0000000000004851
2. 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
3. Fehrmann, M. L. A., Meijer, F. J. A., Mylanus, E. A. M., Pennings, R. J. E., Lanting, C. P., & Huinck, W. J. (2024). Evaluating Cochlear Implant Outcomes in DFNA9 Subjects: A Comprehensive Study on Cerebral White Matter Lesions and Vestibular Abnormalities. European Archives of Oto-Rhino-Laryngology. https://doi.org/10.1007/s00405-024-08933-1
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, 10.1097/AUD.0000000000001544. https://doi.org/10.1097/AUD.0000000000001544
5. 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, Van Dooren, M. F., Kant, S. G., De Gier, H. H. W., Hoefsloot, E. H., Van Der Schroeff, M. P., Rotteveel, L. J. C., … 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, 52(1), 82. https://doi.org/10.1186/s40463-023-00680-3
6. Robijn, S. M. M., Smits, J. J., Sezer, K., Huygen, P. L. M., Beynon, A. J., Van Wijk, E., Kremer, H., De Vrieze, E., Lanting, C. P., & Pennings, R. J. E. (2022). Genotype-Phenotype Correlations of Pathogenic COCH Variants in DFNA9: A HuGE Systematic Review and Audiometric Meta-Analysis. Biomolecules, 12(2), 220. https://doi.org/10.3390/biom12020220
7. Smits, J. J., Van Beelen, E., Weegerink, N. J. D., Oostrik, J., Huygen, P. L. M., Beynon, A. J., Lanting, C. P., Kunst, H. P. M., Schraders, M., Kremer, H., De Vrieze, E., & Pennings, R. J. E. (2021). A Novel COCH Mutation Affects the vWFA2 Domain and Leads to a Relatively Mild DFNA9 Phenotype. Otology & Neurotology, 42(4), e399–e407. https://doi.org/10.1097/MAO.0000000000003004

Posts & write-ups

• Hearing Loss and Vestibular Function in Usher Syndrome Type 2A
  The CRUSH Study: Four Years of Prospective Follow-Up

  Our longitudinal CRUSH study shows measurable hearing progression in USH2a beyond presbycusis, stable speech understanding, and an unexpected pattern of subclinical otolith dysfunction — with implications for follow-up, counseling, and cochlear implant timing.

• Genetic Insights into Cochlear Implant Outcomes
  What We Learned from the Largest Cohort of Genotyped CI Recipients

  New findings from a Dutch cohort reveal that subject-specific factors—not genetic site-of-lesion—best predict CI outcomes.