Open research questions in Hearing, Cochlea, Tinnitus, Genetics

What the literature leaves open

• Despite advances in genetic diagnosis, the development of precision therapies has been limited by the lack of relevant and scalable human model systems that can accommodate the wide spectrum of disease-causing variants and support the evaluation of therapeutic interventions.

  Patient-Derived Inner Ear Organoids as a Disease Modeling and Therapy Validation Platform For Hereditary Inner Ear Disorders · 2026 · DOI

• Future research is warranted to investigate the genotype–phenotype correlations associated with genetic diagnoses within this cohort, thereby enhancing the under- standing of why these patients present with SNHL after passing NHS.

  Sensorineural hearing loss in early childhood after passing newborn hearing screening · 2026 · DOI

• Future research is warranted to investigate the genotype–phenotype correlations associated with genetic diagnoses within this cohort, thereby enhancing the under- standing of why these patients present with SNHL after passing NHS.

  Sensorineural hearing loss in early childhood after passing newborn hearing screening · 2026 · DOI

• However, whether protection associated with SIRT3 modulation in noise-induced hearing loss (NIHL) is accompanied by autophagy-related changes remains unclear.

  AAV-SIRT3 delivery protects against noise-induced hearing loss in association with reduced oxidative injury and autophagy-related changes · 2026 · DOI

• sensory- and synapse-related gene dysregulation, and the mechanistic role of previously uncharacterized genes such as MFAP5, RAB31, and MOXD1 remain incompletely understood.

  Transcriptomic meta-analysis identifies dysregulated pathways and potential therapeutic targets in Vestibular Schwannoma · 2026 · DOI

• 624 Feedback to the cochlea from the brainstem remains poorly understood due to the severance of 625 efferent fibres that occurs when the cochlea is dissected for ex vivo experimentation.

  Kv4, Kv2, and Kv3 currents shape intrinsic lateral olivocochlear excitability independent of hair cell dysfunction during development and ageing. · 2026 · DOI

• This study has a few limitations. As the sample consisted solely of young university students from the occupational therapy and audiology departments, the generalisabil- ity of the findings to the wider student population or the general public is limited. Future research examining a Aktan Yilmaz et al. The Egyptian Journal of Otolaryngology (2026) 42:174 broader age range, clinical samples, objective measure- ments, and multidisciplinary interactions could provide more comprehensive, generalisable results regarding misophonia.

  An investigation into the relationship between misophonia awareness and perceived stress levels among occupational therapy and audiology students · 2026 · DOI

• Though inconsistent results across MRI studies of tinnitus have slowed mechanistic insight, converging evidence across animal and human studies clearly implicate auditory-system dysfunction.

  Auditory Network Discoherence in Chronic Tinnitus · 2026 · DOI

• The medial olivocochlear reflex (MOCR) and the middle ear muscle reflex (MEMR) are two key auditory protective mechanisms, yet their integrity in migraine patients remains to be investigated.

  Migraine impairs the auditory protective mechanism: a potential biomarker · 2026 · DOI

• This study has several limitations. First, we did not mea- sure GSH levels in the cochlear lateral wall tissue, as both NAC and DMET can act as glutathione precursors and may affect the homeostasis of intrinsic antioxidant capac- ity within the cochlea. We also did not quantify NAC or DMET concentrations in cochlear tissues, which could have provided additional insight into the mechanisms Wu et al. Head & Face Medicine (2026) 22:24 Page 10 of 11 underlying their protective effects. Second, while NAC is known to downregulate pro-inflammatory cytokines like TNF-α and IL-1β, our study did not assess the levels of inflammatory markers, which are reported to rise after noise exposure [43, 44]. Thirdly, a DMET-only group was not included in this study; therefore, potential addi- tive or synergistic effects with NAC could not be deter- mined. Fourthly, pre-treatment ABR evaluation was not performed. This omission, therefore, prevents us from definitively confirming that all noise-exposed animals started with perfectly comparable initial hearing damage before the first dose of saline or drug. Fifthly, because the cochlear lateral wall tissues were pooled, we were unable to determine the precise cellular or spatial localization of the Na⁺/K⁺-ATPase, Ca²⁺-ATPase, or LPO changes. This prevented confirmation of whether ATPase restoration occurred in critical stria vascularis cells or if LPO reduc- tion protected specific vulnerable structures. Further- more, the focus only on the Day 14 time point prevents the analysis of the acute phase and the temporal dynam- ics of oxidative stress and enzyme recovery. Sixthly, lack of quantitative food-intake data prevents us from objec- tively linking the reduced weight gain to decreased food intake under stress related to repeated injections and noise exposure. Seventhly, ABR measurements were obtained using click stimuli peaking between 3 and 4 kHz, which do not capture frequency specific deficits, especially at higher frequencies that are more susceptible to broadband noise injury. Future studies using tone burst ABR across a broader frequency range are warranted. Eighthly, we did not perform endocochlear potential or distortion-product otoacoustic emission measurements, which could help clarify the specific cell types protected by NAC and DMET after acoustic trauma. Ninthly, the lack of a combined drug-treated, no-noise group pre- vents us from directly demonstrating the general toxicity and tolerability of the drugs. Moreover, histopathological assessments of outer and inner hair cells, spiral ganglion cells, and ribbon synapses were not conducted in this study, despite these structures being recognized targets of oxidative stress and ROS following noise exposure [40, 45]. Therefore, the protective effects of NAC and DMET on these structures could not be assessed. Lastly, as we did not extract DNA from cochlear lateral wall tissue for methylation analysis, the effect of DMET on epigenetic modifications could not be determined.

  Functional and biochemical protection by combined N-acetylcysteine and D-methionine in guinea pig noise-induced hearing loss · 2026 · DOI

• from 13 Goldstein J, Thomas-Wilson A, Groopman E, et al. ClinGen variant curation expert panel recommendations for classification of variants in GAMT, GATM and SLC6A8 for cerebral creatine deficiency syndromes. Mol Genet Metab. 2024;142(1):108362. 14 Chao X, Xiao Y, Zhang F, et al. Cochlear implantation in a patient with a novel POU3F4 mutation and incomplete partition type-III malformation. Neural Plast. 2020;2020:8829587. 15 Wester JL, Merna C, Peng KA, et al. Facial nerve stimulation implantation for X-linked stapes gusher following cochlear syndrome leading to identification of a novel POU3F4 mutation. Int J Pediatr Otorhinolaryngol. 2016;91:121–123. 16 Smeds H, Wales J, Karltorp E, et al. X-linked malformation deafness: neurodevelopmental symptoms are common in children with IP3 malformation and mutation in POU3F4. Ear Hear. 2022;43(1):53–69. 17 Riggs ER, Andersen EF, Cherry AM, et al. Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020;22(2):245–257. 18 Ahn KJ, Passero F Jr, Crenshaw EB 3rd. Otic mesenchyme inner ear expression of Cre recombinase directed by the enhancer of the Brn4/Pou3f4 gene. Genesis. 2009;47(3):137–141. 19 Lv J, Wang H, Cheng X, et al. AAV1-hOTOF gene therapy for trial. Lancet autosomal recessive deafness 9: a single-arm (London, England). 2024;403(10441):2317–2325. 20 Valayannopoulos V, Bance M, Carvalho DS, Ishiyama A, et al. DB- OTO gene therapy for inherited deafness. N Engl J Med. 2026;394(11):1074–1083.

  Optimising POU3F4 variant interpretation through gene-specific evidence in X-linked hearing loss · 2026 · DOI

• the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel. Genet Med. 2024;26(2):100992. Roesch S, Rasp G, Sarikas A, Dossena S. Genetic determinants of non-syndromic enlarged vestibular aqueduct: a review. Audiol Res. 2021;11(3):423–442. de Kok YJ, van der Maarel SM, Bitner-Glindzicz M, et al. Association between X-linked mixed deafness and mutations in the POU domain gene POU3F4. Science. 1995;267(5198):685–688. 6 Marlin S, Moizard MP, David A, et al. Phenotype and genotype in females with POU3F4 mutations. Clin Genet. 2009;76(6):558–563. 7 Herr W, Sturm RA, Clerc RG, et al. The POU domain: a large conserved region in the mammalian pit-1, oct-1, oct-2, and Caenorhabditis elegans unc-86 gene products. Genes Dev. 1988;2(12A):1513–1516. Naranjo S, Voesenek K, de la Calle-Mustienes E, et al. Multiple enhancers located in a 1-Mb region upstream of POU3F4 promote expression during inner ear development and may be required for hearing. Hum Genet. 2010;128(4):411–419. Tavtigian SV, Greenblatt MS, Harrison SM, et al. Modeling the ACMG/AMP variant classification guidelines as a Bayesian classification framework. Genet Med. 2018;20(9):1054–1060. 9 8 10 Cheng H, Wang X, Zhong M, et al. GDC: integration of multi-omic and phenotypic resources to unravel the genetic pathogenesis of hearing loss. Adv Sci. 2025;12(29):2408891. 11 Yin X, Richardson M, Laner A, et al. Large-scale application of ClinGen-InSiGHT variant APC-specific classification criteria leads to substantial reduction in VUS. Am J Hum Genet. 2024;111(11):2427–2443. ACMG/AMP 12 Drackley A, Somerville C, Arnaud P, et al. Interpretation and classification of FBN1 variants associated with Marfan syndrome: consensus the Clinical Genome Resource’s FBN1 variant curation expert panel. Genome Med. 2024;16(1):154. recommendations from 13 Goldstein J, Thomas-Wilson A, Groopman E, et al. ClinGen variant curation expert panel recommendations for classification of variants in GAMT, GATM and SLC6A8 for cerebral creatine deficiency syndromes. Mol Genet Metab. 2024;142(1):108362. 14 Chao X, Xiao Y, Zhang F, et al. Cochlear implantation in a patient with a novel POU3F4 mutation and incomplete partition type-III malformation. Neural Plast. 2020;2020:8829587. 15 Wester JL, Merna C, Peng KA, et al. Facial nerve stimulation implantation for X-linked stapes gusher following cochlear syndrome leading to identification of a novel POU3F4 mutation. Int J Pediatr Otorhinolaryngol. 2016;91:121–123. 16 Smeds H, Wales J, Karltorp E, et al. X-linked malformation deafness: neurodevelopmental symptoms are common in children with IP3 malformation and mutation in POU3F4. Ear Hear. 2022;43(1):53–69. 17 Riggs ER, Andersen EF, Cherry AM, et al.

  Optimising POU3F4 variant interpretation through gene-specific evidence in X-linked hearing loss · 2026 · DOI

• Analysis of the survey was limited in many ways, not the least of which relate to the heterogeneity of participants’ relationship to music-related sound exposures. In addition to respondents playing different instruments and styles of music, amount of exposure varied due to distinct roles – touring performers vs. agents vs. venue employees—that contributed to differences in the hours, days, even years of participants’ work.

  Hearing healthcare in the music industry: results from the MusiCares and Tuned partnership survey · 2026 · DOI

• This review has several limitations that should be acknowledged. First, heterogeneity in participant char- acteristics, treatment protocols, and outcome measures Alashram The Egyptian Journal of Otolaryngology (2026) 42:143 limit the identification of lidocaine’s effects and the gen- eralizability of the findings. Second, subgroup analysis was not performed due to the limited number of stud- ies and heterogeneity across studies. Third, the risk-of- bias assessment indicated “some concerns” across many domains, thereby increasing the risk of bias. Fourth, the included studies did not include objective outcome mea- sures. The absence of physiological assessments (e.g., TEOAEs with contralateral masking) increases the risk of measurement bias and limits confidence in the observed treatment effects. Fifth, the included studies used active pharmacological comparators. This may have biased between-group comparisons by introducing independent tinnitus-modifying effects unrelated to lidocaine. Finally, small sample sizes across studies may increase the risk of imprecision and reduce the robustness of the pooled esti- mates. Further randomized controlled trials are needed to understand the effects of the intervention on tinnitus.

  Clinical efficacy of lidocaine in alleviating tinnitus symptoms: a systematic review and meta-analysis of randomized controlled trials · 2026 · DOI

• directions 6.1 Limitations Although mindfulness-based therapy may benefit some patients with chronic tinnitus, several limitations should be recognized. Its effects appear to relate mainly to reductions in tinnitus-related distress and associated psychological burden, rather than to direct reductions in tinnitus loudness.

  Mindfulness-based therapy for chronic tinnitus: a narrative review · 2026 · DOI

• The contribution of cochlear neuropathy versus hair cell loss to overall hearing impairment requires comparative analysis of noise-exposed and genetically-deaf animals, as Furman et al. (2013) demonstrate selective fiber loss in low-spontaneous-rate neurons but do not clarify whether primary neuropathy precedes secondary hair cell degeneration.

  Hair cell loss – cause or consequence of hearing loss? · 2026 · DOI

• The mechanotransduction-dependent control of stereocilia length and row identity (Krey et al. 2020, 2023) requires investigation of how disruptions in mechanotransduction signaling during hair bundle development lead to hair cell dysfunction versus apoptosis, as the threshold between structural defects and cell death has not been systematically defined.

  Hair cell loss – cause or consequence of hearing loss? · 2026 · DOI

• Cisplatin ototoxicity mechanisms require investigation of why cisplatin is retained indefinitely in cochlear tissue (Breglio et al. 2017) and whether continuous drug exposure causes progressive hair cell loss versus acute injury, as the relationship between cellular cisplatin accumulation and the timing of hair cell death remains uncharacterized.

  Hair cell loss – cause or consequence of hearing loss? · 2026 · DOI

• The role of SNARE protein SNAP-25 in auditory ribbon synapse exocytosis requires functional investigation of how SNAP-25 disruption affects neurotransmitter release kinetics and hearing thresholds across frequency ranges, as Calvet et al. (2022) demonstrate SNAP-25 requirement but do not characterize how synaptic dysfunction correlates with behavioral hearing loss.

  Hair cell loss – cause or consequence of hearing loss? · 2026 · DOI

• The mechanisms underlying prestin-dependent outer hair cell survival require investigation of partial rescue in PrestinV499G/Y501H knockin mice to determine whether prestin loss directly causes hair cell degeneration or triggers secondary degeneration pathways, as Cheatham et al. (2015) demonstrate partial rescue but do not elucidate the molecular cascade linking prestin function to cell viability.

  Hair cell loss – cause or consequence of hearing loss? · 2026 · DOI

• The discrepancy between mouse model hearing loss mechanisms and human cochlear pathology requires comparative analysis of stereocilia ultrastructural defects and tectorial membrane changes across aging mouse and human specimens, as Bullen et al. (2020) identify ultrastructural abnormalities but do not systematically correlate these with functional hearing loss severity in human subjects.

  Hair cell loss – cause or consequence of hearing loss? · 2026 · DOI

• The timing mechanisms of auditory sensory deficits in genetic hearing loss models like Norrie disease require longitudinal investigation to determine critical developmental windows for therapeutic intervention, as Bryant et al. (2022) note that the timing of deficits has implications for intervention but do not systematically characterize when hair cell dysfunction precedes morphological loss.

  Hair cell loss – cause or consequence of hearing loss? · 2026 · DOI

• The identified novel variants in hearing impairment genes lack comparative splicing prediction analysis using consistent tools; variants were evaluated with SpliceAI and Human Splicing Finder but systematic concordance assessment across splicing prediction algorithms for Cameroonian variants is not documented.

  Exome sequencing identifies known and candidate genes in hearing impairment in Cameroon · 2026 · DOI

• Population genetic structure analysis of Cameroonian samples uses ancestry estimation methods, but fine-scale linkage disequilibrium mapping and haplotype-phase analysis specific to Central African populations with hearing loss have not been performed to improve variant interpretation.

  Exome sequencing identifies known and candidate genes in hearing impairment in Cameroon · 2026 · DOI

• The paper references recent gene therapy successes for DFNB9 deafness but does not assess which candidate genes identified in Cameroonian families would be suitable targets for AAV-mediated gene therapy approaches or bilateral gene therapy interventions.

  Exome sequencing identifies known and candidate genes in hearing impairment in Cameroon · 2026 · DOI

Most-cited papers in Hearing, Cochlea, Tinnitus, Genetics

• Prevalence of Hearing Loss and Differences by Demographic Characteristics Among US Adults<subtitle>Data From the National Health and Nutrition Examination Survey, 1999-2004</subtitle> · Archives of Internal Medicine · 2008 · 802 citations
• AAV1-hOTOF gene therapy for autosomal recessive deafness 9: a single-arm trial · The Lancet · 2024 · 296 citations
• Hearing Loss in Infants with Microcephaly and Evidence of Congenital Zika Virus Infection — Brazil, November 2015–May 2016 · MMWR Morbidity and Mortality Weekly Report · 2016 · 177 citations
• AAV‐Mediated Gene Therapy Restores Hearing in Patients with DFNB9 Deafness · Advanced Science · 2024 · 150 citations
• Coaches roles in the academic success of male student athletes. · The Sport Journal · 2005 · 148 citations
• Thinking About Your Next OPAC · Computers in libraries · 2007 · 133 citations
• Bilateral gene therapy in children with autosomal recessive deafness 9: single-arm trial results · Nature Medicine · 2024 · 125 citations
• The prevalence of tinnitus and the relationship with neuroticism in a middle-aged UK population · Journal of Psychosomatic Research · 2013 · 118 citations
• Mechanisms of Aminoglycoside- and Cisplatin-Induced Ototoxicity · American Journal of Audiology · 2021 · 68 citations
• Macrophage depletion protects against cisplatin-induced ototoxicity and nephrotoxicity · Science Advances · 2024 · 61 citations

Most recent work

• Bimodal Neuromodulation for Tinnitus in a Clinical Practice Setting: Clinically Significant Benefit for Patients With Moderate or Worse Symptoms · American Journal of Audiology · 2026
• Exome sequencing identifies known and candidate genes in hearing impairment in Cameroon · Communications Medicine · 2026
• Exosomes as Targeted Drug Delivery Systems: Strategies and Mechanisms for Mitigating Cisplatin-Induced Hair Cell Damage · International Journal of Biology and Life Sciences · 2026
• Hair cell loss – cause or consequence of hearing loss? · Frontiers in Cell and Developmental Biology · 2026
• BAX-dependent mitochondrial outer membrane rupture in cochlear hair cells facilitates cisplatin ototoxicity · Communications Biology · 2026
• Ferritin light-chain contributes to hair cells function and survival · Communications Biology · 2026
• Rediscovering the Gut–Mito–Ear Axis: A Systems-Biology Framework for Ototoxic Vulnerability and Microbiome-Targeted Prevention · Cells · 2026
• Evaluation of the Effects of Caloric Vestibular Stimulations on Distortion Product Otoacoustic Emission Responses · American Journal of Audiology · 2026
• Identification of vulnerable ribbon synapses in aged C57BL/6 mouse cochlea · Clinical and Experimental Otorhinolaryngology · 2026
• Burden of novel and ultra-rare missense variants in the NF-κB pathway genes associated to Ménière’s disease · Frontiers in Immunology · 2026

Related topics in Neuroscience