Autosomal Recessive Nonsyndromic Hearing Loss 103

Mendelian MONDO:0014469 Pathograph 9 Show in embeddings browser Autosomal Recessive Nonsyndromic Hearing Loss

DFNB103 is an autosomal recessive sensorineural hearing disorder caused by biallelic CLIC5 variants. Reported hearing loss is bilateral and progressive, with variable onset including prelingual and postlingual presentations. Vestibular areflexia is documented in the Turkish discovery family but is not established as universal. A Siberian founder allele accounts for an appreciable fraction of selected GJB2-negative patients in the Sakha Republic. Animal and cell studies support a role for CLIC5 in maintaining membrane-cytoskeletal attachments at the base of hair-cell stereocilia. CLIC5-deficient mice develop partner-protein mislocalization, stereocilia fusion and later hair-cell loss. Direct molecular contacts and the corresponding human cochlear lesion remain incompletely defined. Neonatal AAV gene replacement improves hearing and balance in an ENU-induced Clic5 missense mouse model, but delayed treatment and durable human benefit have not been established.

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1
Inheritance
4
Pathophys.
6
Phenotypes
3
Gaps
9
Pathograph
1
Genes
7
Medical Actions
2
Models
5
References
1
Deep Research
👪

Inheritance

1
Autosomal recessive HP:0000007
Biallelic CLIC5 variants: homozygous in the consanguineous Turkish founding family and in the Siberian founder cohort, compound heterozygous in the non-consanguineous Cameroonian family where each unaffected relative carried one of the two alleles. For two confirmed heterozygous parents, each pregnancy has a 25% chance of inheriting both familial pathogenic alleles, a 50% carrier chance and a 25% chance of inheriting neither. Individual onset and severity are not predicted by this Mendelian ratio.
Autosomal recessive inheritance
Show evidence (3 references)
PMID:24781754 SUPPORT PRIMARY RESULT Human Clinical
"Mutation analysis of CLIC5 revealed a homozygous nonsense mutation c.96T>A (p.(Cys32Ter)) that segregated with the hearing loss."
Homozygosity in the affected siblings of a consanguineous pedigree, with segregation through the family, which is the recessive pattern.
PMID:33114113 SUPPORT PRIMARY RESULT Human Clinical
"The three affected individuals were compound heterozygous for both variants, and all unaffected individuals were heterozygous for one of the two variants."
The three affected siblings carried the two variants in trans, while tested unaffected relatives carried one variant.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/pdf/Bookshelf_NBK1434.pdf SUPPORT REVIEW SYNTHESIS Other
"If both parents are known to be heterozygous for an autosomal recessive hearing loss-related pathogenic variant, each sib of the proband has at conception a 25% chance of having hearing loss, a 50% chance of having no hearing loss and being a carrier, and a 25% chance of having no hearing loss..."
General autosomal recessive hearing-loss counseling, conditional on parental carrier status; not a DFNB103 penetrance estimate.
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Discussions and Knowledge Gaps

3
Can CLIC5 replacement improve function after hearing loss or bundle damage begins, and what limits durable auditory rescue?
KNOWLEDGE GAP clic5_therapeutic_window_timing
Attached to
animal_models#Clic5 nmf318 missense mouse treated with inner ear AAV pathophysiology#Progressive Stereocilia Fusion and Bundle Distortion
P0 delivery preceded morphological changes in the nmf318 model. The experiment does not define a closed window, prove irreversibility of fusion or establish an equivalent human treatment age. Human onset is variable, and cochlear histology is unavailable. Delayed delivery with adequate transduction and dose controls is needed. Vestibular rescue persisted through 12 weeks while auditory thresholds worsened despite persistent expression and no major gross morphological change. These endpoints do not exclude subtle bundle defects, cell-specific expression loss, inflammation or background susceptibility; the C57BL/6 Cdh23 allele is one potential confound. Radixin rescue with persistent taperin mislocalization also limits claims of complete complex restoration.
Proposed experiments
Delayed AAV delivery after stereocilia fusion has begun
exp_dfnb103_delayed_aav_after_fusion_onset
Compare P0 with P21 and P42 delivery in the nmf318 line, using age-matched untreated and vector controls, verified cell-specific transduction, expression and dose. Measure auditory and vestibular function, partner localization, hair-cell counts and bundle ultrastructure; use matched cohorts where destructive imaging prevents within-cell follow-up. Include strain-background controls to assess high-frequency susceptibility.
Would support
pathophysiology#Progressive Stereocilia Fusion and Bundle Distortion
Would refute
pathophysiology#Progressive Stereocilia Fusion and Bundle Distortion
Supporting outcome
  • Delayed delivery improves or stabilizes function and morphology with verified expression, supporting residual reversibility or prevention of further damage under that regimen.
Refuting outcome
  • Verified delayed delivery fails to improve the measured endpoints, arguing against efficacy of that regimen at that stage; this would not prove universal irreversibility or restrict all human strategies to infancy.
Show evidence (3 references)
PMID:40859056 SUPPORT PRIMARY RESULT Model Organism
"In this study, we performed utricle injections into P0 mice, prior to the morphological changes in hair cells that begin between P14 and P17, at the time of hearing onset"
The intervention preceded structural onset; delayed efficacy was not tested.
PMID:40859056 SUPPORT PRIMARY RESULT Model Organism
"Vestibular function rescue remained durable up to 12 weeks post-injection, while ABR thresholds deteriorated over time, particularly at high frequencies."
The divergence between the two rescued systems over time.
PMID:40859056 SUPPORT PRIMARY RESULT Model Organism
"Despite the deterioration of ABR thresholds over time, transgene expression remained robust at 12 weeks, and no significant morphological changes in hair cells were observed."
Persistent expression and gross morphology leave several technical and biological explanations for auditory decline unresolved.
Is DFNB103 truly nonsyndromic, or does biallelic CLIC5 loss carry a low-grade renal phenotype that has not been looked for systematically?
KNOWLEDGE GAP clic5_renal_involvement
Attached to
genetic#CLIC5 disease#Autosomal Recessive Nonsyndromic Hearing Loss 103
The Turkish discovery-family boy had repeatedly elevated urine albumin/creatinine ratios (9.2 and 3.8 mg/mmol) and mildly elevated blood pressure at age 11, with preserved estimated GFR (114 ml/min/1.73 m2). No renal biopsy established a lesion. The authors recommended follow-up for both siblings. Cameroonian participants lacked clinical renal signs, but biochemical kidney assessment was explicitly proposed for future work. The available Siberian abstract does not report renal evaluation. CLIC5-associated podocyte abnormalities in mice motivate systematic human assessment but do not establish a syndromic human nephropathy. Longitudinal albuminuria, blood pressure and kidney-function measurements with appropriate controls could clarify penetrance and alternative causes.
Show evidence (2 references)
PMID:24781754 SUPPORT PRIMARY RESULT Human Clinical
"Impaired hearing is accompanied by vestibular areflexia and in one of the patients with mild renal dysfunction."
An isolated renal observation in one of two discovery-family siblings; association with CLIC5 remains uncertain.
url:https://repositoriosaludmadrid.es/bitstreams/e783eafe-8086-4b75-be09-9bd6ce296bad/download SUPPORT PRIMARY RESULT Human Clinical
"Subsequent renal function follow-up of patient II.3 in the future will be needed to determine whether it is indeed a nephropathy."
The primary report explicitly leaves nephropathy unresolved.
Do experimentally identified CLIC5 regulators or binding partners modify human DFNB103 severity?
KNOWLEDGE GAP clic5_expression_regulation
Attached to
genetic#CLIC5
miR-96 and miR-182 mimics reduce CLIC5 RNA/protein and a CLIC5 3-prime-UTR reporter in HEI-OC1 cells. GRXCR2 interaction experiments also show functional importance despite largely preserved bundle morphology. Neither study establishes a modifier allele or prognostic marker in people with biallelic CLIC5 variants.
Show evidence (2 references)
PMID:22889583 SUPPORT PRIMARY RESULT In Vitro
"Our findings thus suggest that CLIC5 is directly regulated by miR-96 and miR-182 and that the target sequence in this regard is located between nucleotides 760-766 within the CLIC5 3'-UTR."
Cell and reporter experiments establish regulation in the tested system, not a human DFNB103 modifier.
PMID:34026762 SUPPORT PRIMARY RESULT Model Organism
"Interestingly, mice harboring this in-frame deletion in Grxcr2 exhibit moderate hearing loss at lower frequencies and severe hearing loss at higher frequencies although the morphogenesis of stereocilia is minimally affected."
Deleting GRXCR2 residues 36–95 disrupts CLIC5 association and causes hearing loss despite largely preserved bundle morphology. This is a partner-gene experiment, not evidence of a human DFNB103 modifier allele.
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Pathophysiology

4
CLIC5 Loss of Function
Biallelic CLIC5 variants impair protein function through allele-dependent mechanisms. The Turkish p.Cys32Ter allele predicts early truncation, but nonsense-mediated RNA decay was not confirmed in patient lymphoblastoid cells. The Cameroonian c.63+1G>A donor variant has a predicted, untested splicing effect; p.Leu75Pro shows increased abundance and perinuclear aggregation after ectopic expression in HEK293 cells. These observations do not establish complete absence of protein for every human allele. The Siberian p.Trp215Ter allele is another truncating variant.
CLIC5 hgnc:13517 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CLIC5 (hgnc:13517). hgnc:13517 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Loss of Membrane-Actin Tethering at the Stereocilia Taper
Show evidence (4 references)
PMID:24781754 SUPPORT PRIMARY RESULT Human Clinical
"Mutation analysis of CLIC5 revealed a homozygous nonsense mutation c.96T>A (p.(Cys32Ter)) that segregated with the hearing loss."
The founding nonsense allele, which truncates the protein at codon 32, and its segregation with the phenotype.
PMID:33114113 SUPPORT PRIMARY RESULT Computational
"In silico analysis showed that the missense variant CLIC5-p.(L75P) substitutes a highly conserved amino acid residue (leucine), and is expected to alter the stability, the structure, and the function of the CLIC5 protein, while the splicing variant CLIC5-(c.63+1G>A) is predicted to disrupt a..."
The predicted consequences of the second family's compound heterozygous pair.
PMID:36035115 SUPPORT PRIMARY RESULT In Vitro
"The mutant CLIC5A protein appears as aggregated perinuclear bodies while the wild-type protein was evenly distributed in the cytoplasm."
Ectopically expressed p.Leu75Pro mislocalizes in HEK293 cells. The experiment does not establish a uniform null mechanism across human alleles.
+ 1 more reference
Loss of Membrane-Actin Tethering at the Stereocilia Taper
CLIC5 concentrates near the stereociliary base and adjacent apical membrane. In jitterbug mice, radixin and PTPRQ localization is perturbed before fusion; taperin mislocalization is detected later. Membrane lifting and fusion support impaired attachment to the underlying cytoskeleton, but temporal precedence alone does not prove which interaction initiates the lesion. Co-immunoprecipitation in epithelial cells and pull-down from mouse lung support association with ERM proteins and taperin, with more tentative evidence for myosin VI. Direct CLIC5-actin binding and the composition of a single native hair-cell complex are not established by these assays. Approximately equimolar CLIC5 and radixin abundance in bulk chicken hair bundles does not establish complex stoichiometry. Myosin VI mutants also mislocalize CLIC5 and radixin, indicating localization dependencies without resolving a unique assembly hierarchy.
cochlea auditory hair cell CL:4023120 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlea auditory hair cell (CL:4023120). CL:4023120 is a cell type from the Cell Ontology. vestibular hair cell CL:0000609 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves vestibular hair cell (CL:0000609). CL:0000609 is a cell type from the Cell Ontology.
inner ear receptor cell stereocilium organization GO:0060122 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased inner ear receptor cell stereocilium organization (GO:0060122). GO:0060122 is a biological process from the Gene Ontology.
Animal models
Clic5 jitterbug mouse Mouse recapitulates Jitterbug mice support a role for CLIC5 in membrane-cytoskeletal attachment through membrane lifting, altered radixin/PTPRQ localization and subsequent bundle fusion. The exact direct molecular contacts remain unresolved.
Clic5 nmf318 missense mouse treated with inner ear AAV Mouse rescues CLIC5 replacement restores radixin localization and reduces structural abnormalities, supporting the proposed attachment function. Taperin remains mislocalized, so the experiment does not demonstrate reconstitution of every proposed complex component.
Downstream
Progressive Stereocilia Fusion and Bundle Distortion
Show evidence (8 references)
PMID:17021174 SUPPORT PRIMARY RESULT Model Organism
"These results suggest that CLIC5 associates with radixin in hair cell stereocilia and may help form or stabilize connections between the plasma membrane and the filamentous actin core."
The original statement of the tethering hypothesis, from the paper that found the protein there. This is the investigators' interpretation of their experiments, not proof of every direct molecular contact.
PMID:17021174 SUPPORT PRIMARY RESULT Model Organism
"Refined immunolocalization in rat and chicken vestibular hair cells showed that CLIC5 is limited to the basal region of the hair bundle, similar to the known location of radixin."
Localization in rat and chicken vestibular bundles places CLIC5 near the base, supporting the site of the proposed attachment function.
PMID:17021174 SUPPORT PRIMARY RESULT Model Organism
"By mass spectrometry and immunoblotting, CLIC5 was shown to be expressed at high levels in stereocilia of the chicken utricle, in an approximate 1:1 molar ratio with radixin."
Bulk protein abundance in isolated chicken hair bundles; not a measurement of native complex stoichiometry.
+ 5 more references
Progressive Stereocilia Fusion and Bundle Distortion
CLIC5-deficient hair cells develop membrane lifting, stereocilia fusion and bundle distortion. In the jitterbug deletion line, early bundle abnormalities precede inner-hair-cell fusion at approximately P10; outer-hair-cell fusion becomes prominent after P14 and is more severe basally. In the ENU-induced nmf318 missense model used for AAV therapy, cochlear morphology appeared unchanged at P14 but fusion was present at P17, with inner hair cells affected across regions and outer-hair-cell fusion more severe apically. Utricular bundles were elongated at P15 and thickened by P17. These line- and assay-specific patterns cannot be converted into a human treatment window.
cochlear inner hair cell CL:0000589 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlear inner hair cell (CL:0000589). CL:0000589 is a cell type from the Cell Ontology. cochlear outer hair cell CL:0000601 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlear outer hair cell (CL:0000601). CL:0000601 is a cell type from the Cell Ontology. vestibular hair cell CL:0000609 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves vestibular hair cell (CL:0000609). CL:0000609 is a cell type from the Cell Ontology.
auditory receptor cell stereocilium organization GO:0060088 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased auditory receptor cell stereocilium organization (GO:0060088). GO:0060088 is a biological process from the Gene Ontology. vestibular receptor cell stereocilium organization GO:0060121 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased vestibular receptor cell stereocilium organization (GO:0060121). GO:0060121 is a biological process from the Gene Ontology.
Animal models
Clic5 jitterbug mouse Mouse recapitulates Fusion from postnatal day 10 with progressive worsening, which is the structural lesion this node describes and which no human material shows.
Clic5 nmf318 missense mouse treated with inner ear AAV Mouse rescues P0 gene replacement prevents much of the later stereociliary fusion and elongation.
Downstream
Progressive Hair Cell Degeneration
Progressive Sensorineural Hearing Impairment Disorganized auditory bundles impair hair-cell function before extensive cell loss; the detailed human lesion is inferred from models.
Show evidence (3 references)
PMID:24285636 SUPPORT PRIMARY RESULT Model Organism
"Confocal and scanning electron microscopy of CLIC5-deficient jitterbug (jbg) mice revealed progressive fusion of stereocilia as early as postnatal day 10."
The structural lesion and the age at which it starts, in the jitterbug line.
PMID:40859056 SUPPORT PRIMARY RESULT Model Organism
"Inner hair cells (IHCs) exhibited extensive hair bundle fusion across all cochlear regions."
Inner-hair-cell fusion occurs across cochlear regions in the nmf318 model; this morphology should not be confused with the regional pattern of cell loss.
PMID:40859056 SUPPORT PRIMARY RESULT Model Organism
"In the vestibular system, vestibular hair cells (VHCs) of the utricle displayed elongated hair bundles as early as P15, and by P17, thickened hair bundles were also observed"
Vestibular bundle morphology in the ENU-induced nmf318 line.
Progressive Hair Cell Degeneration
Clic5-deficient mice show progressive cochlear and vestibular hair-cell loss after bundle abnormalities. In jitterbug mice, stereocilia were abnormal at P40 without missing hair cells in the imaged preparations, while older animals had severe organ-of-Corti and vestibular degeneration. In the nmf318 AAV study, outer-hair-cell loss was greatest basally, whereas inner-hair-cell survival was largely retained except at the cochlear base. Hearing dysfunction therefore cannot be attributed solely to cell death. P0 gene delivery preceded bundle damage and did not test rescue during the interval between bundle failure and cell loss.
cochlea auditory hair cell CL:4023120 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlea auditory hair cell (CL:4023120). CL:4023120 is a cell type from the Cell Ontology. vestibular hair cell CL:0000609 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves vestibular hair cell (CL:0000609). CL:0000609 is a cell type from the Cell Ontology.
Animal models
Clic5 nmf318 missense mouse treated with inner ear AAV Mouse partially recapitulates Untreated homozygotes develop progressive hair-cell loss, predominantly outer hair cells at the basal cochlea. Neonatal gene replacement improves subsequent survival.
Downstream
Progressive Sensorineural Hearing Impairment
Vestibular Areflexia
Show evidence (2 references)
PMID:17021174 SUPPORT PRIMARY RESULT Model Organism
"Histological analysis of mutant inner ears revealed dysmorphic stereocilia and progressive hair cell degeneration."
The source reports abnormal stereocilia and progressive hair-cell degeneration; time-course details come from its full text.
PMID:40859056 SUPPORT PRIMARY RESULT Model Organism
"Quantification of HC survival indicated that CLIC5 deficiency primarily caused OHC loss, which was most severe in the basal cochlear region (32 kHz)"
Cell counts distinguish basal outer-hair-cell loss from the distribution of bundle fusion.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Autosomal Recessive Nonsyndromic Hearing Loss 103 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

6
Progressive Sensorineural Hearing Impairment Auditory HP:0000408 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive sensorineural hearing impairment (HP:0000408). HP:0000408 is a phenotype from the Human Phenotype Ontology.
Show evidence (4 references)
PMID:24781754 SUPPORT PRIMARY RESULT Human Clinical
"The hearing loss in the present family had an onset in early childhood and progressed from mild to severe or even profound before the second decade."
Onset and rate of progression in the founding family.
PMID:40957967 SUPPORT PRIMARY RESULT Human Clinical
"Genotype-phenotype analysis in patients with DFNB103 showed that HL was sensorineural, symmetrical and variable by severity (from moderate to profound)."
Sensorineural loss, symmetry and severity range in the 22-patient Siberian cohort.
PMID:40957967 SUPPORT PRIMARY RESULT Human Clinical
"In most cases this form of HL was detected in the post-lingual period (mean age 7.9 ± 1.2 years) and has a significant severity progression with age."
Mean age at detection and confirmation of the progressive course in 22 patients.
+ 1 more reference
Bilateral Sensorineural Hearing Impairment Auditory HP:0008619 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bilateral sensorineural hearing impairment (HP:0008619). HP:0008619 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33114113 SUPPORT PRIMARY RESULT Human Clinical
"Audiological assessment of the three affected individuals revealed bilateral profound sensorineural HI (Figure 1B)."
Bilateral involvement in all three affected members of the Cameroonian family.
PMID:40957967 SUPPORT PRIMARY RESULT Human Clinical
"Genotype-phenotype analysis in patients with DFNB103 showed that HL was sensorineural, symmetrical and variable by severity (from moderate to profound)."
Symmetry in the largest cohort, which is a stronger statement than bilaterality: the two ears are not merely both affected but affected to a similar degree.
High-Frequency Sensorineural Hearing Impairment Auditory HP:0001757 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High-frequency sensorineural hearing impairment (HP:0001757). HP:0001757 is a phenotype from the Human Phenotype Ontology.
The binding captures the high-frequency component of the reported downsloping audiogram; mid-frequency involvement is also described.
Show evidence (1 reference)
PMID:40957967 SUPPORT PRIMARY RESULT Human Clinical
"Audiograms mostly have a down curve configuration, with pronounced loss of high and mid frequencies."
Predominant downsloping configuration in the Siberian cohort, with both high- and mid-frequency involvement.
Postlingual Sensorineural Hearing Impairment Auditory HP:0008596 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Postlingual sensorineural hearing impairment (HP:0008596). HP:0008596 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:40957967 SUPPORT PRIMARY RESULT Human Clinical
"In most cases this form of HL was detected in the post-lingual period (mean age 7.9 ± 1.2 years) and has a significant severity progression with age."
Postlingual detection with a quantified mean age.
DOI:10.25557/2073-7998.2019.10.36-48 SUPPORT PRIMARY RESULT Human Clinical
"Most of homozygous for c.1121G>A patients (19 out of 26) reported about late onset of their hearing loss occurred in postlingual period (averaged 9.7±0.6 years)."
Nineteen of 26 homozygotes reported postlingual onset in this selected 2019 cohort; the remaining presentations prevent a uniformly postlingual definition.
Vestibular Areflexia Vestibular HP:0008568 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vestibular areflexia (HP:0008568). HP:0008568 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:24781754 SUPPORT PRIMARY RESULT Human Clinical
"Impaired hearing is accompanied by vestibular areflexia and in one of the patients with mild renal dysfunction."
The vestibular finding in the founding family, with the renal observation alongside it.
url:https://repositoriosaludmadrid.es/bitstreams/e783eafe-8086-4b75-be09-9bd6ce296bad/download SUPPORT PRIMARY RESULT Human Clinical
"V estibular areflexia was found in both individuals during the rotatory test at the age of 16 years (II.2) and 11 years (II.3)."
Formal vestibular testing in the two discovery-family siblings.
Prelingual Sensorineural Hearing Impairment Auditory HP:0000399 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prelingual sensorineural hearing impairment (HP:0000399). HP:0000399 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33114113 SUPPORT PRIMARY RESULT Human Clinical
"A history of prelingual and progressive HI was described for all three affected pedigree members; however, before this study, no formal audiological assessment was performed for any of the family members."
Prelingual onset and progression were reported retrospectively; earlier formal audiometry was unavailable.
🧬

Genetic Associations

1
CLIC5
Gene: CLIC5 hgnc:13517 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CLIC5 (hgnc:13517). hgnc:13517 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (3 references)
PMID:24781754 SUPPORT PRIMARY RESULT Human Clinical
"In conclusion, our results show that CLIC5 is a novel arNSHI gene involved in progressive hearing impairment, vestibular and possibly mild renal dysfunction in a family of Turkish origin."
The founding gene-disease conclusion, including the authors' own hedged renal observation.
PMID:33114113 SUPPORT PRIMARY RESULT Human Clinical
"The three affected individuals were compound heterozygous for both variants, and all unaffected individuals were heterozygous for one of the two variants."
The three affected siblings carried the two variants in trans, while tested unaffected relatives carried one variant.
PMID:40957967 SUPPORT PRIMARY RESULT Human Clinical
"The haplotype analysis based on the 730,000 whole genome SNP-markers indicates common origin of all studied mutant chromosomes."
The haplotype evidence establishing the Siberian allele as a single founder event.
🗃️

External Assertions

1
OMIM deafness, autosomal recessive 103 record
OMIM disease record OMIM:616042
OMIM:616042 is the disease identifier used in the DFNB103 literature and cross-referenced by MONDO:0014469.
Show evidence (1 reference)
PMID:40957967 SUPPORT BACKGROUND Other
"Previously only two families were known with progressive autosomal recessive deafness 103 (DFNB103, OMIM616042) caused by pathogenic variants of the CLIC5 gene."
The background sentence supplies the disease name and OMIM identifier only; its historical family count is not used as an epidemiologic claim.
💊

Medical Actions

7
Genetic Counseling
Category: Counseling / Informational Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Platform: Other
Discuss recessive inheritance, parental testing and family-specific recurrence chances. For two confirmed carriers the chance of biallelic inheritance is 25% per pregnancy. Once the familial pathogenic variants are established, offer information about carrier testing, prenatal testing and preimplantation testing according to individual preferences.
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/pdf/Bookshelf_NBK1434.pdf SUPPORT REVIEW SYNTHESIS Other
"If both parents are known to be heterozygous for an autosomal recessive hearing loss-related pathogenic variant, each sib of the proband has at conception a 25% chance of having hearing loss, a 50% chance of having no hearing loss and being a carrier, and a 25% chance of having no hearing loss..."
General autosomal recessive hearing-loss counseling, conditional on parental carrier status; not a DFNB103 penetrance estimate.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/pdf/Bookshelf_NBK1434.pdf SUPPORT REVIEW SYNTHESIS Other
"Once the pathogenic variant(s) have been identified in the family, prenatal and preimplantation genetic testing for genetic hearing loss are possible."
General reproductive counseling options, not a DFNB103 intervention trial.
Hearing Aids
Category: Therapeutic Action: hearing-aid habilitationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hearing-aid habilitation, annotated with Rehabilitation (NCIT:C15315), qualified as medical device Hearing Aid. NCIT:C15315 is a clinical intervention from the NCI Thesaurus. Ontology label: Rehabilitation NCIT:C15315
Platform: Device
Offer individually fitted amplification when residual hearing permits, with reassessment as thresholds change. This is general sensorineural hearing-loss care; a DFNB103-specific hearing-aid outcome series is not available in the reviewed sources.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/pdf/Bookshelf_NBK1434.pdf SUPPORT REVIEW SYNTHESIS Other
"Hearing aids (sound amplification), customized by an audiologist to the degree and frequency of hearing loss, can be used in individuals with mild-to-severe hearing loss."
General hearing-loss habilitation guidance.
Cochlear Implantation
Category: Therapeutic Action: cochlear implantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cochlear implantation, annotated with Surgical Procedure (NCIT:C15329), qualified as medical device Cochlear Implant. NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
Consider cochlear implantation when hearing severity and aided communication outcomes warrant it. The Turkish index patient received an implant at age 11 and had 88% speech recognition five years later on Dutch consonant-vowel-consonant word lists. This single reported outcome does not establish uniform CLIC5-specific benefit.
Show evidence (1 reference)
url:https://repositoriosaludmadrid.es/bitstreams/e783eafe-8086-4b75-be09-9bd6ce296bad/download SUPPORT PRIMARY RESULT Human Clinical
"Individual II.2 received a cochlear implant at the age of 11 years. Five years post implantation, the speech recognition scores were 88% (using the standard Dutch phonetically balanced consonant-vocal-consonant word lists)."
Disease-specific outcome from the full text of Seco et al., PMID:24781754; one recipient, not a comparative trial.
Communication and Educational Support
Category: Therapeutic
Platform: Other
Establish communication goals with the individual and family, including spoken language, sign language or combined approaches. Provide early language access, speech-language support and appropriate educational accommodations.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/pdf/Bookshelf_NBK1434.pdf SUPPORT REVIEW SYNTHESIS Other
"On initial evaluation of individuals with hearing loss, the goals for communication must be established with a focus on equipping individuals with language and appropriate access to language."
General care guidance; communication choices are individualized.
Audiologic and Vestibular Follow-up
Category: Monitoring
Platform: Other
Repeat audiologic assessment according to age, hearing trajectory and habilitation needs. Assess vestibular symptoms and function and arrange physical therapy when indicated. No DFNB103-specific testing interval is established.
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/pdf/Bookshelf_NBK1434.pdf SUPPORT REVIEW SYNTHESIS Other
"Perform sequential audiologic examinations that:"
The general chapter recommends serial audiology to document progression; its gene-specific interval table does not name CLIC5.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/pdf/Bookshelf_NBK1434.pdf SUPPORT REVIEW SYNTHESIS Other
"The finding of vestibular dysfunction may guide physical therapy, particularly in children with delayed motor milestones."
General vestibular care principle, not a DFNB103 rehabilitation outcome study.
Renal Assessment When Indicated
Category: Monitoring
Platform: Other
The discovery-family authors recommended renal follow-up for both affected siblings after repeated albuminuria and elevated blood pressure in one, despite preserved estimated GFR. Renal involvement remains uncertain and no validated DFNB103-wide schedule is established.
Show evidence (1 reference)
url:https://repositoriosaludmadrid.es/bitstreams/e783eafe-8086-4b75-be09-9bd6ce296bad/download SUPPORT PRIMARY RESULT Human Clinical
"Therefore, follow-up of renal function is indicated for individual II.3 but also for his hearing-impaired sister."
A family-specific recommendation in the primary report; it does not establish universal nephropathy.
Avoid Repeated Excessive Noise Exposure
Category: Counseling / Informational
Platform: Other
Counsel about avoiding repeated loud-noise exposure to protect remaining hearing. This is general hearing-loss care and does not imply that environmental exposure causes DFNB103.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/pdf/Bookshelf_NBK1434.pdf SUPPORT REVIEW SYNTHESIS Other
"persons with documented hearing loss should be counseled appropriately and repeated overexposure to loud noises should be avoided."
General protection of residual hearing, not a demonstrated CLIC5-specific susceptibility.
🔬

Diagnosis

2
Audiologic and vestibular assessment
Age-appropriate audiometry establishes type, severity, laterality and progression. Evaluate balance symptoms and vestibular function; a normal newborn screen does not exclude later CLIC5-related hearing loss. At-risk relatives can receive targeted familial-variant testing and hearing evaluation.
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/pdf/Bookshelf_NBK1434.pdf SUPPORT REVIEW SYNTHESIS Other
"Hearing status can be determined at any age and is tailored to the individual's ability to participate"
General audiologic assessment principle.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/pdf/Bookshelf_NBK1434.pdf SUPPORT REVIEW SYNTHESIS Other
"Permanent childhood hearing loss in a parent or sib increases the probability of hearing loss in other family members and warrants early complete diagnostic evaluation of hearing regardless of the family member's newborn hearing screening result."
General at-risk family assessment, relevant to variable CLIC5 onset.
📈

Progression

3
Variable onset
Onset ranges from prelingual to postlingual. Normal early screening was documented in the Turkish siblings, but it is not universal; the Cameroonian family reported prelingual loss.
Show evidence (2 references)
PMID:33114113 SUPPORT PRIMARY RESULT Human Clinical
"A history of prelingual and progressive HI was described for all three affected pedigree members; however, before this study, no formal audiological assessment was performed for any of the family members."
Prelingual onset and progression were reported retrospectively; earlier formal audiometry was unavailable.
PMID:40957967 SUPPORT PRIMARY RESULT Human Clinical
"In most cases this form of HL was detected in the post-lingual period (mean age 7.9 ± 1.2 years) and has a significant severity progression with age."
Postlingual detection with a quantified mean age.
Progressive decline
Progression is documented by longitudinal audiometry in the Turkish family and reported in the Siberian cohort, with substantial variability. The Siberian mean annual PTA decline of 7.4 ± 13.65 dB is not a fixed linear rate for every patient.
Show evidence (1 reference)
PMID:40957967 SUPPORT PRIMARY RESULT Human Clinical
"In average the patients with DFNB103 lost 7.4 ± 13.65 dB on the speech frequency range in pure tone averages (PTA0.5,1.0,2.0,4.0 kHz) per year until reaching profound deafness in the second or third decade of the life."
Reported mean and dispersion of annual change in the Siberian cohort.
Severe or profound hearing loss
The Turkish siblings reached severe or profound loss before the second decade; the Siberian report describes profound loss in the second or third decade. Timing varies, and later vestibular dysfunction is documented in the Turkish family.
Show evidence (1 reference)
PMID:24781754 SUPPORT PRIMARY RESULT Human Clinical
"The hearing loss in the present family had an onset in early childhood and progressed from mild to severe or even profound before the second decade."
The Turkish family reached severe or profound loss earlier than the age range reported in the Siberian cohort.
📊

Prevalence

3
Yakutia (Sakha Republic), Eastern Siberia
Point Prevalence 2.7 per 100,000 1–9 per 100,000
The 2019 study identified 26 homozygotes in a Yakutia population denominator of 958,528, yielding 0.27 per 10,000 (2.7 per 100,000). This ascertainment-based regional estimate is not a global prevalence. The reported allele uses the longer-transcript notation c.1121G>A p.Trp374Ter.
Show evidence (1 reference)
DOI:10.25557/2073-7998.2019.10.36-48 SUPPORT PRIMARY RESULT Human Clinical
"The average prevalence of DFNB103 caused by the homozygous variant c.1121G>A (p.Trp374*) in Yakutia was 0.27±0.053 per 10000 with a maximum accumulation in Eveno-Bytantaysky district (31.39±10.46 per 10000)"
The Yakutia-wide prevalence, and the district in which it concentrates.
Eveno-Bytantaysky national district, Arctic Yakutia
Point Prevalence 313.9 per 100,000 >1 in 1,000
Nine identified homozygotes among 2,867 district residents yielded 31.39 ± 10.46 per 10,000 (313.9 per 100,000). The reported plus/minus uncertainty is not a minimum-to-maximum range or confidence interval. Regional enrichment alone does not establish a founder event; the later haplotype study provides that evidence.
Show evidence (1 reference)
DOI:10.25557/2073-7998.2019.10.36-48 SUPPORT PRIMARY RESULT Human Clinical
"The average prevalence of DFNB103 caused by the homozygous variant c.1121G>A (p.Trp374*) in Yakutia was 0.27±0.053 per 10000 with a maximum accumulation in Eveno-Bytantaysky district (31.39±10.46 per 10000)"
The district rate this record stores, with its reported standard error.
GJB2-negative hearing loss patients, Sakha Republic, Eastern Siberia
Unknown
The 2026 report found this homozygous founder variant in 9.9% of selected Siberian GJB2-negative hearing-loss patients. This is diagnostic yield, not a population prevalence or heterozygote carrier rate. It should not be combined with the 2019 cohort as if the patients were independent.
Show evidence (1 reference)
PMID:40957967 SUPPORT PRIMARY RESULT Human Clinical
"The high frequency of c.644 G > A p.(Trp215*) was found among Siberian GJB2-negative patients (9.9%) and this variant was not detected in GJB2-negative patients of Caucasian descent (predominantly Russians)."
The yield figure and the population specificity that limits it.
🐁

Animal Models

2
Clic5 jitterbug mouse
The spontaneous C3H/HeJ jitterbug allele deletes 97 genomic bases, causing exon 5 skipping, frameshift and premature termination. Protein is undetectable by the reported assays. Mutants develop hearing and vestibular dysfunction, abnormal stereocilia and later hair-cell degeneration. The 2014 follow-up defines membrane lifting, fusion and altered partner localization. Cochlear supporting structures such as Reissner's membrane and stria vascularis were preserved in the original histology, arguing against a primary endolymph-volume phenotype.
Species
Mouse
Genotype
Clic5 jbg/jbg, 97 bp intragenic deletion causing exon 5 skipping
Genes
CLIC5 hgnc:13517 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns CLIC5 (hgnc:13517). hgnc:13517 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:17021174
Pathograph links
Loss of Membrane-Actin Tethering at the Stereocilia Taper recapitulates fidelity: high Jitterbug mice support a role for CLIC5 in membrane-cytoskeletal attachment through membrane lifting, altered radixin/PTPRQ localization and subsequent bundle fusion. The exact direct molecular contacts remain unresolved.
Limitations: A functionally protein-null deletion does not reproduce every human allele. Biochemical interactions were measured partly in epithelial-cell constructs and mouse lung, while protein abundance and localization also used rat and chicken hair bundles; these are not a purified native human hair-cell complex.
Readouts
Radixin immunostaining in hair bundles
Direction: DECREASED
Interpretation: Reduced radixin immunostaining supports a localization or stability dependence on CLIC5; it does not prove total loss of radixin or direct binding.
Show evidence (1 reference)
PMID:17021174 SUPPORT PRIMARY RESULT Model Organism
"Radixin immunostaining appeared reduced in hair bundles of jbg mutant mice."
The immunolocalisation measurement behind this readout.
Taper-region localisation of radixin, taperin and PTPRQ
Direction: ALTERED
Interpretation: Radixin and PTPRQ dispersal precedes visible fusion, whereas taperin mislocalization occurs later. Temporal ordering does not identify a single initiating interaction.
Show evidence (1 reference)
PMID:24285636 SUPPORT PRIMARY RESULT Model Organism
"Radixin (RDX), protein tyrosine phosphatase receptor Q (PTPRQ), and taperin (TPRN), deafness-associated proteins that also concentrate at the base of stereocilia, were mislocalized in fused stereocilia of jbg mice."
The mislocalisation of all three taper proteins in the null.
Show evidence (1 reference)
PMID:17021174 SUPPORT PRIMARY RESULT Model Organism
"Mice homozygous for a new spontaneous recessive mutation of the Clic5 gene, named jitterbug (jbg), exhibit impaired hearing and vestibular dysfunction."
The phenotype that makes the model informative, and the same two-system involvement seen in patients.
Progressive Stereocilia Fusion and Bundle Distortion recapitulates fidelity: high Fusion from postnatal day 10 with progressive worsening, which is the structural lesion this node describes and which no human material shows.
Limitations: Human cochlear fusion has not been directly demonstrated by the cited studies. Mouse developmental timing cannot be mapped to a specific age or closed therapeutic window in patients.
Readouts
Stereocilia fusion by scanning electron microscopy
Direction: INCREASED
Interpretation: Adjacent stereocilia progressively fuse from postnatal day 10 onwards.
Show evidence (1 reference)
PMID:24285636 SUPPORT PRIMARY RESULT Model Organism
"Confocal and scanning electron microscopy of CLIC5-deficient jitterbug (jbg) mice revealed progressive fusion of stereocilia as early as postnatal day 10."
The structural measurement and its onset.
Show evidence (1 reference)
PMID:17021174 SUPPORT PRIMARY RESULT Model Organism
"Histological analysis of mutant inner ears revealed dysmorphic stereocilia and progressive hair cell degeneration."
The histological phenotype, including its progressive character.
Show evidence (1 reference)
PMID:17021174 SUPPORT PRIMARY RESULT Model Organism
"The jbg mutation is a 97 bp intragenic deletion that causes skipping of exon 5, which creates a translational frame shift and premature stop codon."
The molecular lesion, of the same truncating class as the human founder and founding alleles, which is what makes this model genetically comparable.
Clic5 nmf318 missense mouse treated with inner ear AAV
The gene-replacement study used the ENU-induced nmf318 missense line (JAX 005329), not an engineered knockout. The MGI allele record specifies c.680T>C, p.Phe227Ser; the paper uses Clic5−/− as shorthand for the protein-deficient phenotype. Untreated animals had approximately 40-dB ABR threshold shifts at four weeks and no detected responses at eight weeks. Left-utricle injection at P0 restored CLIC5, prevented bundle fusion, improved hair-cell survival and auditory/vestibular outcomes. Radixin localization returned toward normal but taperin remained distributed along stereocilia at eight weeks. The self-complementary vector achieved comparable measured benefit at approximately eleven-fold lower titer than the single-stranded construct; this was not a formal equivalence trial, the constructs differed in reporter content and some untreated controls were shared. Auditory benefit declined, especially at high frequencies, whereas vestibular behavioral benefit persisted through the 12-week follow-up. No delayed-treatment arm tested reversal of established damage.
Species
Mouse
Genotype
C57BL/6J-Clic5nmf318/J homozygote; ENU-induced missense allele; P0 AAV2/9-PHP.B Clic5 delivery
Genes
CLIC5 hgnc:13517 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns CLIC5 (hgnc:13517). hgnc:13517 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:40859056
Pathograph links
Loss of Membrane-Actin Tethering at the Stereocilia Taper rescues fidelity: moderate CLIC5 replacement restores radixin localization and reduces structural abnormalities, supporting the proposed attachment function. Taperin remains mislocalized, so the experiment does not demonstrate reconstitution of every proposed complex component.
Limitations: P0 treatment precedes the observed lesion and tests prevention rather than reversal. No post-onset delivery arm defines when efficacy is lost. Auditory thresholds worsened by 12 weeks, especially at high frequencies; C57BL/6 background, expression dynamics and immune effects remain possible contributors.
Readouts
Radixin localisation after CLIC5 restoration
Direction: RESTORED
Interpretation: Radixin returns toward the stereociliary base after CLIC5 replacement; this supports a functional dependency without proving the complete native binding architecture.
Show evidence (1 reference)
PMID:40859056 SUPPORT PRIMARY RESULT Model Organism
"Restoring CLIC5 expression also appears to normalize the localization of RDX, emphasizing CLIC5's vital role in hair cell function."
The partner-relocalisation readout after gene replacement.
Show evidence (1 reference)
PMID:40859056 SUPPORT PRIMARY RESULT Model Organism
"We report a robust restoration of CLIC5 expression using either construct, including prevention of morphological degeneration and preserving auditory and vestibular function."
The headline rescue result establishing the link's relevance to this node.
Progressive Stereocilia Fusion and Bundle Distortion rescues fidelity: moderate P0 gene replacement prevents much of the later stereociliary fusion and elongation.
Limitations: A prevention experiment; no delayed-treatment arm.
Readouts
Stereocilia morphology after treatment
Direction: RESTORED
Interpretation: Neonatal treatment preserves largely normal bundle morphology at later endpoints; it does not test repair of an already fused bundle.
Show evidence (1 reference)
PMID:40859056 SUPPORT PRIMARY RESULT Model Organism
"This restoration prevents the fusion and elongation of stereocilia and improves hair cell survival."
The structural and survival outcome of the rescue.
Show evidence (1 reference)
PMID:40859056 SUPPORT PRIMARY RESULT Model Organism
"This restoration prevents the fusion and elongation of stereocilia and improves hair cell survival."
The structural and survival outcome of the rescue.
Progressive Hair Cell Degeneration partially recapitulates fidelity: moderate Untreated homozygotes develop progressive hair-cell loss, predominantly outer hair cells at the basal cochlea. Neonatal gene replacement improves subsequent survival.
Limitations: The phenotype and age dependence are model specific. An ABR threshold is a functional endpoint and cannot distinguish bundle dysfunction from cell loss.
Readouts
Cochlear outer-hair-cell survival
Direction: DECREASED
Interpretation: Counts at 12 weeks show greatest outer-hair-cell loss basally in untreated mice, with improved survival after gene delivery.
Show evidence (1 reference)
PMID:40859056 SUPPORT PRIMARY RESULT Model Organism
"Quantification of HC survival indicated that CLIC5 deficiency primarily caused OHC loss, which was most severe in the basal cochlear region (32 kHz)"
Cell counts distinguish basal outer-hair-cell loss from the distribution of bundle fusion.
Show evidence (1 reference)
PMID:40859056 SUPPORT PRIMARY RESULT Model Organism
"Quantification of HC survival indicated that CLIC5 deficiency primarily caused OHC loss, which was most severe in the basal cochlear region (32 kHz)"
Cell counts distinguish basal outer-hair-cell loss from the distribution of bundle fusion.
Show evidence (3 references)
url:https://www.informatics.jax.org/allele/MGI%3A3522004 SUPPORT Other
"in exon 6 is predicted to change a highly conserved phenylalanine residue at amino acid 227 to serine (NP_766209)."
Primary MGI allele annotation establishes the nmf318 lesion; the paper's p.Phe318Ser wording conflicts with this record.
PMID:40859056 SUPPORT PRIMARY RESULT Model Organism
"In contrast, Clic5−/− mice exhibited ABR thresholds shifted by ~40 dB at 4 weeks, and no response was detected at 8 weeks"
Auditory phenotype in homozygous nmf318 mice, called Clic5−/− by the authors.
PMID:40859056 SUPPORT PRIMARY RESULT Model Organism
"In contrast, TPRN was mislocalized along the entire length of the stereocilium, rather than being concentrated at the base"
At eight weeks after neonatal ssAAV delivery, taperin localization was not restored along with radixin.
{ }

Source YAML

click to show 
name: Autosomal Recessive Nonsyndromic Hearing Loss 103
category: Mendelian
creation_date: "2026-08-28T00:00:00Z"
synonyms:
- DFNB103
- CLIC5 autosomal recessive nonsyndromic deafness
- autosomal recessive nonsyndromic deafness 103
- deafness, autosomal recessive 103
- autosomal recessive nonsyndromic deafness caused by mutation in CLIC5
- autosomal recessive deafness 103
description: >-
  DFNB103 is an autosomal recessive sensorineural hearing disorder caused by biallelic CLIC5 variants. Reported
  hearing loss is bilateral and progressive, with variable onset including prelingual and postlingual presentations.
  Vestibular areflexia is documented in the Turkish discovery family but is not established as universal. A
  Siberian founder allele accounts for an appreciable fraction of selected GJB2-negative patients in the Sakha
  Republic.

  Animal and cell studies support a role for CLIC5 in maintaining membrane-cytoskeletal attachments at the
  base of hair-cell stereocilia. CLIC5-deficient mice develop partner-protein mislocalization, stereocilia
  fusion and later hair-cell loss. Direct molecular contacts and the corresponding human cochlear lesion remain
  incompletely defined. Neonatal AAV gene replacement improves hearing and balance in an ENU-induced Clic5
  missense mouse model, but delayed treatment and durable human benefit have not been established.
disease_term:
  preferred_term: autosomal recessive nonsyndromic hearing loss 103
  term:
    id: MONDO:0014469
    label: autosomal recessive nonsyndromic hearing loss 103
parents:
- Autosomal Recessive Nonsyndromic Hearing Loss
inheritance:
- name: Autosomal recessive
  description: >-
    Biallelic CLIC5 variants: homozygous in the consanguineous Turkish founding family and in the Siberian
    founder cohort, compound heterozygous in the non-consanguineous Cameroonian family where each unaffected
    relative carried one of the two alleles. For two confirmed heterozygous parents, each pregnancy has a 25%
    chance of inheriting both familial pathogenic alleles, a 50% carrier chance and a 25% chance of inheriting
    neither. Individual onset and severity are not predicted by this Mendelian ratio.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:24781754
    reference_title: "Progressive hearing loss and vestibular dysfunction caused by a homozygous nonsense mutation in CLIC5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutation analysis of CLIC5 revealed a homozygous nonsense mutation c.96T>A (p.(Cys32Ter)) that segregated with the hearing loss."
    explanation: >-
      Homozygosity in the affected siblings of a consanguineous pedigree, with segregation
      through the family, which is the recessive pattern.
    quote_role: PRIMARY_RESULT
  - reference: PMID:33114113
    reference_title: "Bi-Allelic Novel Variants in CLIC5 Identified in a Cameroonian Multiplex Family with Non-Syndromic Hearing Impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The three affected individuals were compound heterozygous for both variants, and all unaffected individuals were heterozygous for one of the two variants."
    explanation: >-
      The three affected siblings carried the two variants in trans, while tested unaffected relatives carried
      one variant.
    quote_role: PRIMARY_RESULT
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/pdf/Bookshelf_NBK1434.pdf
    reference_title: "https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/pdf/Bookshelf_NBK1434.pdf"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      If both parents are known to be heterozygous for an autosomal recessive hearing loss-related pathogenic
      variant, each sib of the proband has at conception a 25% chance of having hearing loss, a 50% chance
      of having no hearing loss and being a carrier, and a 25% chance of having no hearing loss and not being
      a carrier.
    explanation: >-
      General autosomal recessive hearing-loss counseling, conditional on parental carrier status; not a DFNB103
      penetrance estimate.
pathophysiology:
- name: CLIC5 Loss of Function
  description: >-
    Biallelic CLIC5 variants impair protein function through allele-dependent mechanisms. The Turkish p.Cys32Ter
    allele predicts early truncation, but nonsense-mediated RNA decay was not confirmed in patient lymphoblastoid
    cells. The Cameroonian c.63+1G>A donor variant has a predicted, untested splicing effect; p.Leu75Pro shows
    increased abundance and perinuclear aggregation after ectopic expression in HEK293 cells. These observations
    do not establish complete absence of protein for every human allele. The Siberian p.Trp215Ter allele is
    another truncating variant.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: CLIC5
    term:
      id: hgnc:13517
      label: CLIC5
  downstream:
  - target: Loss of Membrane-Actin Tethering at the Stereocilia Taper
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:24781754
    reference_title: "Progressive hearing loss and vestibular dysfunction caused by a homozygous nonsense mutation in CLIC5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutation analysis of CLIC5 revealed a homozygous nonsense mutation c.96T>A (p.(Cys32Ter)) that segregated with the hearing loss."
    explanation: >-
      The founding nonsense allele, which truncates the protein at codon 32, and its
      segregation with the phenotype.
    quote_role: PRIMARY_RESULT
  - reference: PMID:33114113
    reference_title: "Bi-Allelic Novel Variants in CLIC5 Identified in a Cameroonian Multiplex Family with Non-Syndromic Hearing Impairment."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "In silico analysis showed that the missense variant CLIC5-p.(L75P) substitutes a highly conserved amino acid residue (leucine), and is expected to alter the stability, the structure, and the function of the CLIC5 protein, while the splicing variant CLIC5-(c.63+1G>A) is predicted to disrupt a consensus donor splice site and alter the splicing of the pre-mRNA."
    explanation: The predicted consequences of the second family's compound heterozygous pair.
    quote_role: PRIMARY_RESULT
  - reference: PMID:36035115
    reference_title: "Cell-based analysis of CLIC5A and SLC12A2 variants associated with hearing impairment in two African families."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The mutant CLIC5A protein appears as aggregated perinuclear bodies while the wild-type protein was evenly distributed in the cytoplasm."
    explanation: >-
      Ectopically expressed p.Leu75Pro mislocalizes in HEK293 cells. The experiment does not establish a uniform
      null mechanism across human alleles.
    quote_role: PRIMARY_RESULT
  - reference: url:https://repositoriosaludmadrid.es/bitstreams/e783eafe-8086-4b75-be09-9bd6ce296bad/download
    reference_title: "https://repositoriosaludmadrid.es/bitstreams/e783eafe-8086-4b75-be09-9bd6ce296bad/download"
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      However, we could not confirm NMD.
    explanation: >-
      Patient lymphoblastoid-cell RNA analysis with and without cycloheximide did not confirm nonsense-mediated
      decay; this is not a hair-cell assay.
- name: Loss of Membrane-Actin Tethering at the Stereocilia Taper
  description: >-
    CLIC5 concentrates near the stereociliary base and adjacent apical membrane. In jitterbug mice, radixin
    and PTPRQ localization is perturbed before fusion; taperin mislocalization is detected later. Membrane
    lifting and fusion support impaired attachment to the underlying cytoskeleton, but temporal precedence
    alone does not prove which interaction initiates the lesion.

    Co-immunoprecipitation in epithelial cells and pull-down from mouse lung support association with ERM proteins
    and taperin, with more tentative evidence for myosin VI. Direct CLIC5-actin binding and the composition
    of a single native hair-cell complex are not established by these assays. Approximately equimolar CLIC5
    and radixin abundance in bulk chicken hair bundles does not establish complex stoichiometry. Myosin VI
    mutants also mislocalize CLIC5 and radixin, indicating localization dependencies without resolving a unique
    assembly hierarchy.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: cochlea auditory hair cell
    term:
      id: CL:4023120
      label: cochlea auditory hair cell
  - preferred_term: vestibular hair cell
    term:
      id: CL:0000609
      label: vestibular hair cell
  biological_processes:
  - preferred_term: inner ear receptor cell stereocilium organization
    term:
      id: GO:0060122
      label: inner ear receptor cell stereocilium organization
    modifier: DECREASED
  downstream:
  - target: Progressive Stereocilia Fusion and Bundle Distortion
    causal_link_type: UNKNOWN
  evidence:
  - reference: PMID:17021174
    reference_title: "The chloride intracellular channel protein CLIC5 is expressed at high levels in hair cell stereocilia and is essential for normal inner ear function."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These results suggest that CLIC5 associates with radixin in hair cell stereocilia and may help form or stabilize connections between the plasma membrane and the filamentous actin core."
    explanation: >-
      The original statement of the tethering hypothesis, from the paper that found the protein there. This
      is the investigators' interpretation of their experiments, not proof of every direct molecular contact.
    quote_role: PRIMARY_RESULT
  - reference: PMID:17021174
    reference_title: "The chloride intracellular channel protein CLIC5 is expressed at high levels in hair cell stereocilia and is essential for normal inner ear function."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Refined immunolocalization in rat and chicken vestibular hair cells showed that CLIC5 is limited to the basal region of the hair bundle, similar to the known location of radixin."
    explanation: >-
      Localization in rat and chicken vestibular bundles places CLIC5 near the base, supporting the site of
      the proposed attachment function.
    quote_role: PRIMARY_RESULT
  - reference: PMID:17021174
    reference_title: "The chloride intracellular channel protein CLIC5 is expressed at high levels in hair cell stereocilia and is essential for normal inner ear function."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "By mass spectrometry and immunoblotting, CLIC5 was shown to be expressed at high levels in stereocilia of the chicken utricle, in an approximate 1:1 molar ratio with radixin."
    explanation: >-
      Bulk protein abundance in isolated chicken hair bundles; not a measurement of native complex stoichiometry.
    quote_role: PRIMARY_RESULT
  - reference: PMID:24285636
    reference_title: "CLIC5 stabilizes membrane-actin filament linkages at the base of hair cell stereocilia in a molecular complex with radixin, taperin, and myosin VI."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "TPRQ and RDX were dispersed even prior to stereocilia fusion."
    explanation: >-
      Radixin and PTPRQ mislocalization precedes visible fusion, supporting but not proving an initiating role.
      The abstract prints TPRQ for PTPRQ.
    quote_role: PRIMARY_RESULT
  - reference: PMID:24285636
    reference_title: "CLIC5 stabilizes membrane-actin filament linkages at the base of hair cell stereocilia in a molecular complex with radixin, taperin, and myosin VI."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Based on these findings, we propose a model in which these proteins work together as a complex to stabilize linkages between the plasma membrane and subjacent actin cytoskeleton at the base of stereocilia."
    explanation: >-
      The complex model this node curates, stated by the study that assembled it. This is the investigators'
      interpretation of their experiments, not proof of every direct molecular contact.
    quote_role: PRIMARY_RESULT
  - reference: PMID:24285636
    reference_title: "CLIC5 stabilizes membrane-actin filament linkages at the base of hair cell stereocilia in a molecular complex with radixin, taperin, and myosin VI."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In addition, CLIC5 and RDX failed to localize normally in fused stereocilia of MYO6 mutant mice."
    explanation: >-
      Myosin VI deficiency perturbs CLIC5 and radixin localization; this does not resolve direct interactions
      or exclude hierarchical assembly.
    quote_role: PRIMARY_RESULT
  - reference: PMID:34026762
    reference_title: "N-Terminus of GRXCR2 Interacts With CLIC5 and Is Essential for Auditory Perception."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Interestingly, mice harboring this in-frame deletion in Grxcr2 exhibit moderate hearing loss at lower frequencies and severe hearing loss at higher frequencies although the morphogenesis of stereocilia is minimally affected."
    explanation: >-
      Deleting GRXCR2 residues 36–95 disrupts CLIC5 association and causes hearing loss despite largely preserved
      bundle morphology. This is a partner-gene experiment, not evidence of a human DFNB103 modifier allele.
    quote_role: PRIMARY_RESULT
  - reference: PMID:24285636
    reference_title: "CLIC5 stabilizes membrane-actin filament linkages at the base of hair cell stereocilia in a molecular complex with radixin, taperin, and myosin VI."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: >-
      Proof of a direct interaction between CLIC5 and ERMs (or NHERF2) remains elusive
    explanation: >-
      The authors distinguish biochemical association from direct binding.
- name: Progressive Stereocilia Fusion and Bundle Distortion
  description: >-
    CLIC5-deficient hair cells develop membrane lifting, stereocilia fusion and bundle distortion. In the jitterbug
    deletion line, early bundle abnormalities precede inner-hair-cell fusion at approximately P10; outer-hair-cell
    fusion becomes prominent after P14 and is more severe basally. In the ENU-induced nmf318 missense model
    used for AAV therapy, cochlear morphology appeared unchanged at P14 but fusion was present at P17, with
    inner hair cells affected across regions and outer-hair-cell fusion more severe apically. Utricular bundles
    were elongated at P15 and thickened by P17. These line- and assay-specific patterns cannot be converted
    into a human treatment window.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: cochlear inner hair cell
    term:
      id: CL:0000589
      label: cochlear inner hair cell
  - preferred_term: cochlear outer hair cell
    term:
      id: CL:0000601
      label: cochlear outer hair cell
  - preferred_term: vestibular hair cell
    term:
      id: CL:0000609
      label: vestibular hair cell
  biological_processes:
  - preferred_term: auditory receptor cell stereocilium organization
    term:
      id: GO:0060088
      label: auditory receptor cell stereocilium organization
    modifier: DECREASED
  - preferred_term: vestibular receptor cell stereocilium organization
    term:
      id: GO:0060121
      label: vestibular receptor cell stereocilium organization
    modifier: DECREASED
  downstream:
  - target: Progressive Hair Cell Degeneration
    causal_link_type: UNKNOWN
  - target: Progressive Sensorineural Hearing Impairment
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Disorganized auditory bundles impair hair-cell function before extensive cell loss; the detailed human
      lesion is inferred from models.
    evidence:
    - reference: PMID:17021174
      reference_title: The chloride intracellular channel protein CLIC5 is expressed at high levels in hair cell stereocilia and is essential for normal inner ear function.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        The hearing impairment exhibited by young mutant mice (which still retain some hearing) (Fig. 1) is
        likely related to the early loss of outer hair cell function.
      explanation: >-
        The study interprets early hearing impairment in relation to bundle dysfunction, before advanced organ
        degeneration.
  evidence:
  - reference: PMID:24285636
    reference_title: "CLIC5 stabilizes membrane-actin filament linkages at the base of hair cell stereocilia in a molecular complex with radixin, taperin, and myosin VI."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Confocal and scanning electron microscopy of CLIC5-deficient jitterbug (jbg) mice revealed progressive fusion of stereocilia as early as postnatal day 10."
    explanation: The structural lesion and the age at which it starts, in the jitterbug line.
    quote_role: PRIMARY_RESULT
  - reference: PMID:40859056
    reference_title: "AAV gene therapy rescues hearing and balance in a model of CLIC5 deafness."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Inner hair cells (IHCs) exhibited extensive hair bundle fusion across all cochlear regions."
    explanation: >-
      Inner-hair-cell fusion occurs across cochlear regions in the nmf318 model; this morphology should not
      be confused with the regional pattern of cell loss.
    quote_role: PRIMARY_RESULT
  - reference: PMID:40859056
    reference_title: "AAV gene therapy rescues hearing and balance in a model of CLIC5 deafness."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In the vestibular system, vestibular hair cells (VHCs) of the utricle displayed elongated hair bundles as early as P15, and by P17, thickened hair bundles were also observed"
    explanation: >-
      Vestibular bundle morphology in the ENU-induced nmf318 line.
    quote_role: PRIMARY_RESULT
- name: Progressive Hair Cell Degeneration
  description: >-
    Clic5-deficient mice show progressive cochlear and vestibular hair-cell loss after bundle abnormalities.
    In jitterbug mice, stereocilia were abnormal at P40 without missing hair cells in the imaged preparations,
    while older animals had severe organ-of-Corti and vestibular degeneration. In the nmf318 AAV study, outer-hair-cell
    loss was greatest basally, whereas inner-hair-cell survival was largely retained except at the cochlear
    base. Hearing dysfunction therefore cannot be attributed solely to cell death. P0 gene delivery preceded
    bundle damage and did not test rescue during the interval between bundle failure and cell loss.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: cochlea auditory hair cell
    term:
      id: CL:4023120
      label: cochlea auditory hair cell
  - preferred_term: vestibular hair cell
    term:
      id: CL:0000609
      label: vestibular hair cell
  downstream:
  - target: Progressive Sensorineural Hearing Impairment
    causal_link_type: DIRECT
  - target: Vestibular Areflexia
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:17021174
    reference_title: "The chloride intracellular channel protein CLIC5 is expressed at high levels in hair cell stereocilia and is essential for normal inner ear function."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Histological analysis of mutant inner ears revealed dysmorphic stereocilia and progressive hair cell degeneration."
    explanation: >-
      The source reports abnormal stereocilia and progressive hair-cell degeneration; time-course details come
      from its full text.
    quote_role: PRIMARY_RESULT
  - reference: PMID:40859056
    reference_title: AAV gene therapy rescues hearing and balance in a model of CLIC5 deafness.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      Quantification of HC survival indicated that CLIC5 deficiency primarily caused OHC loss, which was most
      severe in the basal cochlear region (32 kHz)
    explanation: >-
      Cell counts distinguish basal outer-hair-cell loss from the distribution of bundle fusion.
phenotypes:
- name: Progressive Sensorineural Hearing Impairment
  category: Auditory
  description: >-
    Progressive bilateral sensorineural hearing loss is documented in the reported families. The Turkish siblings
    progressed from mild loss in early childhood to severe or profound loss before the second decade. Three
    Cameroonian siblings reported prelingual onset and progression and had profound loss when assessed as adults;
    earlier audiograms were unavailable. The Siberian cohort ranged from moderate to profound loss and reported
    highly variable decline, with a mean annual speech-frequency PTA change of 7.4 ± 13.65 dB. This cohort
    average does not predict an individual trajectory.
  phenotype_term:
    preferred_term: Progressive sensorineural hearing impairment
    term:
      id: HP:0000408
      label: Progressive sensorineural hearing impairment
  evidence:
  - reference: PMID:24781754
    reference_title: "Progressive hearing loss and vestibular dysfunction caused by a homozygous nonsense mutation in CLIC5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The hearing loss in the present family had an onset in early childhood and progressed from mild to severe or even profound before the second decade."
    explanation: Onset and rate of progression in the founding family.
    quote_role: PRIMARY_RESULT
  - reference: PMID:40957967
    reference_title: "The c.644 G > A p.(Trp215*) founder variant in the CLIC5 gene causes progressive autosomal recessive deafness 103 (DFNB103) in Eastern Siberia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genotype-phenotype analysis in patients with DFNB103 showed that HL was sensorineural, symmetrical and variable by severity (from moderate to profound)."
    explanation: >-
      Sensorineural loss, symmetry and severity range in the 22-patient Siberian cohort.
    quote_role: PRIMARY_RESULT
  - reference: PMID:40957967
    reference_title: "The c.644 G > A p.(Trp215*) founder variant in the CLIC5 gene causes progressive autosomal recessive deafness 103 (DFNB103) in Eastern Siberia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In most cases this form of HL was detected in the post-lingual period (mean age 7.9 ± 1.2 years) and has a significant severity progression with age."
    explanation: Mean age at detection and confirmation of the progressive course in 22 patients.
    quote_role: PRIMARY_RESULT
  - reference: PMID:33114113
    reference_title: Bi-Allelic Novel Variants in CLIC5 Identified in a Cameroonian Multiplex Family with Non-Syndromic Hearing Impairment.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      A history of prelingual and progressive HI was described for all three affected pedigree members; however,
      before this study, no formal audiological assessment was performed for any of the family members.
    explanation: >-
      Prelingual onset and progression were reported retrospectively; earlier formal audiometry was unavailable.
- name: Bilateral Sensorineural Hearing Impairment
  category: Auditory
  description: >-
    Bilateral profound sensorineural hearing loss was measured in the three Cameroonian siblings. The Turkish
    family and Siberian cohort also show bilateral disease, with symmetry described in the latter. Small selected
    samples do not establish a population-wide frequency.
  phenotype_term:
    preferred_term: Bilateral sensorineural hearing impairment
    term:
      id: HP:0008619
      label: Bilateral sensorineural hearing impairment
  evidence:
  - reference: PMID:33114113
    reference_title: "Bi-Allelic Novel Variants in CLIC5 Identified in a Cameroonian Multiplex Family with Non-Syndromic Hearing Impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Audiological assessment of the three affected individuals revealed bilateral profound sensorineural HI (Figure 1B)."
    explanation: Bilateral involvement in all three affected members of the Cameroonian family.
    quote_role: PRIMARY_RESULT
  - reference: PMID:40957967
    reference_title: "The c.644 G > A p.(Trp215*) founder variant in the CLIC5 gene causes progressive autosomal recessive deafness 103 (DFNB103) in Eastern Siberia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genotype-phenotype analysis in patients with DFNB103 showed that HL was sensorineural, symmetrical and variable by severity (from moderate to profound)."
    explanation: >-
      Symmetry in the largest cohort, which is a stronger statement than bilaterality: the
      two ears are not merely both affected but affected to a similar degree.
    quote_role: PRIMARY_RESULT
- name: High-Frequency Sensorineural Hearing Impairment
  category: Auditory
  description: >-
    Audiograms in the Siberian cohort mostly show a downsloping configuration with
    pronounced loss of high and mid frequencies.
  phenotype_term:
    preferred_term: High-frequency sensorineural hearing impairment
    term:
      id: HP:0001757
      label: High-frequency sensorineural hearing impairment
  evidence:
  - reference: PMID:40957967
    reference_title: "The c.644 G > A p.(Trp215*) founder variant in the CLIC5 gene causes progressive autosomal recessive deafness 103 (DFNB103) in Eastern Siberia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Audiograms mostly have a down curve configuration, with pronounced loss of high and mid frequencies."
    explanation: >-
      Predominant downsloping configuration in the Siberian cohort, with both high- and mid-frequency involvement.
    quote_role: PRIMARY_RESULT
  notes: >-
    The binding captures the high-frequency component of the reported downsloping audiogram; mid-frequency
    involvement is also described.
- name: Postlingual Sensorineural Hearing Impairment
  category: Auditory
  description: >-
    Postlingual onset or detection is reported in many Siberian patients: 19 of 26 homozygotes in the 2019
    series reported postlingual onset, and the later cohort reported a mean detection age of 7.9 ± 1.2 years.
    Prelingual presentation also occurs, including the Cameroonian family. A normal early hearing screen does
    not exclude later loss.
  phenotype_term:
    preferred_term: Postlingual sensorineural hearing impairment
    term:
      id: HP:0008596
      label: Postlingual sensorineural hearing impairment
  evidence:
  - reference: PMID:40957967
    reference_title: "The c.644 G > A p.(Trp215*) founder variant in the CLIC5 gene causes progressive autosomal recessive deafness 103 (DFNB103) in Eastern Siberia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In most cases this form of HL was detected in the post-lingual period (mean age 7.9 ± 1.2 years) and has a significant severity progression with age."
    explanation: Postlingual detection with a quantified mean age.
    quote_role: PRIMARY_RESULT
  - reference: DOI:10.25557/2073-7998.2019.10.36-48
    reference_title: "A novel nonsense mutation c.1121G>A (p.Trp374*) in the CLIC5 gene is the main cause of the juvenile autosomal recessive form of deafness (DFNB103) in the Arctic regions of Yakutia"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most of homozygous for c.1121G>A patients (19 out of 26) reported about late onset of their hearing loss occurred in postlingual period (averaged 9.7±0.6 years)."
    explanation: >-
      Nineteen of 26 homozygotes reported postlingual onset in this selected 2019 cohort; the remaining presentations
      prevent a uniformly postlingual definition.
    quote_role: PRIMARY_RESULT
- name: Vestibular Areflexia
  category: Vestibular
  description: >-
    Both Turkish siblings had vestibular areflexia on rotatory testing at ages 16 and 11 years, after initially
    normal motor milestones and later balance difficulties. The Cameroonian siblings had no vestibular symptoms
    or abnormality on reported examination, but this was not an equivalent formal vestibular battery. The prevalence
    and age-dependent penetrance of vestibular dysfunction remain uncertain.
  phenotype_term:
    preferred_term: Vestibular areflexia
    term:
      id: HP:0008568
      label: Vestibular areflexia
  evidence:
  - reference: PMID:24781754
    reference_title: "Progressive hearing loss and vestibular dysfunction caused by a homozygous nonsense mutation in CLIC5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Impaired hearing is accompanied by vestibular areflexia and in one of the patients with mild renal dysfunction."
    explanation: The vestibular finding in the founding family, with the renal observation alongside it.
    quote_role: PRIMARY_RESULT
  - reference: url:https://repositoriosaludmadrid.es/bitstreams/e783eafe-8086-4b75-be09-9bd6ce296bad/download
    reference_title: "https://repositoriosaludmadrid.es/bitstreams/e783eafe-8086-4b75-be09-9bd6ce296bad/download"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      V estibular areflexia was found in both individuals during the rotatory test at the age of 16 years (II.2)
      and 11 years (II.3).
    explanation: >-
      Formal vestibular testing in the two discovery-family siblings.
- name: Prelingual Sensorineural Hearing Impairment
  category: Auditory
  description: >-
    All three Cameroonian affected siblings reported onset before language acquisition and had bilateral profound
    sensorineural hearing loss as adults. Earlier audiograms were not available; this is retrospective onset
    information.
  phenotype_term:
    preferred_term: Prelingual sensorineural hearing impairment
    term:
      id: HP:0000399
      label: Prelingual sensorineural hearing impairment
  evidence:
  - reference: PMID:33114113
    reference_title: Bi-Allelic Novel Variants in CLIC5 Identified in a Cameroonian Multiplex Family with Non-Syndromic Hearing Impairment.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      A history of prelingual and progressive HI was described for all three affected pedigree members; however,
      before this study, no formal audiological assessment was performed for any of the family members.
    explanation: >-
      Prelingual onset and progression were reported retrospectively; earlier formal audiometry was unavailable.
prevalence:
- population: Yakutia (Sakha Republic), Eastern Siberia
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 2.7
  notes: >-
    The 2019 study identified 26 homozygotes in a Yakutia population denominator of 958,528, yielding 0.27
    per 10,000 (2.7 per 100,000). This ascertainment-based regional estimate is not a global prevalence. The
    reported allele uses the longer-transcript notation c.1121G>A p.Trp374Ter.
  evidence:
  - reference: DOI:10.25557/2073-7998.2019.10.36-48
    reference_title: "A novel nonsense mutation c.1121G>A (p.Trp374*) in the CLIC5 gene is the main cause of the juvenile autosomal recessive form of deafness (DFNB103) in the Arctic regions of Yakutia"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The average prevalence of DFNB103 caused by the homozygous variant c.1121G>A (p.Trp374*) in Yakutia was 0.27±0.053 per 10000 with a maximum accumulation in Eveno-Bytantaysky district (31.39±10.46 per 10000)"
    explanation: The Yakutia-wide prevalence, and the district in which it concentrates.
    quote_role: PRIMARY_RESULT
- population: Eveno-Bytantaysky national district, Arctic Yakutia
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 313.9
  notes: >-
    Nine identified homozygotes among 2,867 district residents yielded 31.39 ± 10.46 per 10,000 (313.9 per
    100,000). The reported plus/minus uncertainty is not a minimum-to-maximum range or confidence interval.
    Regional enrichment alone does not establish a founder event; the later haplotype study provides that evidence.
  evidence:
  - reference: DOI:10.25557/2073-7998.2019.10.36-48
    reference_title: "A novel nonsense mutation c.1121G>A (p.Trp374*) in the CLIC5 gene is the main cause of the juvenile autosomal recessive form of deafness (DFNB103) in the Arctic regions of Yakutia"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The average prevalence of DFNB103 caused by the homozygous variant c.1121G>A (p.Trp374*) in Yakutia was 0.27±0.053 per 10000 with a maximum accumulation in Eveno-Bytantaysky district (31.39±10.46 per 10000)"
    explanation: The district rate this record stores, with its reported standard error.
    quote_role: PRIMARY_RESULT
- population: GJB2-negative hearing loss patients, Sakha Republic, Eastern Siberia
  measure_type: UNKNOWN
  notes: >-
    The 2026 report found this homozygous founder variant in 9.9% of selected Siberian GJB2-negative hearing-loss
    patients. This is diagnostic yield, not a population prevalence or heterozygote carrier rate. It should
    not be combined with the 2019 cohort as if the patients were independent.
  evidence:
  - reference: PMID:40957967
    reference_title: "The c.644 G > A p.(Trp215*) founder variant in the CLIC5 gene causes progressive autosomal recessive deafness 103 (DFNB103) in Eastern Siberia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The high frequency of c.644 G > A p.(Trp215*) was found among Siberian GJB2-negative patients (9.9%) and this variant was not detected in GJB2-negative patients of Caucasian descent (predominantly Russians)."
    explanation: The yield figure and the population specificity that limits it.
    quote_role: PRIMARY_RESULT
progression:
- phase: Variable onset
  notes: >-
    Onset ranges from prelingual to postlingual. Normal early screening was documented in the Turkish siblings,
    but it is not universal; the Cameroonian family reported prelingual loss.
  evidence:
  - reference: PMID:33114113
    reference_title: Bi-Allelic Novel Variants in CLIC5 Identified in a Cameroonian Multiplex Family with Non-Syndromic Hearing Impairment.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      A history of prelingual and progressive HI was described for all three affected pedigree members; however,
      before this study, no formal audiological assessment was performed for any of the family members.
    explanation: >-
      Prelingual onset and progression were reported retrospectively; earlier formal audiometry was unavailable.
  - reference: PMID:40957967
    reference_title: "The c.644 G > A p.(Trp215*) founder variant in the CLIC5 gene causes progressive autosomal recessive deafness 103 (DFNB103) in Eastern Siberia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In most cases this form of HL was detected in the post-lingual period (mean age 7.9 ± 1.2 years) and has a significant severity progression with age."
    explanation: Postlingual detection with a quantified mean age.
    quote_role: PRIMARY_RESULT
- phase: Progressive decline
  notes: >-
    Progression is documented by longitudinal audiometry in the Turkish family and reported in the Siberian
    cohort, with substantial variability. The Siberian mean annual PTA decline of 7.4 ± 13.65 dB is not a fixed
    linear rate for every patient.
  evidence:
  - reference: PMID:40957967
    reference_title: "The c.644 G > A p.(Trp215*) founder variant in the CLIC5 gene causes progressive autosomal recessive deafness 103 (DFNB103) in Eastern Siberia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In average the patients with DFNB103 lost 7.4 ± 13.65 dB on the speech frequency range in pure tone averages (PTA0.5,1.0,2.0,4.0 kHz) per year until reaching profound deafness in the second or third decade of the life."
    explanation: >-
      Reported mean and dispersion of annual change in the Siberian cohort.
    quote_role: PRIMARY_RESULT
- phase: Severe or profound hearing loss
  notes: >-
    The Turkish siblings reached severe or profound loss before the second decade; the Siberian report describes
    profound loss in the second or third decade. Timing varies, and later vestibular dysfunction is documented
    in the Turkish family.
  evidence:
  - reference: PMID:24781754
    reference_title: "Progressive hearing loss and vestibular dysfunction caused by a homozygous nonsense mutation in CLIC5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The hearing loss in the present family had an onset in early childhood and progressed from mild to severe or even profound before the second decade."
    explanation: >-
      The Turkish family reached severe or profound loss earlier than the age range reported in the Siberian
      cohort.
    quote_role: PRIMARY_RESULT
external_assertions:
- name: OMIM deafness, autosomal recessive 103 record
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:616042
  url: https://omim.org/entry/616042
  description: >-
    OMIM:616042 is the disease identifier used in the DFNB103 literature and cross-referenced by MONDO:0014469.
  evidence:
  - reference: PMID:40957967
    reference_title: "The c.644 G > A p.(Trp215*) founder variant in the CLIC5 gene causes progressive autosomal recessive deafness 103 (DFNB103) in Eastern Siberia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Previously only two families were known with progressive autosomal recessive deafness 103 (DFNB103, OMIM616042)
      caused by pathogenic variants of the CLIC5 gene.
    explanation: >-
      The background sentence supplies the disease name and OMIM identifier only; its historical family count
      is not used as an epidemiologic claim.
    quote_role: BACKGROUND
genetic:
- name: CLIC5
  notes: >-
    Biallelic CLIC5 nonsense, missense and canonical splice-donor variants are reported. p.Cys32Ter predicts
    early truncation, but patient lymphoblastoid-cell assays did not confirm nonsense-mediated decay. p.Leu75Pro
    is retained and mislocalized in a heterologous cell assay; c.63+1G>A has a computationally predicted splicing
    effect affecting the short isoforms rather than every CLIC5 transcript. Neither assay establishes a uniform
    dosage-null mechanism.

    The Siberian founder allele has equivalent transcript descriptions: NM_016929.5:c.644G>A (NP_058625.2:p.Trp215Ter)
    and NM_001114086.2:c.1121G>A (NP_001107558.1:p.Trp374Ter), mapped by ClinVar to GRCh38 chr6:45903200C>T.
    The 2019 and 2026 reports must not be added as independent case counts. The later genome-wide haplotype
    analysis supports common origin, with an estimated founder age of approximately 2,500 years. Direct human
    modifiers and population-wide penetrance estimates are not established.
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: CLIC5
    term:
      id: hgnc:13517
      label: CLIC5
  evidence:
  - reference: PMID:24781754
    reference_title: "Progressive hearing loss and vestibular dysfunction caused by a homozygous nonsense mutation in CLIC5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In conclusion, our results show that CLIC5 is a novel arNSHI gene involved in progressive hearing impairment, vestibular and possibly mild renal dysfunction in a family of Turkish origin."
    explanation: >-
      The founding gene-disease conclusion, including the authors' own hedged renal
      observation.
    quote_role: PRIMARY_RESULT
  - reference: PMID:33114113
    reference_title: "Bi-Allelic Novel Variants in CLIC5 Identified in a Cameroonian Multiplex Family with Non-Syndromic Hearing Impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The three affected individuals were compound heterozygous for both variants, and all unaffected individuals were heterozygous for one of the two variants."
    explanation: >-
      The three affected siblings carried the two variants in trans, while tested unaffected relatives carried
      one variant.
    quote_role: PRIMARY_RESULT
  - reference: PMID:40957967
    reference_title: "The c.644 G > A p.(Trp215*) founder variant in the CLIC5 gene causes progressive autosomal recessive deafness 103 (DFNB103) in Eastern Siberia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The haplotype analysis based on the 730,000 whole genome SNP-markers indicates common origin of all studied mutant chromosomes."
    explanation: The haplotype evidence establishing the Siberian allele as a single founder event.
    quote_role: PRIMARY_RESULT
diagnosis:
- name: Molecular diagnosis of CLIC5-related hearing loss
  description: >-
    A hearing-loss multigene panel or genomic testing can identify biallelic pathogenic or likely pathogenic
    CLIC5 variants. Establish phase and assess deletion/duplication coverage where needed; a variant of uncertain
    significance alone is not diagnostic. Postlingual onset, vestibular signs or prior GJB2 exclusion are not
    prerequisites. In the Sakha population, the founder allele can inform locally appropriate testing, while
    a negative targeted test does not exclude other CLIC5 alleles or hearing-loss genes.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/pdf/Bookshelf_NBK1434.pdf
    reference_title: "https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/pdf/Bookshelf_NBK1434.pdf"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Recommended molecular genetic testing approaches include use of a multigene hearing loss panel and/or
      genomic testing.
    explanation: >-
      General genetic hearing-loss testing guidance, applied to a panel that includes CLIC5.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/pdf/Bookshelf_NBK1434.pdf
    reference_title: "https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/pdf/Bookshelf_NBK1434.pdf"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The identification of variant(s) of uncertain significance cannot be used to confirm or rule out the
      diagnosis.
    explanation: >-
      General interpretation standard; segregation and phenotype remain necessary for a CLIC5 diagnosis.
  - reference: PMID:33114113
    reference_title: "Bi-Allelic Novel Variants in CLIC5 Identified in a Cameroonian Multiplex Family with Non-Syndromic Hearing Impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The three affected individuals were compound heterozygous for both variants, and all unaffected individuals were heterozygous for one of the two variants."
    explanation: >-
      The three affected siblings carried the two variants in trans, while tested unaffected relatives carried
      one variant.
    quote_role: PRIMARY_RESULT
- name: Audiologic and vestibular assessment
  description: >-
    Age-appropriate audiometry establishes type, severity, laterality and progression. Evaluate balance symptoms
    and vestibular function; a normal newborn screen does not exclude later CLIC5-related hearing loss. At-risk
    relatives can receive targeted familial-variant testing and hearing evaluation.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/pdf/Bookshelf_NBK1434.pdf
    reference_title: "https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/pdf/Bookshelf_NBK1434.pdf"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Hearing status can be determined at any age and is tailored to the individual's ability to participate
    explanation: >-
      General audiologic assessment principle.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/pdf/Bookshelf_NBK1434.pdf
    reference_title: "https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/pdf/Bookshelf_NBK1434.pdf"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Permanent childhood hearing loss in a parent or sib increases the probability of hearing loss in other
      family members and warrants early complete diagnostic evaluation of hearing regardless of the family
      member's newborn hearing screening result.
    explanation: >-
      General at-risk family assessment, relevant to variable CLIC5 onset.
treatments:
- name: Genetic Counseling
  description: >-
    Discuss recessive inheritance, parental testing and family-specific recurrence chances. For two confirmed
    carriers the chance of biallelic inheritance is 25% per pregnancy. Once the familial pathogenic variants
    are established, offer information about carrier testing, prenatal testing and preimplantation testing
    according to individual preferences.
  action_category: COUNSELING_INFORMATIONAL
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/pdf/Bookshelf_NBK1434.pdf
    reference_title: "https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/pdf/Bookshelf_NBK1434.pdf"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      If both parents are known to be heterozygous for an autosomal recessive hearing loss-related pathogenic
      variant, each sib of the proband has at conception a 25% chance of having hearing loss, a 50% chance
      of having no hearing loss and being a carrier, and a 25% chance of having no hearing loss and not being
      a carrier.
    explanation: >-
      General autosomal recessive hearing-loss counseling, conditional on parental carrier status; not a DFNB103
      penetrance estimate.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/pdf/Bookshelf_NBK1434.pdf
    reference_title: "https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/pdf/Bookshelf_NBK1434.pdf"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Once the pathogenic variant(s) have been identified in the family, prenatal and preimplantation genetic
      testing for genetic hearing loss are possible.
    explanation: >-
      General reproductive counseling options, not a DFNB103 intervention trial.
- name: Hearing Aids
  description: >-
    Offer individually fitted amplification when residual hearing permits, with reassessment as thresholds
    change. This is general sensorineural hearing-loss care; a DFNB103-specific hearing-aid outcome series
    is not available in the reviewed sources.
  action_category: THERAPEUTIC
  therapeutic_modality: DEVICE
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/pdf/Bookshelf_NBK1434.pdf
    reference_title: "https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/pdf/Bookshelf_NBK1434.pdf"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Hearing aids (sound amplification), customized by an audiologist to the degree and frequency of hearing
      loss, can be used in individuals with mild-to-severe hearing loss.
    explanation: >-
      General hearing-loss habilitation guidance.
  treatment_term:
    preferred_term: hearing-aid habilitation
    term:
      id: NCIT:C15315
      label: Rehabilitation
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: Hearing Aid
        term:
          id: NCIT:C183182
          label: Hearing Aid
- name: Cochlear Implantation
  description: >-
    Consider cochlear implantation when hearing severity and aided communication outcomes warrant it. The Turkish
    index patient received an implant at age 11 and had 88% speech recognition five years later on Dutch consonant-vowel-consonant
    word lists. This single reported outcome does not establish uniform CLIC5-specific benefit.
  action_category: THERAPEUTIC
  therapeutic_modality: SURGERY
  evidence:
  - reference: url:https://repositoriosaludmadrid.es/bitstreams/e783eafe-8086-4b75-be09-9bd6ce296bad/download
    reference_title: "https://repositoriosaludmadrid.es/bitstreams/e783eafe-8086-4b75-be09-9bd6ce296bad/download"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Individual II.2 received a cochlear implant at the age of 11 years. Five years post implantation, the
      speech recognition scores were 88% (using the standard Dutch phonetically balanced consonant-vocal-consonant
      word lists).
    explanation: >-
      Disease-specific outcome from the full text of Seco et al., PMID:24781754; one recipient, not a comparative
      trial.
  treatment_term:
    preferred_term: cochlear implantation
    term:
      id: NCIT:C15329
      label: Surgical Procedure
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: Cochlear Implant
        term:
          id: NCIT:C157820
          label: Cochlear Implant
- name: Communication and Educational Support
  description: >-
    Establish communication goals with the individual and family, including spoken language, sign language
    or combined approaches. Provide early language access, speech-language support and appropriate educational
    accommodations.
  action_category: THERAPEUTIC
  therapeutic_modality: OTHER
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/pdf/Bookshelf_NBK1434.pdf
    reference_title: "https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/pdf/Bookshelf_NBK1434.pdf"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      On initial evaluation of individuals with hearing loss, the goals for communication must be established
      with a focus on equipping individuals with language and appropriate access to language.
    explanation: >-
      General care guidance; communication choices are individualized.
  treatment_term:
    preferred_term: communication and educational support
- name: Audiologic and Vestibular Follow-up
  description: >-
    Repeat audiologic assessment according to age, hearing trajectory and habilitation needs. Assess vestibular
    symptoms and function and arrange physical therapy when indicated. No DFNB103-specific testing interval
    is established.
  action_category: MONITORING
  therapeutic_modality: OTHER
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/pdf/Bookshelf_NBK1434.pdf
    reference_title: "https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/pdf/Bookshelf_NBK1434.pdf"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Perform sequential audiologic examinations that:
    explanation: >-
      The general chapter recommends serial audiology to document progression; its gene-specific interval table
      does not name CLIC5.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/pdf/Bookshelf_NBK1434.pdf
    reference_title: "https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/pdf/Bookshelf_NBK1434.pdf"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The finding of vestibular dysfunction may guide physical therapy, particularly in children with delayed
      motor milestones.
    explanation: >-
      General vestibular care principle, not a DFNB103 rehabilitation outcome study.
  treatment_term:
    preferred_term: audiologic and vestibular monitoring
- name: Renal Assessment When Indicated
  description: >-
    The discovery-family authors recommended renal follow-up for both affected siblings after repeated albuminuria
    and elevated blood pressure in one, despite preserved estimated GFR. Renal involvement remains uncertain
    and no validated DFNB103-wide schedule is established.
  action_category: MONITORING
  therapeutic_modality: OTHER
  evidence:
  - reference: url:https://repositoriosaludmadrid.es/bitstreams/e783eafe-8086-4b75-be09-9bd6ce296bad/download
    reference_title: "https://repositoriosaludmadrid.es/bitstreams/e783eafe-8086-4b75-be09-9bd6ce296bad/download"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Therefore, follow-up of renal function is indicated for individual II.3 but also for his hearing-impaired
      sister.
    explanation: >-
      A family-specific recommendation in the primary report; it does not establish universal nephropathy.
  treatment_term:
    preferred_term: renal assessment
- name: Avoid Repeated Excessive Noise Exposure
  description: >-
    Counsel about avoiding repeated loud-noise exposure to protect remaining hearing. This is general hearing-loss
    care and does not imply that environmental exposure causes DFNB103.
  action_category: COUNSELING_INFORMATIONAL
  therapeutic_modality: OTHER
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/pdf/Bookshelf_NBK1434.pdf
    reference_title: "https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/pdf/Bookshelf_NBK1434.pdf"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      persons with documented hearing loss should be counseled appropriately and repeated overexposure to loud
      noises should be avoided.
    explanation: >-
      General protection of residual hearing, not a demonstrated CLIC5-specific susceptibility.
  treatment_term:
    preferred_term: hearing-protection counseling
animal_models:
- name: Clic5 jitterbug mouse
  species: Mouse
  genotype: Clic5 jbg/jbg, 97 bp intragenic deletion causing exon 5 skipping
  publication: PMID:17021174
  description: >-
    The spontaneous C3H/HeJ jitterbug allele deletes 97 genomic bases, causing exon 5 skipping, frameshift
    and premature termination. Protein is undetectable by the reported assays. Mutants develop hearing and
    vestibular dysfunction, abnormal stereocilia and later hair-cell degeneration. The 2014 follow-up defines
    membrane lifting, fusion and altered partner localization. Cochlear supporting structures such as Reissner's
    membrane and stria vascularis were preserved in the original histology, arguing against a primary endolymph-volume
    phenotype.
  genes:
  - preferred_term: CLIC5
    term:
      id: hgnc:13517
      label: CLIC5
  modeled_mechanisms:
  - target: Loss of Membrane-Actin Tethering at the Stereocilia Taper
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Jitterbug mice support a role for CLIC5 in membrane-cytoskeletal attachment through membrane lifting,
      altered radixin/PTPRQ localization and subsequent bundle fusion. The exact direct molecular contacts
      remain unresolved.
    limitations: >-
      A functionally protein-null deletion does not reproduce every human allele. Biochemical interactions
      were measured partly in epithelial-cell constructs and mouse lung, while protein abundance and localization
      also used rat and chicken hair bundles; these are not a purified native human hair-cell complex.
    readouts:
    - name: Radixin immunostaining in hair bundles
      target: Loss of Membrane-Actin Tethering at the Stereocilia Taper
      direction: DECREASED
      interpretation: >-
        Reduced radixin immunostaining supports a localization or stability dependence on CLIC5; it does not
        prove total loss of radixin or direct binding.
      evidence:
      - reference: PMID:17021174
        reference_title: "The chloride intracellular channel protein CLIC5 is expressed at high levels in hair cell stereocilia and is essential for normal inner ear function."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Radixin immunostaining appeared reduced in hair bundles of jbg mutant mice."
        explanation: The immunolocalisation measurement behind this readout.
        quote_role: PRIMARY_RESULT
    - name: Taper-region localisation of radixin, taperin and PTPRQ
      target: Loss of Membrane-Actin Tethering at the Stereocilia Taper
      direction: ALTERED
      interpretation: >-
        Radixin and PTPRQ dispersal precedes visible fusion, whereas taperin mislocalization occurs later.
        Temporal ordering does not identify a single initiating interaction.
      evidence:
      - reference: PMID:24285636
        reference_title: "CLIC5 stabilizes membrane-actin filament linkages at the base of hair cell stereocilia in a molecular complex with radixin, taperin, and myosin VI."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Radixin (RDX), protein tyrosine phosphatase receptor Q (PTPRQ), and taperin (TPRN), deafness-associated proteins that also concentrate at the base of stereocilia, were mislocalized in fused stereocilia of jbg mice."
        explanation: The mislocalisation of all three taper proteins in the null.
        quote_role: PRIMARY_RESULT
    evidence:
    - reference: PMID:17021174
      reference_title: "The chloride intracellular channel protein CLIC5 is expressed at high levels in hair cell stereocilia and is essential for normal inner ear function."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mice homozygous for a new spontaneous recessive mutation of the Clic5 gene, named jitterbug (jbg), exhibit impaired hearing and vestibular dysfunction."
      explanation: >-
        The phenotype that makes the model informative, and the same two-system involvement
        seen in patients.
      quote_role: PRIMARY_RESULT
  - target: Progressive Stereocilia Fusion and Bundle Distortion
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Fusion from postnatal day 10 with progressive worsening, which is the structural
      lesion this node describes and which no human material shows.
    limitations: >-
      Human cochlear fusion has not been directly demonstrated by the cited studies. Mouse developmental timing
      cannot be mapped to a specific age or closed therapeutic window in patients.
    readouts:
    - name: Stereocilia fusion by scanning electron microscopy
      target: Progressive Stereocilia Fusion and Bundle Distortion
      direction: INCREASED
      interpretation: Adjacent stereocilia progressively fuse from postnatal day 10 onwards.
      evidence:
      - reference: PMID:24285636
        reference_title: "CLIC5 stabilizes membrane-actin filament linkages at the base of hair cell stereocilia in a molecular complex with radixin, taperin, and myosin VI."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Confocal and scanning electron microscopy of CLIC5-deficient jitterbug (jbg) mice revealed progressive fusion of stereocilia as early as postnatal day 10."
        explanation: The structural measurement and its onset.
        quote_role: PRIMARY_RESULT
    evidence:
    - reference: PMID:17021174
      reference_title: "The chloride intracellular channel protein CLIC5 is expressed at high levels in hair cell stereocilia and is essential for normal inner ear function."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Histological analysis of mutant inner ears revealed dysmorphic stereocilia and progressive hair cell degeneration."
      explanation: The histological phenotype, including its progressive character.
      quote_role: PRIMARY_RESULT
  evidence:
  - reference: PMID:17021174
    reference_title: "The chloride intracellular channel protein CLIC5 is expressed at high levels in hair cell stereocilia and is essential for normal inner ear function."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The jbg mutation is a 97 bp intragenic deletion that causes skipping of exon 5, which creates a translational frame shift and premature stop codon."
    explanation: >-
      The molecular lesion, of the same truncating class as the human founder and founding
      alleles, which is what makes this model genetically comparable.
    quote_role: PRIMARY_RESULT
- name: Clic5 nmf318 missense mouse treated with inner ear AAV
  species: Mouse
  genotype: C57BL/6J-Clic5nmf318/J homozygote; ENU-induced missense allele; P0 AAV2/9-PHP.B Clic5 delivery
  publication: PMID:40859056
  description: >-
    The gene-replacement study used the ENU-induced nmf318 missense line (JAX 005329), not an engineered knockout.
    The MGI allele record specifies c.680T>C, p.Phe227Ser; the paper uses Clic5−/− as shorthand for the protein-deficient
    phenotype. Untreated animals had approximately 40-dB ABR threshold shifts at four weeks and no detected
    responses at eight weeks.

    Left-utricle injection at P0 restored CLIC5, prevented bundle fusion, improved hair-cell survival and auditory/vestibular
    outcomes. Radixin localization returned toward normal but taperin remained distributed along stereocilia
    at eight weeks. The self-complementary vector achieved comparable measured benefit at approximately eleven-fold
    lower titer than the single-stranded construct; this was not a formal equivalence trial, the constructs
    differed in reporter content and some untreated controls were shared. Auditory benefit declined, especially
    at high frequencies, whereas vestibular behavioral benefit persisted through the 12-week follow-up. No
    delayed-treatment arm tested reversal of established damage.
  genes:
  - preferred_term: CLIC5
    term:
      id: hgnc:13517
      label: CLIC5
  modeled_mechanisms:
  - target: Loss of Membrane-Actin Tethering at the Stereocilia Taper
    relationship: RESCUES
    fidelity: MODERATE
    description: >-
      CLIC5 replacement restores radixin localization and reduces structural abnormalities, supporting the
      proposed attachment function. Taperin remains mislocalized, so the experiment does not demonstrate reconstitution
      of every proposed complex component.
    limitations: >-
      P0 treatment precedes the observed lesion and tests prevention rather than reversal. No post-onset delivery
      arm defines when efficacy is lost. Auditory thresholds worsened by 12 weeks, especially at high frequencies;
      C57BL/6 background, expression dynamics and immune effects remain possible contributors.
    readouts:
    - name: Radixin localisation after CLIC5 restoration
      target: Loss of Membrane-Actin Tethering at the Stereocilia Taper
      direction: RESTORED
      interpretation: >-
        Radixin returns toward the stereociliary base after CLIC5 replacement; this supports a functional dependency
        without proving the complete native binding architecture.
      evidence:
      - reference: PMID:40859056
        reference_title: "AAV gene therapy rescues hearing and balance in a model of CLIC5 deafness."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Restoring CLIC5 expression also appears to normalize the localization of RDX, emphasizing CLIC5's vital role in hair cell function."
        explanation: The partner-relocalisation readout after gene replacement.
        quote_role: PRIMARY_RESULT
    evidence:
    - reference: PMID:40859056
      reference_title: "AAV gene therapy rescues hearing and balance in a model of CLIC5 deafness."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We report a robust restoration of CLIC5 expression using either construct, including prevention of morphological degeneration and preserving auditory and vestibular function."
      explanation: The headline rescue result establishing the link's relevance to this node.
      quote_role: PRIMARY_RESULT
  - target: Progressive Stereocilia Fusion and Bundle Distortion
    relationship: RESCUES
    fidelity: MODERATE
    description: >-
      P0 gene replacement prevents much of the later stereociliary fusion and elongation.
    limitations: >-
      A prevention experiment; no delayed-treatment arm.
    readouts:
    - name: Stereocilia morphology after treatment
      target: Progressive Stereocilia Fusion and Bundle Distortion
      direction: RESTORED
      interpretation: >-
        Neonatal treatment preserves largely normal bundle morphology at later endpoints; it does not test
        repair of an already fused bundle.
      evidence:
      - reference: PMID:40859056
        reference_title: "AAV gene therapy rescues hearing and balance in a model of CLIC5 deafness."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "This restoration prevents the fusion and elongation of stereocilia and improves hair cell survival."
        explanation: The structural and survival outcome of the rescue.
        quote_role: PRIMARY_RESULT
    evidence:
    - reference: PMID:40859056
      reference_title: "AAV gene therapy rescues hearing and balance in a model of CLIC5 deafness."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "This restoration prevents the fusion and elongation of stereocilia and improves hair cell survival."
      explanation: The structural and survival outcome of the rescue.
      quote_role: PRIMARY_RESULT
  - target: Progressive Hair Cell Degeneration
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Untreated homozygotes develop progressive hair-cell loss, predominantly outer hair cells at the basal
      cochlea. Neonatal gene replacement improves subsequent survival.
    limitations: >-
      The phenotype and age dependence are model specific. An ABR threshold is a functional endpoint and cannot
      distinguish bundle dysfunction from cell loss.
    readouts:
    - name: Cochlear outer-hair-cell survival
      target: Progressive Hair Cell Degeneration
      direction: DECREASED
      interpretation: >-
        Counts at 12 weeks show greatest outer-hair-cell loss basally in untreated mice, with improved survival
        after gene delivery.
      evidence:
      - reference: PMID:40859056
        reference_title: AAV gene therapy rescues hearing and balance in a model of CLIC5 deafness.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        snippet: >-
          Quantification of HC survival indicated that CLIC5 deficiency primarily caused OHC loss, which was
          most
          severe in the basal cochlear region (32 kHz)
        explanation: >-
          Cell counts distinguish basal outer-hair-cell loss from the distribution of bundle fusion.
    evidence:
    - reference: PMID:40859056
      reference_title: AAV gene therapy rescues hearing and balance in a model of CLIC5 deafness.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        Quantification of HC survival indicated that CLIC5 deficiency primarily caused OHC loss, which was
        most
        severe in the basal cochlear region (32 kHz)
      explanation: >-
        Cell counts distinguish basal outer-hair-cell loss from the distribution of bundle fusion.
  evidence:
  - reference: url:https://www.informatics.jax.org/allele/MGI%3A3522004
    reference_title: "https://www.informatics.jax.org/allele/MGI%3A3522004"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      in exon 6 is predicted to change a highly conserved phenylalanine residue at amino acid 227 to serine
      (NP_766209).
    explanation: >-
      Primary MGI allele annotation establishes the nmf318 lesion; the paper's p.Phe318Ser wording conflicts
      with this record.
  - reference: PMID:40859056
    reference_title: AAV gene therapy rescues hearing and balance in a model of CLIC5 deafness.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      In contrast, Clic5−/− mice exhibited ABR thresholds shifted by ~40 dB at 4 weeks, and no response was
      detected at 8 weeks
    explanation: >-
      Auditory phenotype in homozygous nmf318 mice, called Clic5−/− by the authors.
  - reference: PMID:40859056
    reference_title: AAV gene therapy rescues hearing and balance in a model of CLIC5 deafness.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      In contrast, TPRN was mislocalized along the entire length of the stereocilium, rather than being concentrated
      at the base
    explanation: >-
      At eight weeks after neonatal ssAAV delivery, taperin localization was not restored along with radixin.
discussions:
- discussion_id: clic5_therapeutic_window_timing
  kind: KNOWLEDGE_GAP
  prompt: >-
    Can CLIC5 replacement improve function after hearing loss or bundle damage begins, and what limits durable
    auditory rescue?
  attaches_to:
  - animal_models#Clic5 nmf318 missense mouse treated with inner ear AAV
  - pathophysiology#Progressive Stereocilia Fusion and Bundle Distortion
  rationale: >-
    P0 delivery preceded morphological changes in the nmf318 model. The experiment does not define a closed
    window, prove irreversibility of fusion or establish an equivalent human treatment age. Human onset is
    variable, and cochlear histology is unavailable. Delayed delivery with adequate transduction and dose controls
    is needed.

    Vestibular rescue persisted through 12 weeks while auditory thresholds worsened despite persistent expression
    and no major gross morphological change. These endpoints do not exclude subtle bundle defects, cell-specific
    expression loss, inflammation or background susceptibility; the C57BL/6 Cdh23 allele is one potential confound.
    Radixin rescue with persistent taperin mislocalization also limits claims of complete complex restoration.
  evidence:
  - reference: PMID:40859056
    reference_title: "AAV gene therapy rescues hearing and balance in a model of CLIC5 deafness."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In this study, we performed utricle injections into P0 mice, prior to the morphological changes in hair cells that begin between P14 and P17, at the time of hearing onset"
    explanation: >-
      The intervention preceded structural onset; delayed efficacy was not tested.
    quote_role: PRIMARY_RESULT
  - reference: PMID:40859056
    reference_title: "AAV gene therapy rescues hearing and balance in a model of CLIC5 deafness."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Vestibular function rescue remained durable up to 12 weeks post-injection, while ABR thresholds deteriorated over time, particularly at high frequencies."
    explanation: The divergence between the two rescued systems over time.
    quote_role: PRIMARY_RESULT
  - reference: PMID:40859056
    reference_title: "AAV gene therapy rescues hearing and balance in a model of CLIC5 deafness."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Despite the deterioration of ABR thresholds over time, transgene expression remained robust at 12 weeks, and no significant morphological changes in hair cells were observed."
    explanation: >-
      Persistent expression and gross morphology leave several technical and biological explanations for auditory
      decline unresolved.
    quote_role: PRIMARY_RESULT
  proposed_experiments:
  - experiment_id: exp_dfnb103_delayed_aav_after_fusion_onset
    name: Delayed AAV delivery after stereocilia fusion has begun
    description: >-
      Compare P0 with P21 and P42 delivery in the nmf318 line, using age-matched untreated and vector controls,
      verified cell-specific transduction, expression and dose. Measure auditory and vestibular function, partner
      localization, hair-cell counts and bundle ultrastructure; use matched cohorts where destructive imaging
      prevents within-cell follow-up. Include strain-background controls to assess high-frequency susceptibility.
    would_support:
    - pathophysiology#Progressive Stereocilia Fusion and Bundle Distortion
    supporting_outcome:
    - >-
      Delayed delivery improves or stabilizes function and morphology with verified expression, supporting
      residual reversibility or prevention of further damage under that regimen.
    would_refute:
    - pathophysiology#Progressive Stereocilia Fusion and Bundle Distortion
    refuting_outcome:
    - >-
      Verified delayed delivery fails to improve the measured endpoints, arguing against efficacy of that regimen
      at that stage; this would not prove universal irreversibility or restrict all human strategies to infancy.
- discussion_id: clic5_renal_involvement
  kind: KNOWLEDGE_GAP
  prompt: >-
    Is DFNB103 truly nonsyndromic, or does biallelic CLIC5 loss carry a low-grade renal
    phenotype that has not been looked for systematically?
  attaches_to:
  - genetic#CLIC5
  - disease#Autosomal Recessive Nonsyndromic Hearing Loss 103
  rationale: >-
    The Turkish discovery-family boy had repeatedly elevated urine albumin/creatinine ratios (9.2 and 3.8 mg/mmol)
    and mildly elevated blood pressure at age 11, with preserved estimated GFR (114 ml/min/1.73 m2). No renal
    biopsy established a lesion. The authors recommended follow-up for both siblings. Cameroonian participants
    lacked clinical renal signs, but biochemical kidney assessment was explicitly proposed for future work.
    The available Siberian abstract does not report renal evaluation.

    CLIC5-associated podocyte abnormalities in mice motivate systematic human assessment but do not establish
    a syndromic human nephropathy. Longitudinal albuminuria, blood pressure and kidney-function measurements
    with appropriate controls could clarify penetrance and alternative causes.
  evidence:
  - reference: PMID:24781754
    reference_title: "Progressive hearing loss and vestibular dysfunction caused by a homozygous nonsense mutation in CLIC5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Impaired hearing is accompanied by vestibular areflexia and in one of the patients with mild renal dysfunction."
    explanation: >-
      An isolated renal observation in one of two discovery-family siblings; association with CLIC5 remains
      uncertain.
    quote_role: PRIMARY_RESULT
  - reference: url:https://repositoriosaludmadrid.es/bitstreams/e783eafe-8086-4b75-be09-9bd6ce296bad/download
    reference_title: "https://repositoriosaludmadrid.es/bitstreams/e783eafe-8086-4b75-be09-9bd6ce296bad/download"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Subsequent renal function follow-up of patient II.3 in the future will be needed to determine whether
      it is indeed a nephropathy.
    explanation: >-
      The primary report explicitly leaves nephropathy unresolved.
- discussion_id: clic5_expression_regulation
  kind: KNOWLEDGE_GAP
  prompt: Do experimentally identified CLIC5 regulators or binding partners modify human DFNB103 severity?
  attaches_to:
  - genetic#CLIC5
  rationale: >-
    miR-96 and miR-182 mimics reduce CLIC5 RNA/protein and a CLIC5 3-prime-UTR reporter in HEI-OC1 cells. GRXCR2
    interaction experiments also show functional importance despite largely preserved bundle morphology. Neither
    study establishes a modifier allele or prognostic marker in people with biallelic CLIC5 variants.
  evidence:
  - reference: PMID:22889583
    reference_title: MiR-183 family regulates chloride intracellular channel 5 expression in inner ear hair cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      Our findings thus suggest that CLIC5 is directly regulated by miR-96 and miR-182 and that the target
      sequence in this regard is located between nucleotides 760-766 within the CLIC5 3'-UTR.
    explanation: >-
      Cell and reporter experiments establish regulation in the tested system, not a human DFNB103 modifier.
  - reference: PMID:34026762
    reference_title: "N-Terminus of GRXCR2 Interacts With CLIC5 and Is Essential for Auditory Perception."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Interestingly, mice harboring this in-frame deletion in Grxcr2 exhibit moderate hearing loss at lower frequencies and severe hearing loss at higher frequencies although the morphogenesis of stereocilia is minimally affected."
    explanation: >-
      Deleting GRXCR2 residues 36–95 disrupts CLIC5 association and causes hearing loss despite largely preserved
      bundle morphology. This is a partner-gene experiment, not evidence of a human DFNB103 modifier allele.
    quote_role: PRIMARY_RESULT
references:
- reference: url:https://repositoriosaludmadrid.es/bitstreams/e783eafe-8086-4b75-be09-9bd6ce296bad/download
  title: "https://repositoriosaludmadrid.es/bitstreams/e783eafe-8086-4b75-be09-9bd6ce296bad/download"
  findings:
  - statement: >-
      Complete six-page discovery paper by Seco et al., PMID:24781754: longitudinal audiology, cochlear implantation,
      vestibular tests, renal measurements and RNA-decay assay.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/pdf/Bookshelf_NBK1434.pdf
  title: "https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/pdf/Bookshelf_NBK1434.pdf"
  findings:
  - statement: >-
      Genetic Hearing Loss Overview (GeneReviews), PMID:20301607, updated June 2026. General diagnosis, habilitation,
      follow-up and counseling; not a CLIC5-specific chapter.
- reference: url:https://www.informatics.jax.org/allele/MGI%3A3522004
  title: "https://www.informatics.jax.org/allele/MGI%3A3522004"
  findings:
  - statement: >-
      MGI allele record for Clic5nmf318, used to verify the ENU missense genotype in the AAV study.
- reference: url:https://www.ncbi.nlm.nih.gov/clinvar/variation/694310/
  title: VCV000694310.3 - ClinVar - NCBI
  findings:
  - statement: >-
      ClinVar variation 694310 maps the short and long CLIC5 transcript HGVS descriptions to the same genomic
      allele.
- reference: PMID:20301607
  title: Genetic Hearing Loss Overview.
  findings:
  - statement: >-
      GeneReviews general hearing-loss overview; section-level evidence is quoted from the corresponding Bookshelf
      full-text PDF.
  tags:
  - GeneReviews
📚

References & Deep Research

References

5
url:https://repositoriosaludmadrid.es/bitstreams/e783eafe-8086-4b75-be09-9bd6ce296bad/download
https://repositoriosaludmadrid.es/bitstreams/e783eafe-8086-4b75-be09-9bd6ce296bad/download
1 finding
Complete six-page discovery paper by Seco et al., PMID:24781754: longitudinal audiology, cochlear implantation, vestibular tests, renal measurements and RNA-decay assay.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/pdf/Bookshelf_NBK1434.pdf
https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/pdf/Bookshelf_NBK1434.pdf
1 finding
Genetic Hearing Loss Overview (GeneReviews), PMID:20301607, updated June 2026. General diagnosis, habilitation, follow-up and counseling; not a CLIC5-specific chapter.
url:https://www.informatics.jax.org/allele/MGI%3A3522004
https://www.informatics.jax.org/allele/MGI%3A3522004
1 finding
MGI allele record for Clic5nmf318, used to verify the ENU missense genotype in the AAV study.
1 finding
ClinVar variation 694310 maps the short and long CLIC5 transcript HGVS descriptions to the same genomic allele.
PMID:20301607
Genetic Hearing Loss Overview.
1 finding
GeneReviews general hearing-loss overview; section-level evidence is quoted from the corresponding Bookshelf full-text PDF.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Autosomal Recessive Nonsyndromic Hearing Loss 103 (DFNB103, CLIC5) · 2026-08-28T19:10:23Z · View source

De novo curation of DFNB103 (MONDO:0014469, CLIC5 hgnc:13517) from the stub queue. entry_type decided as DISEASE: one causal gene, no MONDO descendants, one pathograph from biallelic CLIC5 loss through failure of the stereocilia taper membrane-actin tether to progressive fusion, hair cell degeneration and postlingual progressive hearing loss with vestibular involvement. Nothing in kb/ previously mentioned CLIC5. Mechanistic point of the entry: CLIC5 is a chloride intracellular channel family member that acts as a membrane-cytoskeletal adaptor at the base of the stereocilium rather than as an ion channel, in near 1:1 stoichiometry with radixin and in complex with taperin, PTPRQ and myosin VI. Losing a base-of-bundle tether gives a different phenotype from losing a tip protein, and the mouse shows it as progressive stereocilia fusion from P10 with partner mislocalisation preceding the fusion, which is the timing evidence that makes the complex disassembly upstream rather than consequent. The jitterbug mouse is curated in animal_models with modeled_mechanisms (not experimental_models), with two links (taper tethering, RECAPITULATES HIGH; stereocilia fusion, RECAPITULATES HIGH) and readouts for radixin staining and partner localisation. The 2025 AAV gene-replacement study is curated as a second animal model with a RESCUES link, and its limitations state plainly that treatment was given at P0 before the lesion begins between P14 and P17, so it demonstrates prevention rather than reversal. A HUMAN_MODEL_MISMATCH discussion carries that timing problem against a human disease detected at a mean age of about 8 years, and also records the unexplained divergence in that study between durable vestibular rescue and auditory thresholds that deteriorated despite robust transgene expression and unchanged hair cell morphology. A second KNOWLEDGE_GAP preserves the founding authors' hedge about mild renal dysfunction in one patient. Later descriptions call DFNB103 nonsyndromic without qualification; CLIC5 has an established role in glomerular podocyte maintenance, so the observation points at a mechanism rather than being a chance finding, and the Siberian founder cohort is now large enough to settle it. Evidence: 8 references cited, all fetched with just fetch-reference; 56/56 snippets verified against the local cache. One near-miss caught during curation and fixed: an initial evidence item for PMID:22889583 quoted a paraphrase of the paper title rather than a real substring; the reference validator caught it and it was replaced with a verified sentence from the abstract. Prevalence records the Siberian founder yield (9.9 percent of GJB2-negative patients) as CARRIER_FREQUENCY with a note that it is a diagnostic yield in an ascertained, GJB2-excluded series and does not generalise. Deep research: falcon report run and preflighted against MONDO:0014469, verdict PASS (CLIC5=36 mentions, next gene at 8). Entry curated from primary sources regardless. Validation: just validate exit 0, just validate-terms exit 0, just validate-disorders exit 0, just check-entity-refs exit 0, just check-duplicate-keys exit 0, and check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading, check-environmental-evidence all exit 0.

Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 19 citations 2026-08-28T11:42:28.752132

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Autosomal Recessive Nonsyndromic Hearing Loss 103
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Autosomal Recessive Nonsyndromic Hearing Loss 103 covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Research report: Autosomal recessive nonsyndromic hearing loss 103 (DFNB103)

Executive summary

Autosomal recessive nonsyndromic hearing loss 103 (DFNB103) is an ultra-rare, usually childhood-onset, progressive sensorineural hearing disorder caused by biallelic loss-of-function variants in CLIC5. The best-characterized manifestations are bilateral hearing loss and, in some families, progressive vestibular dysfunction or areflexia. A single Turkish patient had possible mild renal involvement, but a consistent renal syndrome has not been established. The strongest population enrichment is in the Sakha Republic (Yakutia), where the founder variant CLIC5 c.1121G>A, p.(Trp374Ter) was found in 26 of 238 GJB2-negative patients and produced marked regional clustering. Mechanistically, CLIC5 stabilizes plasma-membrane–actin linkages at the base of cochlear and vestibular hair-cell stereocilia through a protein network containing radixin, taperin, PTPRQ, MYO6, and GRXCR2. Loss of this function causes stereocilia disorganization and fusion, hair-cell degeneration, and progressive auditory/vestibular failure. There is no approved disease-modifying treatment or human DFNB103 trial; management is audiologic and vestibular rehabilitation. Mouse AAV gene replacement reported in 2025 provides strong but still preclinical proof of concept. (pshennikova2019…novelnonsense pages 1-2, seco2015progressivehearingloss pages 1-2, salles2014clic5stabilizesmembrane‐actin pages 1-3, hahn2025aavgenetherapy pages 10-12)

The following table provides a compact curation summary.

Knowledge-base field Summary Ontology / identifier suggestions Key evidence
Identity / identifiers Autosomal recessive nonsyndromic hearing loss 103 (DFNB103) is a rare Mendelian form of progressive sensorineural hearing loss caused by biallelic CLIC5 variants. Disease-level information is derived from aggregated literature case reports/series and cohort studies, not EHR data. OMIM phenotype: 616042 (reported in secondary sources/snippets; verify directly in OMIM before database ingestion). MONDO: not verified here. Orphanet / ICD-10 / ICD-11 / MeSH: no disease-specific identifier verified in available evidence. Historical literature may refer to the mapped region as DFNB102 before phenotype naming was stabilized; use caution in synonym mapping. MONDO: unverified; HP:0000365 Hearing impairment; HP:0000407 Sensorineural hearing impairment (pshennikova2019…novelnonsense pages 1-2, seco2015progressivehearingloss pages 1-2)
Causal gene and inheritance CLIC5 (chloride intracellular channel 5), OMIM gene 607293; inheritance is autosomal recessive with segregation shown in Turkish and Cameroonian families and homozygosity/founder enrichment in Yakutia. Functional disease mechanism is most consistent with loss of function. HGNC: CLIC5; HP:0000007 Autosomal recessive inheritance; SO:0002054 loss_of_function_variant (pshennikova2019…novelnonsense pages 1-2, seco2015progressivehearingloss pages 1-2, adadey2022cellbasedanalysisof pages 8-10)
Established human variants Established disease-associated human variants reported in available evidence: c.96T>A (p.Cys32*), homozygous nonsense, Turkish family; c.1121G>A (p.Trp374*), homozygous nonsense, Yakutian founder-enriched juvenile DFNB103; c.224T>C (p.Leu75Pro) plus c.63+1G>A, compound heterozygous in a Cameroonian multiplex family. Variant classes represented: nonsense, splice-donor, missense. Germline origin. Sequence Ontology: nonsense_variant, splice_donor_variant, missense_variant; ACMG class: pathogenic/likely pathogenic (case-level interpretation should be confirmed in ClinVar/ACMG source) (pshennikova2019…novelnonsense pages 1-2, seco2015progressivehearingloss pages 1-2, ott2023anovelrole pages 2-3, adadey2022cellbasedanalysisof pages 8-10)
Core phenotypes Core phenotype is bilateral, predominantly symmetric, progressive sensorineural hearing loss of variable severity. Additional features reported in at least one family: vestibular areflexia / vestibular dysfunction with balance problems; possible mild renal dysfunction in one Turkish patient. No consistent extra-auditory syndrome has yet been established across families. HP:0008619 Progressive hearing impairment; HP:0000407 Sensorineural hearing impairment; HP:0002315 Areflexia of the vestibular system; HP:0002172 Postural instability; HP:0012594 Abnormality of urine albumin excretion (seco2015progressivehearingloss pages 1-2, seco2015progressivehearingloss pages 2-5, pshennikova2019…novelnonsense pages 1-2)
Onset / course Turkish family: onset in early childhood, progressing from mild to severe/profound before the second decade. Yakutian series: among 26/238 GJB2-negative patients homozygous for p.Trp374*, onset varied 0–8 years in the discovery family and was postlingual in most patients (19/26) with mean onset 9.7 ± 0.6 years; audiology in 13/26 showed progressive SNHL ranging from mild to profound. HP:0011463 Childhood onset; HP:0003593 Infantile onset / congenital onset if applicable in some cases; HP:0003676 Progressive; HP:0012716 Bilateral sensorineural hearing impairment (seco2015progressivehearingloss pages 1-2, pshennikova2019…novelnonsense pages 1-2)
Mechanism / pathophysiology CLIC5A is highly expressed at the base of cochlear and vestibular hair-cell stereocilia and functions in a complex with RDX (radixin), TPRN (taperin), PTPRQ, MYO6, and functionally with GRXCR2 to stabilize membrane–actin filament linkages. Loss of CLIC5 causes mislocalization/reduction of basal stereocilia proteins, reduced ERM/radixin phosphorylation, stereocilia fusion, and eventual hair-cell dysfunction/degeneration, producing progressive auditory and vestibular deficits. Cell assays show mutant CLIC5A can form perinuclear aggregates and fail to support filopodia-like protrusions, supporting cytoskeletal dysfunction. GO:0032420 stereocilium organization; GO:0007015 actin filament organization; GO:0005929 cilium / GO:0036064 ciliary basal body-plasma membrane docking (ciliary work extrapolative); CL:0000589 auditory hair cell; CL:0009062 vestibular hair cell; UBERON:0001858 organ of Corti; UBERON:0001717 utricle of membranous labyrinth (salles2014clic5stabilizesmembrane‐actin pages 1-3, adadey2022cellbasedanalysisof pages 8-10, ott2023anovelrole pages 2-3)
Anatomy / cell types Primary anatomy affected: inner ear, especially cochlear and vestibular sensory epithelia. Relevant structures/cells include hair bundles/stereocilia, inner hair cells, outer hair cells, and vestibular hair cells. Subcellular localization is strongest at the basal region of stereocilia. CLIC5 is also expressed in other tissues including kidney-related structures, but clinically consistent non-auditory disease remains unproven. UBERON:0000044 cochlea; UBERON:0000947 inner ear; UBERON:0001987 vestibular system; GO:0032420 stereocilium; CL:0000589 auditory hair cell; CL:0000602 inner hair cell; CL:0000601 outer hair cell (seco2015progressivehearingloss pages 1-2, salles2014clic5stabilizesmembrane‐actin pages 1-3, hahn2025aavgenetherapy pages 17-18)
Epidemiology / population data Ultra-rare globally; no robust global prevalence/incidence estimate identified in available evidence. Strongest quantitative population data come from Yakutia: 26/238 (10.9%) of GJB2-negative patients carried homozygous c.1121G>A (p.Trp374*); estimated average DFNB103 prevalence 0.27 ± 0.053 per 10,000 in Yakutia, with a reported maximum in Eveno-Bytantaysky district of 31.39 ± 10.46 per 10,000. Geographic enrichment suggests a founder effect. Seco et al. found no additional pathogenic CLIC5 variants among 213 mainly Dutch/Spanish arNSHI patients screened, supporting rarity in those populations. Population/founder annotation; HP:0032113 Founder effect (term label to verify in ontology implementation) (pshennikova2019…novelnonsense pages 1-2, seco2015progressivehearingloss pages 1-2, seco2015progressivehearingloss pages 5-6)
Diagnostics Recommended diagnostic approach from available disease-specific evidence: phenotype-confirming audiometry, evaluation for vestibular dysfunction (e.g., rotatory/electronystagmography in reported family), exclusion of conductive/anatomic causes including temporal-bone CT, and molecular testing. For genetics, WES identified the Yakutian founder variant; targeted testing for known regional founder alleles may be efficient in enriched populations; otherwise include CLIC5 on comprehensive hereditary hearing-loss panels. No disease-specific biomarker or imaging signature beyond standard audiovestibular assessment was identified. LOINC/functional audiology terms not verified here; HP:0000365, HP:0001751 Vestibular dysfunction; NCIT: Whole Exome Sequencing; NCIT: Genetic Testing (seco2015progressivehearingloss pages 1-2, pshennikova2019…novelnonsense pages 1-2)
Current care / real-world management No approved DFNB103-specific pharmacotherapy or gene therapy is currently established in humans in available evidence. Real-world care is therefore supportive and rehabilitative, following standard monogenic hearing-loss practice: early audiologic follow-up, hearing aids when useful, cochlear implantation if hearing becomes severe/profound and candidacy criteria are met, plus vestibular rehabilitation/safety counseling for balance dysfunction. Because progression can occur in childhood, serial monitoring is important. NCIT: Hearing Aid Device; NCIT: Cochlear Implantation; NCIT: Rehabilitation; HP management terms as above (seco2015progressivehearingloss pages 1-2, seco2015progressivehearingloss pages 5-6)
Experimental therapy / latest research No human DFNB103 interventional trial was identified in the available ClinicalTrials.gov search. Recent/preclinical advances: 2023 zebrafish study showed isoform-specific Clic5 roles in ciliogenesis, ERM phosphorylation, and Wnt-signaling dysregulation; 2022 cell assays functionally supported pathogenicity of African variants; 2025 mouse study showed AAV2/9-PHP.B Clic5 delivered by P0 utricle injection restored localization and preserved hearing/balance in Clic5-deficient mice. Reported quantitative details include 1.2 µL ssAAV.Clic5 at 1.69 × 10^14 gc/mL and self-complementary AAV efficacy at lower titer, but this remains preclinical. NCIT: Gene Therapy; CHEBI/viral vector terms not mapped here; evidence type = mouse / zebrafish / cell (hahn2025aavgenetherapy pages 1-2, hahn2025aavgenetherapy pages 10-12, ott2023anovelrole pages 2-3, adadey2022cellbasedanalysisof pages 8-10)
Key evidence limitations Evidence base is small: a few families/case series, one regional prevalence study, and substantial mechanistic reliance on mouse, zebrafish, and cell models. Several identifiers (MONDO/Orphanet/ICD/MeSH) were not directly verified in the available sources. Some clinical features such as renal involvement and degree of vestibular penetrance remain uncertain because they were not consistent across all reported families. Human natural history, penetrance, carrier frequency, and treatment-outcome data remain limited. Evidence tags: human case report/series, cohort, mouse model, zebrafish model, cell assay (seco2015progressivehearingloss pages 1-2, pshennikova2019…novelnonsense pages 1-2, ott2023anovelrole pages 2-3, adadey2022cellbasedanalysisof pages 8-10)

Table: This table summarizes the key disease knowledge-base facts for CLIC5-related DFNB103, including identity, variants, phenotype, mechanism, Yakutian epidemiology, diagnostics, and therapy status. It is designed as a concise, citation-backed artifact for structured curation.

1. Disease information

Definition and identifiers

DFNB103 is a Mendelian autosomal-recessive form of nonsyndromic sensorineural hearing loss attributable to biallelic CLIC5 variants. The original report described the locus as DFNB102 during mapping; subsequent disease nomenclature uses DFNB103, so these labels should not automatically be treated as separate diseases when curating older literature. (seco2015progressivehearingloss pages 1-2, seco2015progressivehearingloss pages 2-5)

  • Preferred name: Autosomal recessive nonsyndromic hearing loss 103.
  • Synonyms: DFNB103; deafness, autosomal recessive 103; CLIC5-related hearing loss; CLIC5-related autosomal-recessive deafness; progressive autosomal-recessive deafness 103.
  • OMIM phenotype: 616042, reported for DFNB103 in the retrieved literature.
  • Causal-gene OMIM: CLIC5, 607293; cytogenetic location 6p21.1. (pshennikova2019…novelnonsense pages 1-2)
  • MONDO: no disease-specific MONDO identifier was verified from the retrieved authoritative text; it should therefore be left unresolved rather than inferred.
  • Orphanet: no dedicated identifier verified.
  • ICD-10/ICD-11 and MeSH: no genotype-specific code verified. In clinical systems the condition is generally represented under hereditary or sensorineural hearing-loss categories rather than a DFNB103-specific billing code.

The evidence is aggregated disease-level information from pedigrees, case series, cohort screening, and experimental models—not individual-level EHR data.

2. Etiology

Causal factors and genetic risk

The primary cause is inheritance of two damaging germline CLIC5 alleles. Established reports include:

  1. c.96T>A, p.(Cys32Ter), homozygous nonsense variant in two affected siblings from a consanguineous Turkish family. It segregated with disease and was absent from 222 Turkish control alleles, the Exome Variant Server, and a 1,302-exome local database. The premature stop is predicted to cause severe loss of function, although nonsense-mediated decay was not demonstrated in lymphoblastoid cells. (seco2015progressivehearingloss pages 1-2, seco2015progressivehearingloss pages 2-5)
  2. c.1121G>A, p.(Trp374Ter), homozygous nonsense variant in Yakutia. This truncates CLIC5 at residue 374 and is strongly enriched regionally, consistent with a founder effect. (pshennikova2019…novelnonsense pages 1-2)
  3. c.224T>C, p.(Leu75Pro) in trans with c.63+1G>A, a missense plus canonical splice-donor combination in three affected members of a Cameroonian multiplex family. Cell experiments support functional disruption by p.Leu75Pro. (ott2023anovelrole pages 2-3, adadey2022cellbasedanalysisof pages 8-10)

All are germline variants. No somatic disease mechanism, repeat expansion, aneuploidy, or recurrent pathogenic chromosomal rearrangement is established.

Environmental, protective, and gene–environment factors

No environmental exposure, infectious agent, lifestyle factor, sex-specific factor, or gene–environment interaction is known to cause DFNB103. Noise, ototoxic drugs, meningitis, and congenital infection remain important alternative or additive causes of hearing loss, but they are not demonstrated components of this Mendelian disorder. Avoidance of noise and ototoxic exposure is sensible hearing preservation, not primary prevention of the genotype.

No validated protective allele or modifier gene has been reported. RDX, TPRN, PTPRQ, MYO6, and GRXCR2 are mechanistic partners and plausible modifiers, but human modifier effects have not been proven. (adadey2022cellbasedanalysisof pages 8-10, salles2014clic5stabilizesmembrane‐actin pages 1-3)

3. Phenotypes

Auditory phenotype

The core manifestation is bilateral, predominantly symmetric, progressive sensorineural hearing loss. In the Turkish siblings, hearing loss began in early childhood, initially mild and most evident at middle/high frequencies, and advanced to severe or profound loss before the second decade. The discovery article states directly: “The hearing loss … had an onset in early childhood and progressed from mild to severe or even profound before the second decade.” (seco2015progressivehearingloss pages 1-2)

In Yakutia, the discovery family contained five affected people with onset from birth to eight years. Across 26 p.Trp374Ter-homozygous patients, 19/26 had postlingual onset, averaging 9.7 ± 0.6 years. Audiometry in 13/26 showed predominantly symmetric, progressive sensorineural loss ranging from mild to profound. These figures should not be interpreted as universal frequencies because the cohort was regionally and genetically ascertained. (pshennikova2019…novelnonsense pages 1-2)

Suggested HPO terms include Sensorineural hearing impairment (HP:0000407), Progressive hearing impairment (HP:0008619), Bilateral sensorineural hearing impairment, Childhood onset (HP:0011463), and Postlingual hearing loss.

Vestibular and other findings

Both Turkish siblings developed balance difficulty, including trouble walking in darkness and cycling. Rotatory testing demonstrated vestibular areflexia at ages 16 and 11 years. Early motor milestones were normal, indicating that vestibular deterioration may emerge after initially normal development. Suggested terms are Vestibular dysfunction, Bilateral vestibular areflexia, and Postural instability. (seco2015progressivehearingloss pages 2-5)

One sibling had repeated elevated urine albumin/creatinine ratios of 9.2 and 3.8 mg/mmol (reference <2.5), mildly elevated blood pressure, but normal estimated glomerular filtration rate (114 mL/min/1.73 m²). This was considered possible early nephropathy, not proven CLIC5-related renal disease. The other sibling had normal renal findings, and no consistent renal phenotype is established in later families. (seco2015progressivehearingloss pages 2-5)

No consistent dysmorphism, thyroid disease, intellectual disability, retinal disease, or other syndromic feature has been documented. Quality-of-life effects have not been quantified with EQ-5D, SF-36, or PROMIS in DFNB103. Expected impacts include impaired speech access, education, communication, localization of sound, and mobility/safety when vestibular dysfunction is present.

4. Genetic and molecular information

CLIC5 encodes chloride intracellular channel protein 5, with CLIC5A and CLIC5B isoforms. Despite its name and reported membrane-channel properties, the disease-relevant evidence strongly supports a structural/signaling role for CLIC5A in actin-rich stereocilia. CLIC5A occurs in soluble and membrane-associated forms, interacts with actin and ERM-family proteins, and is concentrated at the stereocilia base. (adadey2022cellbasedanalysisof pages 8-10, salles2014clic5stabilizesmembrane‐actin pages 1-3)

The disease mechanism is predominantly loss of function. Nonsense and essential splice variants are expected to abolish or markedly reduce functional protein. In transfected cells, p.Leu75Pro CLIC5A accumulated as perinuclear aggregates instead of showing the diffuse cytoplasmic distribution of wild type; mutant-expressing cells also lacked the thin filopodia-like projections induced by wild-type CLIC5A. This provides in-vitro functional support but does not alone quantify clinical pathogenicity. (adadey2022cellbasedanalysisof pages 8-10)

Population allele frequencies should be retrieved variant-by-variant from the current gnomAD release before production ingestion. The discovery p.Cys32Ter variant was absent from the historical control resources tested, while p.Trp374Ter is regionally enriched in Yakutia. ClinVar classifications and HGNC identifiers were not directly available in the retrieved evidence and should not be inferred from case reports alone.

No reproducible epigenetic abnormality, disease-specific methylation signature, somatic mosaicism, germline mosaicism, anticipation, or pathogenic large chromosomal abnormality is known.

5. Environmental information

Environmental toxins, radiation, pollution, occupation, smoking, alcohol, diet, and infectious organisms are not established etiologic factors. They may independently worsen hearing and should be assessed during differential diagnosis. There is no vaccine, antimicrobial prophylaxis, dietary intervention, or environmental remediation specific to DFNB103.

6. Mechanism and pathophysiology

Causal chain

  1. Upstream trigger: biallelic damaging CLIC5 variants reduce or eliminate functional CLIC5A.
  2. Molecular complex failure: normal CLIC5 associates with RDX, TPRN, PTPRQ, MYO6, and functionally with GRXCR2 at the stereociliary taper. It promotes/stabilizes active phosphorylated ERM proteins and links the plasma membrane to the actin core. (salles2014clic5stabilizesmembrane‐actin pages 1-3, waddell2016clic5maintainslifelong pages 1-5)
  3. Cellular structural defect: loss of CLIC5 causes early mislocalization of RDX/PTPRQ/TPRN and weakens membrane–actin coupling. In jitterbug mice, stereocilia fusion is detectable by postnatal day 10, followed by dysmorphic bundles and progressive hair-cell degeneration. (salles2014clic5stabilizesmembrane‐actin pages 1-3)
  4. Physiological defect: disordered hair bundles cannot maintain normal mechanosensory architecture and sound-evoked transduction. Equivalent injury in vestibular hair cells disrupts balance sensing.
  5. Clinical manifestation: progressive sensorineural hearing loss, with vestibular areflexia in at least some genotypes/families. (seco2015progressivehearingloss pages 1-2, salles2014clic5stabilizesmembrane‐actin pages 1-3)

Suggested GO biological-process annotations are stereocilium organization, actin filament organization, plasma membrane–actin cytoskeleton organization, sensory perception of sound, mechanosensory behavior, and protein phosphorylation. Relevant cellular components are stereocilium (GO:0032420), actin cytoskeleton, plasma membrane, and hair bundle. Relevant Cell Ontology concepts are auditory inner hair cell, auditory outer hair cell, and vestibular hair cell.

Recent mechanistic developments

A 2023 zebrafish study found isoform-specific roles: Clic5a contributed to the glomerular filtration barrier, whereas Clic5b localized to pronephric cilia. Clic5b deficiency impaired ciliogenesis and produced otolith deposition abnormalities, laterality defects, hydrocephalus, and pronephric cysts, with altered cilia-dependent Wnt components and reduced ERM activation. This broadens CLIC5 biology but should not be equated directly with human DFNB103, whose reproducible phenotype remains auditory/vestibular. (ott2023anovelrole pages 2-3)

No disease-specific human single-cell, spatial-transcriptomic, proteomic, metabolomic, lipidomic, or integrated multi-omic signature is established. Available molecular profiling consists mainly of tissue expression, localization, interaction, and perturbation studies.

7. Anatomical structures affected

The primary organ is the inner ear, involving:

  • cochlea and organ of Corti;
  • inner and outer auditory hair cells;
  • vestibular sensory epithelia and vestibular hair cells;
  • stereociliary hair bundles, particularly the basal taper region where CLIC5 is concentrated. (salles2014clic5stabilizesmembrane‐actin pages 1-3)

Suggested anatomy annotations include inner ear (UBERON:0001846; verify release), cochlea (UBERON:0001848; verify release), organ of Corti, utricle, saccule, and semicircular-duct sensory epithelium. Suggested cellular-component annotation is stereocilium (GO:0032420). Disease is usually bilateral; consistent anatomical asymmetry or structural temporal-bone malformation has not been reported.

Kidney involvement remains uncertain. CLIC5 has experimentally demonstrated renal and ciliary functions, but this does not establish the kidney as a consistently affected organ in human DFNB103. (ott2023anovelrole pages 2-3, seco2015progressivehearingloss pages 2-5)

8. Temporal development

DFNB103 is chronic and lifelong. Onset ranges from congenital/infantile in a minority of reported Yakutian cases to childhood or postlingual juvenile onset in most characterized patients. Progression is usually gradual rather than acute, episodic, fluctuating, or relapsing. Severity may evolve from mild loss to severe/profound deafness during childhood or adolescence. (pshennikova2019…novelnonsense pages 1-2, seco2015progressivehearingloss pages 1-2)

No formal staging system exists. A practical clinical sequence is: normal or mildly impaired early hearing → progressive threshold elevation → severe/profound hearing loss, with later vestibular difficulty in susceptible individuals. There is no spontaneous remission. Childhood auditory development is a critical intervention period because delayed audibility can impair speech and language even when onset is postlingual.

9. Inheritance and population

Inheritance is autosomal recessive. For two carrier parents, each pregnancy has a 25% probability of an affected child, 50% probability of an unaffected carrier, and 25% probability of inheriting neither familial variant. Both sexes are expected to be affected equally.

Penetrance appears high for biallelic truncating alleles in reported families, but the number of families is too small to estimate penetrance precisely. Expressivity is variable in age at onset, severity, and vestibular involvement. Anticipation is not expected. Consanguinity aided discovery in the Turkish family and can increase the probability that a rare allele is inherited homozygously. (seco2015progressivehearingloss pages 1-2)

Global prevalence and incidence are unknown. In Yakutia, homozygous p.Trp374Ter occurred in 26/238 (10.9%) GJB2-negative hearing-loss patients. Estimated prevalence was 0.27 ± 0.053 per 10,000 across Yakutia and 31.39 ± 10.46 per 10,000 in Eveno-Bytantaysky district, a striking regional founder concentration. Conversely, screening of 213 predominantly Dutch/Spanish autosomal-recessive nonsyndromic hearing-loss patients found no additional pathogenic CLIC5 variants, indicating that CLIC5 is not a common cause in those populations. (seco2015progressivehearingloss pages 5-6, pshennikova2019…novelnonsense pages 1-2, seco2015progressivehearingloss pages 1-2)

Carrier frequency is not established globally and will differ substantially by ancestry and founder population.

10. Diagnostics

Clinical evaluation

Evaluation should include otoscopy, air- and bone-conduction pure-tone audiometry, age-appropriate speech testing, tympanometry, otoacoustic emissions, and auditory brainstem responses when behavioral testing is unreliable. Serial audiograms are essential because progression is a defining feature. Vestibular history and testing—video head-impulse testing, calorics, vestibular-evoked myogenic potentials, or rotatory-chair testing—are appropriate when balance symptoms occur. The discovery study used electronystagmography/rotatory testing and temporal-bone CT to exclude alternative anatomical causes. (seco2015progressivehearingloss pages 1-2, seco2015progressivehearingloss pages 2-5)

Renal blood pressure, urinalysis, and urine albumin/creatinine assessment may be considered at baseline, particularly for truncating variants, but evidence is insufficient to mandate a DFNB103 renal surveillance guideline.

Genetic testing strategy

  1. Use a comprehensive hereditary-hearing-loss panel that includes CLIC5, with sequencing and copy-number analysis.
  2. In Yakutian/Even populations, targeted p.Trp374Ter testing is efficient, but a negative result does not exclude another hearing-loss gene.
  3. If panel testing is negative, trio or family-based exome/genome sequencing is appropriate; WES identified the Yakutian variant. (pshennikova2019…novelnonsense pages 1-2)
  4. Confirm candidate variants by orthogonal sequencing, phase compound heterozygous alleles, and test segregation.
  5. Interpret variants under ACMG/AMP criteria using population frequency, predicted consequence, segregation, phenotype, and functional evidence.

CMA, karyotyping, FISH, mitochondrial sequencing, and repeat-expansion testing are not first-line DFNB103 assays unless the broader phenotype suggests another diagnosis. RNA analysis can clarify splice variants. There is no validated blood biomarker, metabolomic assay, biopsy criterion, or liquid biopsy.

Differential diagnosis includes other progressive recessive nonsyndromic hearing-loss genes—especially GJB2, STRC, OTOF, MYO15A, MYO6, TPRN, RDX, PTPRQ, and GRXCR2—as well as Usher syndrome, enlarged vestibular aqueduct/Pendred spectrum, congenital CMV, meningitis, ototoxicity, and noise-induced loss.

11. Outcome and prognosis

DFNB103 is not known to shorten life expectancy or cause disease-specific mortality. Morbidity arises from progressive auditory disability and, where present, vestibular impairment. Untreated severe hearing loss can affect language access, education, employment, social participation, and safety. Vestibular areflexia may impair mobility in darkness or on uneven surfaces. Disease-specific survival statistics, standardized quality-of-life scores, and validated prognostic calculators do not exist.

The strongest prognostic indicator is serial measured hearing trajectory. Genotype–phenotype relationships remain preliminary: p.Trp374Ter commonly produced juvenile/postlingual progressive loss in Yakutia, while p.Cys32Ter caused early-childhood progression with vestibular areflexia in the Turkish siblings. These observations are not sufficient for deterministic individual prediction. (pshennikova2019…novelnonsense pages 1-2, seco2015progressivehearingloss pages 1-2)

12. Treatment

Current care

There is no approved CLIC5-targeted drug, RNA therapy, genome editor, or gene therapy. Standard treatment is individualized:

  • prompt hearing-aid fitting for aidable mild-to-severe loss;
  • remote-microphone and educational accommodations;
  • speech-language, auditory-verbal, or sign-language support according to patient goals;
  • cochlear-implant evaluation for severe/profound loss with insufficient aided speech access;
  • vestibular physiotherapy, fall-prevention measures, and mobility counseling;
  • continued audiologic surveillance because thresholds can deteriorate rapidly during childhood.

Suggested NCIT intervention concepts are Hearing Aid, Cochlear Implantation, Audiologic Rehabilitation, Speech Therapy, Vestibular Rehabilitation, and Genetic Counseling. No DFNB103-specific pharmacogenomic relationship is known.

Experimental therapy

A 2025 mouse study delivered wild-type Clic5 by utricular injection at postnatal day 0 using single-stranded or self-complementary AAV2/9-PHP.B. A reported ssAAV regimen used 1.2 μL at 1.69×10^14 genome copies/mL. Treatment restored CLIC5 at the hair-bundle base, limited stereocilia degeneration, and preserved auditory and vestibular function through 12 weeks. Self-complementary AAV achieved comparable recovery at a lower titer—reported as 1.52×10^13 gc/mL—which may reduce dose-related toxicity. (hahn2025aavgenetherapy pages 10-12, hahn2025aavgenetherapy pages 17-18, hahn2025aavgenetherapy pages 1-2)

This is compelling model-organism proof of concept, not evidence of human efficacy or safety. Neonatal mouse delivery, inner-ear scaling, surgical route, immune responses, durability, genotype-specific windows, and treatment after established degeneration remain translational barriers. No relevant human DFNB103 interventional trial or NCT identifier was found.

13. Prevention

The inherited genotype cannot currently be prevented by lifestyle modification.

  • Primary/reproductive prevention: genetic counseling, carrier testing of relatives, partner testing, prenatal diagnosis, and preimplantation genetic testing for a known familial variant.
  • Secondary prevention: newborn hearing screening alone may miss later-onset DFNB103; molecular diagnosis and scheduled audiometry permit detection before substantial language-access loss.
  • Tertiary prevention: early amplification/implant assessment, communication support, vestibular rehabilitation, fall prevention, and avoidance of unnecessary ototoxic exposure can reduce disability.

Vaccination is not disease-specific, although routine immunization against causes of acquired meningitis helps prevent competing acquired hearing loss. Cascade testing is especially relevant in founder populations.

14. Other species and natural disease

No naturally occurring veterinary DFNB103 syndrome with established breed prevalence was identified. CLIC5 orthologues are conserved across vertebrates. The principal naturally arising comparative model is the jitterbug mouse, carrying a spontaneous recessive 97-bp intragenic Clic5 deletion that causes exon-5 skipping, frameshift, premature termination, absent CLIC5 protein, impaired hearing, vestibular dysfunction, dysmorphic stereocilia, and progressive hair-cell degeneration. (salles2014clic5stabilizesmembrane‐actin pages 1-3)

Relevant taxonomy identifiers are Mus musculus, NCBI Taxonomy 10090; Danio rerio, 7955; and Drosophila melanogaster, 7227. These models have no zoonotic or cross-species-transmission implications.

15. Model organisms

Mouse

The homozygous Clic5 jitterbug mouse closely recapitulates human auditory and vestibular disease. CLIC5 is normally present in cochlear and vestibular stereocilia; mutants show progressive stereocilia fusion from approximately postnatal day 10, mislocalization of RDX/PTPRQ/TPRN, hair-cell degeneration, hearing impairment, and balance abnormalities. Its advantages are mammalian inner-ear anatomy and a progressive therapeutic window; limitations include neonatal cochlear maturation, compressed timescale, and uncertain correspondence between mouse and human treatment timing. (salles2014clic5stabilizesmembrane‐actin pages 1-3)

The model has been used for localization, biochemical interaction, longitudinal pathology, modifier-network studies, and AAV gene replacement. The rescue study’s abstract-level conclusion was that treatment produced “prevention of morphological degeneration and preserving auditory and vestibular function.” (hahn2025aavgenetherapy pages 10-12, hahn2025aavgenetherapy pages 1-2)

Zebrafish

Isoform-specific clic5 knockdown models revealed glomerular and ciliary functions. Clic5b deficiency caused defective ciliogenesis, abnormal otolith deposition, laterality defects, hydrocephalus, and pronephric cysts, with Wnt and ERM abnormalities. Zebrafish are useful for developmental imaging and rapid functional studies, but their otic anatomy and duplicated isoform biology limit direct extrapolation to progressive human cochlear disease. (ott2023anovelrole pages 2-3)

Cellular and biochemical systems

Transfected-cell assays distinguish wild-type CLIC5A distribution and membrane protrusion formation from p.Leu75Pro aggregation and cytoskeletal defects. Co-immunoprecipitation/localization approaches demonstrate interactions with ERM proteins, taperin, PTPRQ, MYO6, and GRXCR2. These systems define molecular effects but cannot reproduce cochlear mechanics, tonotopy, or long-term hair-cell degeneration. (adadey2022cellbasedanalysisof pages 8-10, salles2014clic5stabilizesmembrane‐actin pages 1-3)

Evidence assessment and knowledge gaps

The human evidence base remains small: one deeply phenotyped Turkish sibship, a Yakutian founder cohort, a Cameroonian multiplex family, and limited additional reports. Consequently, penetrance, vestibular frequency, renal significance, variant-specific prognosis, global prevalence, carrier frequency, and treatment outcomes are uncertain. The proposed membrane–actin mechanism is strong because human genetics converges with mouse pathology, biochemical interactions, and cell assays. In contrast, renal/ciliary and Wnt findings are biologically credible but not yet established as routine human manifestations. (ott2023anovelrole pages 2-3, adadey2022cellbasedanalysisof pages 8-10, pshennikova2019…novelnonsense pages 1-2, seco2015progressivehearingloss pages 1-2)

Key publications and URLs

  • Seco CZ et al. Progressive hearing loss and vestibular dysfunction caused by a homozygous nonsense mutation in CLIC5. European Journal of Human Genetics. Published online 30 April 2014; print 2015. DOI/URL: https://doi.org/10.1038/ejhg.2014.83. (seco2015progressivehearingloss pages 1-2)
  • Salles FT et al. CLIC5 stabilizes membrane-actin filament linkages at the base of hair cell stereocilia… Cytoskeleton. January 2014. DOI/URL: https://doi.org/10.1002/cm.21159. (salles2014clic5stabilizesmembrane‐actin pages 1-3)
  • Pshennikova VG et al. A novel nonsense mutation c.1121G>A (p.Trp374*)… in Yakutia. Medical Genetics. 2019;18(10):36–48. DOI/URL: https://doi.org/10.25557/2073-7998.2019.10.36-48. (pshennikova2019…novelnonsense pages 1-2)
  • Adadey SM et al. Cell-based analysis of CLIC5A and SLC12A2 variants… Frontiers in Genetics. August 2022. DOI/URL: https://doi.org/10.3389/fgene.2022.924904. (adadey2022cellbasedanalysisof pages 8-10)
  • Ott E et al. A novel role for the chloride intracellular channel protein Clic5 in ciliary function. Scientific Reports. October 2023. DOI/URL: https://doi.org/10.1038/s41598-023-44235-y. (ott2023anovelrole pages 2-3)
  • Hahn R et al. AAV gene therapy rescues hearing and balance in a model of CLIC5 deafness. EMBO Molecular Medicine. August 2025. DOI/URL: https://doi.org/10.1038/s44321-025-00275-7. This post-2024 paper is included because it is the most important current disease-specific therapeutic development. (hahn2025aavgenetherapy pages 10-12, hahn2025aavgenetherapy pages 1-2)

PMIDs were not consistently present in the retrieved full texts and are therefore not supplied where they could not be verified reliably.

References

  1. (pshennikova2019…novelnonsense pages 1-2): VG Pshennikova, GP Romanov, and TM Nikolaeva. … novel nonsense mutation c. 1121g> a (p. trp374*) in the clic5 gene is the main cause of the juvenile autosomal recessive form of deafness (dfnb103) in the arctic …. Unknown journal, 2019.

  2. (seco2015progressivehearingloss pages 1-2): Celia Zazo Seco, Anne MM Oonk, María Domínguez-Ruiz, Jos MT Draaisma, Marta Gandía, Jaap Oostrik, Kornelia Neveling, Henricus PM Kunst, Lies H Hoefsloot, Ignacio del Castillo, Ronald JE Pennings, Hannie Kremer, Ronald JC Admiraal, and Margit Schraders. Progressive hearing loss and vestibular dysfunction caused by a homozygous nonsense mutation in clic5. European Journal of Human Genetics, 23:189-194, Apr 2015. URL: https://doi.org/10.1038/ejhg.2014.83, doi:10.1038/ejhg.2014.83. This article has 75 citations and is from a domain leading peer-reviewed journal.

  3. (salles2014clic5stabilizesmembrane‐actin pages 1-3): Felipe T. Salles, Leonardo R. Andrade, Soichi Tanda, M'hamed Grati, Kathleen L. Plona, Leona H. Gagnon, Kenneth R. Johnson, Bechara Kachar, and Mark A. Berryman. Clic5 stabilizes membrane‐actin filament linkages at the base of hair cell stereocilia in a molecular complex with radixin, taperin, and myosin vi. Cytoskeleton, 71:61-78, Jan 2014. URL: https://doi.org/10.1002/cm.21159, doi:10.1002/cm.21159. This article has 82 citations and is from a peer-reviewed journal.

  4. (hahn2025aavgenetherapy pages 10-12): Roni Hahn, Shahar Taiber, Olga Shubina-Oleinik, Gwenaëlle S G Géléoc, Jeffrey R Holt, and Karen B Avraham. Aav gene therapy rescues hearing and balance in a model of clic5 deafness. EMBO Molecular Medicine, Aug 2025. URL: https://doi.org/10.1038/s44321-025-00275-7, doi:10.1038/s44321-025-00275-7. This article has 6 citations and is from a highest quality peer-reviewed journal.

  5. (adadey2022cellbasedanalysisof pages 8-10): Samuel Mawuli Adadey, Edmond Wonkam-Tingang, Leonardo Alves de Souza Rios, Elvis Twumasi Aboagye, Kevin Esoh, Noluthando Manyisa, Carmen De Kock, Gordon A. Awandare, Shaheen Mowla, and Ambroise Wonkam. Cell-based analysis of clic5a and slc12a2 variants associated with hearing impairment in two african families. Frontiers in Genetics, Aug 2022. URL: https://doi.org/10.3389/fgene.2022.924904, doi:10.3389/fgene.2022.924904. This article has 2 citations and is from a peer-reviewed journal.

  6. (ott2023anovelrole pages 2-3): Elisabeth Ott, Sylvia Hoff, Lara Indorf, Franck Anicet Ditengou, Julius Müller, Gina Renschler, Soeren S. Lienkamp, Albrecht Kramer-Zucker, Carsten Bergmann, and Daniel Epting. A novel role for the chloride intracellular channel protein clic5 in ciliary function. Scientific Reports, Oct 2023. URL: https://doi.org/10.1038/s41598-023-44235-y, doi:10.1038/s41598-023-44235-y. This article has 9 citations and is from a peer-reviewed journal.

  7. (seco2015progressivehearingloss pages 2-5): Celia Zazo Seco, Anne MM Oonk, María Domínguez-Ruiz, Jos MT Draaisma, Marta Gandía, Jaap Oostrik, Kornelia Neveling, Henricus PM Kunst, Lies H Hoefsloot, Ignacio del Castillo, Ronald JE Pennings, Hannie Kremer, Ronald JC Admiraal, and Margit Schraders. Progressive hearing loss and vestibular dysfunction caused by a homozygous nonsense mutation in clic5. European Journal of Human Genetics, 23:189-194, Apr 2015. URL: https://doi.org/10.1038/ejhg.2014.83, doi:10.1038/ejhg.2014.83. This article has 75 citations and is from a domain leading peer-reviewed journal.

  8. (hahn2025aavgenetherapy pages 17-18): Roni Hahn, Shahar Taiber, Olga Shubina-Oleinik, Gwenaëlle S G Géléoc, Jeffrey R Holt, and Karen B Avraham. Aav gene therapy rescues hearing and balance in a model of clic5 deafness. EMBO Molecular Medicine, Aug 2025. URL: https://doi.org/10.1038/s44321-025-00275-7, doi:10.1038/s44321-025-00275-7. This article has 6 citations and is from a highest quality peer-reviewed journal.

  9. (seco2015progressivehearingloss pages 5-6): Celia Zazo Seco, Anne MM Oonk, María Domínguez-Ruiz, Jos MT Draaisma, Marta Gandía, Jaap Oostrik, Kornelia Neveling, Henricus PM Kunst, Lies H Hoefsloot, Ignacio del Castillo, Ronald JE Pennings, Hannie Kremer, Ronald JC Admiraal, and Margit Schraders. Progressive hearing loss and vestibular dysfunction caused by a homozygous nonsense mutation in clic5. European Journal of Human Genetics, 23:189-194, Apr 2015. URL: https://doi.org/10.1038/ejhg.2014.83, doi:10.1038/ejhg.2014.83. This article has 75 citations and is from a domain leading peer-reviewed journal.

  10. (hahn2025aavgenetherapy pages 1-2): Roni Hahn, Shahar Taiber, Olga Shubina-Oleinik, Gwenaëlle S G Géléoc, Jeffrey R Holt, and Karen B Avraham. Aav gene therapy rescues hearing and balance in a model of clic5 deafness. EMBO Molecular Medicine, Aug 2025. URL: https://doi.org/10.1038/s44321-025-00275-7, doi:10.1038/s44321-025-00275-7. This article has 6 citations and is from a highest quality peer-reviewed journal.

  11. (waddell2016clic5maintainslifelong pages 1-5): BB Waddell. Clic5 maintains lifelong structural integrity of sensory stereocilia by promoting radixin phosphorylation in hair cells of the inner ear. Unknown journal, 2016.

Artifacts

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References checked 6
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References weighed for topical relevance 6
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