Autosomal Recessive Nonsyndromic Hearing Loss 103

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

DFNB103 is progressive, postlingual autosomal recessive sensorineural hearing loss caused by biallelic loss of CLIC5, often accompanied by vestibular involvement, though not in every reported individual. It is not a congenital profound deafness: hearing begins mild in early childhood and deteriorates to severe or profound over the second and third decades, and vestibular areflexia, when present, tends to appear later still. CLIC5 is not a chloride channel in any functionally relevant sense here. It is a member of the chloride intracellular channel family that behaves as a cytoskeletal adaptor, and it occupies a very specific address: the taper region at the base of the stereocilium, not the tip. There it sits in an approximately one-to-one stoichiometry with radixin and works with taperin, PTPRQ and myosin VI to pin the plasma membrane to the underlying actin core. The mechanism this entry curates is the failure of that pinning. What follows from a base-of-bundle adhesion defect is different from what follows from a tip defect, and the mouse shows it. Stereocilia in CLIC5-deficient mice do not simply shorten; they fuse with one another from postnatal day 10 onwards, and radixin, taperin and PTPRQ disperse out of the taper region rather than staying put - PTPRQ and radixin already before fusion is visible, which is what makes the mislocalisation causal rather than a consequence of the fusion. Loss of a membrane-to-actin tether at the base lets adjacent membranes come together. DFNB103 was defined in one Turkish family in 2015 and confirmed in a Cameroonian family in 2020, and until 2026 those were the only two. A founder truncating variant has since been found homozygous in 22 patients from 16 unrelated families in the Sakha Republic of Eastern Siberia, accounting for about one in ten GJB2-negative hearing loss patients there and traced to a single origin about 2,500 years ago. The disease went from an ultra-rare curiosity to a population-level cause in one region. There is now a proof of concept for treatment. Inner ear delivery of wild-type Clic5 by adeno-associated virus in neonatal Clic5-null mice prevented stereocilia fusion, restored radixin localisation, improved hair cell survival and rescued both auditory and vestibular function. Two features of that result are worth holding onto: the vestibular rescue was durable to 12 weeks while auditory thresholds drifted back up despite transgene expression remaining robust, and the injections were done at postnatal day 0, well before the mouse phenotype begins - neither of which maps cleanly onto a human disease that declares itself in childhood.

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Inheritance
4
Pathophys.
5
Phenotypes
2
Gaps
9
Pathograph
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Genes
1
Medical Actions
2
Models
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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.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:24781754 SUPPORT 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 Human Clinical
"The three affected individuals were compound heterozygous for both variants, and all unaffected individuals were heterozygous for one of the two variants."
Textbook recessive segregation in a non-consanguineous family, which is stronger evidence for the inheritance mode than a homozygous consanguineous pedigree alone.
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Discussions and Knowledge Gaps

2
Gene replacement prevents the CLIC5 phenotype when given at birth in mice, before the lesion starts. Human DFNB103 is diagnosed on an audiogram at around age 8, after stereocilia fusion would already have occurred. Can restoring CLIC5 rescue a bundle that has already fused, or only protect one that has not?
HUMAN MODEL MISMATCH clic5_therapeutic_window_timing
Attached to
animal_models#Clic5 knockout mouse treated with inner ear AAV pathophysiology#Progressive Stereocilia Fusion and Bundle Distortion treatments#Genetic Counselling with Audiologic and Vestibular Surveillance
The rescue experiment is genuinely encouraging and it does not answer the question a patient would ask. Injections were given at postnatal day 0. The cochlear lesion begins between postnatal days 14 and 17. So what was demonstrated is that a hair cell which has never lost its taper complex can be kept intact, which is a prevention result. Nobody has injected a mouse after fusion has begun. The human timing makes this the central question rather than a detail. DFNB103 is not congenital, hearing is normal or near-normal at birth, and detection is at a mean of about 8 years - by which time the equivalent mouse would be long past the treatment window used. Any clinical translation therefore depends on an experiment that has not been done, and the founder cohort in the Sakha Republic, where the genotype is known and the population is identifiable, is exactly the setting where presymptomatic genetic diagnosis in infancy would be feasible if the answer turned out to be that only prevention works. There is a second, more specific worry inside the same result. Vestibular rescue was stable to 12 weeks while auditory thresholds deteriorated over the same period even though transgene expression remained robust and hair cell morphology looked unchanged. Something is failing in the treated cochlea that is neither loss of transgene nor visible loss of cells, and until that is understood the durability of any human auditory benefit is unpredictable.
Proposed experiments
Delayed AAV delivery after stereocilia fusion has begun
exp_dfnb103_delayed_aav_after_fusion_onset
Deliver the same self-complementary Clic5 vector to Clic5-null mice at postnatal days 21 and 42, after fusion is established, with auditory brainstem response, distortion product otoacoustic emission, open-field circling and scanning electron microscopy at matched endpoints against the postnatal day 0 arm and untreated controls. Include a group in which transgene expression is confirmed but bundles are imaged before and after to distinguish arrest of progression from structural repair.
Would support
pathophysiology#Progressive Stereocilia Fusion and Bundle Distortion
Would refute
pathophysiology#Progressive Stereocilia Fusion and Bundle Distortion
Supporting outcome
  • Delayed treatment arrests further threshold loss and stabilises bundle morphology relative to untreated nulls, which would mean the tethering defect is continuously required and a post-diagnosis human intervention is coherent.
Refuting outcome
  • Delayed treatment restores CLIC5 protein and partner localisation but changes neither thresholds nor bundle morphology, which would mean fusion is irreversible once formed and would confine any therapeutic strategy to presymptomatic infants identified by genotype.
Show evidence (4 references)
PMID:40859056 SUPPORT 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 authors state plainly that treatment preceded the lesion. That is the mismatch with human diagnostic timing.
PMID:40859056 SUPPORT 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 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."
Rules out the two obvious explanations for the auditory drift, which is what makes it an open mechanistic question rather than a technical shortfall.
+ 1 more reference
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
One patient in the founding Turkish family had mild renal dysfunction, and the authors were careful to describe the gene as involved in hearing, vestibular and possibly mild renal dysfunction rather than asserting the last. That hedge has largely dropped out of subsequent descriptions, which now call the disease nonsyndromic without qualification. The observation deserves better than to be forgotten, because CLIC5 has an established role outside the ear in glomerular podocyte and endothelial cell maintenance. A podocyte adaptor protein whose loss produces a membrane-cytoskeletal failure in one specialised cell type has an obvious reason to do something similar in another. A single patient with mild dysfunction is weak evidence, but it is evidence pointing at a mechanism rather than a chance finding. What is missing is measurement. Neither the Cameroonian family nor the 22 Siberian patients have reported renal assessment, and the Siberian founder cohort is now large enough and genotypically homogeneous enough that urinalysis and estimated glomerular filtration rate against matched heterozygous relatives would settle the question cheaply. If a subclinical renal phenotype exists, DFNB103 patients need monitoring that nobody currently offers them; if it does not, the founding hedge can be retired on evidence rather than by attrition.
Show evidence (3 references)
PMID:24781754 SUPPORT Human Clinical
"Impaired hearing is accompanied by vestibular areflexia and in one of the patients with mild renal dysfunction."
Graded PARTIAL: a single patient with a mild finding, which is the entire human basis for the question.
PMID:24781754 SUPPORT 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 authors' own hedged wording, preserved here because later descriptions drop it and the hedge is the accurate statement of what is known.
PMID:33114113 SUPPORT Other
"The encoded protein associates with actin-based cytoskeletal structures and may play a role in multiple processes including hair cell stereocilia formation, myoblast proliferation, and glomerular podocyte and endothelial cell maintenance."
The biological reason the renal observation is plausible: the same class of membrane-cytoskeletal role in a different specialised cell type. Graded OTHER, not HUMAN_CLINICAL, because it is background prose summarising prior gene-function knowledge - grading it as clinical evidence would imply human podocyte data that this gap says does not exist.
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Pathophysiology

4
CLIC5 Loss of Function
Biallelic CLIC5 alleles that abolish or cripple the protein. The reported human spectrum is a nonsense variant p.Cys32Ter in the founding Turkish family, a compound heterozygous pair in the Cameroonian family consisting of a missense p.L75P and a canonical donor splice-site variant, and a founder nonsense variant p.Trp215Ter in Eastern Siberia. Even the one missense allele behaves as a loss of function in cells: expressed CLIC5A p.L75P forms perinuclear aggregates instead of distributing evenly in the cytoplasm, and fails to produce the thin filopodia-like membrane protrusions the wild-type protein induces.
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 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 Human Clinical
"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 In Vitro
"The mutant CLIC5A protein appears as aggregated perinuclear bodies while the wild-type protein was evenly distributed in the cytoplasm."
Functional confirmation that the missense allele mislocalises, so the human allelic spectrum is uniformly loss of function rather than mixed.
+ 1 more reference
Loss of Membrane-Actin Tethering at the Stereocilia Taper
CLIC5 concentrates at the base of hair cell stereocilia, in the taper region, and not at the tips. Mass spectrometry of chicken utricle stereocilia puts it there at roughly a one-to-one molar ratio with radixin, and biochemical assays show it interacts with ezrin-radixin-moesin proteins, with taperin and possibly with myosin VI. The proposed job of the complex is to hold the plasma membrane against the underlying actin core at the point where the stereocilium narrows. In CLIC5-deficient mice, radixin immunostaining at the bundle is reduced, and radixin, taperin and PTPRQ are all mislocalised in fused stereocilia. The timing is what makes this the primary lesion rather than a byproduct: PTPRQ and radixin are already dispersed before any fusion is visible. The dependency also runs the other way, since CLIC5 and radixin fail to localise properly in myosin VI mutant mice, so the complex is mutually stabilising rather than hierarchical.
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 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. ↓ DECREASED
actin filament binding GO:0051015 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased actin filament binding (GO:0051015). GO:0051015 is a molecular function from the Gene Ontology. ↓ DECREASED
Animal models
Clic5 jitterbug mouse Mouse recapitulates This is where the mechanism was established. Stereocilia taper composition cannot be examined in living patients, so the jitterbug mouse is not corroborating a human observation; it is where the tethering claim was tested in the first place, and tested in both directions, since CLIC5 and radixin also fail to localise in myosin VI mutants. It is not the only mouse bearing on the claim - the independent Clic5-null line used in the 2025 gene-therapy study shows the same radixin dependence, and is curated separately below.
Clic5 knockout mouse treated with inner ear AAV Mouse rescues The strongest available test of the tethering mechanism, because it runs the experiment forwards: restoring the protein restores its partner's localisation and prevents the structural failure. That is a stronger claim than any correlation between absence and phenotype.
Downstream
Progressive Stereocilia Fusion and Bundle Distortion
Show evidence (7 references)
PMID:17021174 SUPPORT 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.
PMID:17021174 SUPPORT 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."
The subcellular address. Base rather than tip is the whole reason DFNB103 looks unlike the tip-complex deafness genes.
PMID:17021174 SUPPORT 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."
Quantitative stoichiometry with radixin, which is what makes the association a structural partnership rather than a passing interaction.
+ 4 more references
Progressive Stereocilia Fusion and Bundle Distortion
The structural failure. Without the taper tether, adjacent stereocilia fuse. In the cochlea the fusion affects inner hair cells across all regions and outer hair cells most severely at the apex. The reported onset differs between the two mouse lines and they should not be read as one time course. In the jitterbug line, which carries an exon-skipping frameshift, fusion is described from postnatal day 10 onwards. In the Clic5-null line used for the gene therapy work, no cochlear abnormality is detectable at day 14 and the defects are established by day 17, with the vestibular change running slightly ahead - elongated utricular bundles from day 15, thickened by day 17. Both agree that the lesion has a defined postnatal onset rather than being present from birth, which is the structural counterpart of the postlingual, progressive human course; the P14-to-P17 window used by the therapeutic-window discussion and by the AAV model limitations is the null line's, not the jitterbug line's.
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 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. ↓ DECREASED vestibular receptor cell stereocilium organization GO:0060121 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. ↓ DECREASED
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.
Downstream
Progressive Hair Cell Degeneration
Show evidence (3 references)
PMID:24285636 SUPPORT 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 Model Organism
"Inner hair cells (IHCs) exhibited extensive hair bundle fusion across all cochlear regions."
Inner hair cells are the more extensively affected cochlear population - fusion across all regions, against outer hair cell fusion that is worst apically - which is why both cell types are annotated on this node.
PMID:40859056 SUPPORT 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"
The vestibular structural counterpart and its onset in an independent Clic5-null line.
Progressive Hair Cell Degeneration
Hair cells are lost after the bundles fail. The founding mouse description reports dysmorphic stereocilia together with progressive hair cell degeneration, and the vestibular hair cell count in Clic5-null mice is reduced by 12 weeks. Because degeneration follows rather than accompanies the structural lesion, there is a period in which cells are still present with damaged bundles, and that interval is where the gene therapy result sits.
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 knockout mouse treated with inner ear AAV Mouse partially recapitulates The untreated arm characterises the degeneration this node describes, in both the cochlea and the utricle, with a defined onset window between postnatal days 14 and 17 and no abnormality before that.
Downstream
Progressive Sensorineural Hearing Impairment
Vestibular Areflexia
Show evidence (2 references)
PMID:17021174 SUPPORT Model Organism
"Histological analysis of mutant inner ears revealed dysmorphic stereocilia and progressive hair cell degeneration."
The two histological findings and their ordering in the founding mouse description.
PMID:40859056 SUPPORT Model Organism
"Similar to cochlear hair cells of Clic5−/− mice, VHCs also showed progressive degeneration, characterized by elongated stereocilia bundles at 12 weeks of age"
Progressive vestibular hair cell degeneration in an independent null line.
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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

5
Progressive Sensorineural Hearing Impairment OBLIGATE 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 (3 references)
PMID:24781754 SUPPORT 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 Human Clinical
"Genotype-phenotype analysis in patients with DFNB103 showed that HL was sensorineural, symmetrical and variable by severity (from moderate to profound)."
Symmetry and severity range in the largest cohort. The symmetry is worth recording rather than assuming: it is the opposite of what the DFNA7 literature reports, where asymmetry is common enough that it has been proposed as a diagnostic prompt.
PMID:40957967 SUPPORT 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.
Bilateral Sensorineural Hearing Impairment VERY_FREQUENT 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.
VERY_FREQUENT rather than OBLIGATE because no reported series states laterality for every patient - the Turkish founding family's cached abstract does not say - so what is established is that no unilateral case has been described, not that none exists.
Show evidence (2 references)
PMID:33114113 SUPPORT 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 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 and Mid-Frequency Hearing Impairment FREQUENT 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.
Bound to HP:0001757 for the high-frequency component. The mid-frequency involvement reported alongside it is carried in the description rather than by a second binding, because the source describes one downsloping audiogram shape rather than two separable findings.
Show evidence (1 reference)
PMID:40957967 SUPPORT Human Clinical
"Audiograms mostly have a down curve configuration, with pronounced loss of high and mid frequencies."
The audiometric configuration in the only cohort large enough to describe one.
Postlingual Sensorineural Hearing Impairment FREQUENT 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 (3 references)
PMID:40957967 SUPPORT 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 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)."
The denominator behind the frequency grade: 19 of 26 homozygotes, which is 73 percent and so FREQUENT rather than VERY_FREQUENT.
PMID:40859056 SUPPORT Other
"Hearing loss in individuals with pathogenic variants in the CLIC5 gene is not congenital but emerges in early childhood, before the second decade of life, while vestibular areflexia, if present, generally develops later"
The non-congenital onset stated explicitly, together with the later timing of the vestibular component. Graded OTHER rather than HUMAN_CLINICAL: this is a mouse AAV study, and the sentence is its introduction restating human findings it cites from Seco 2015 and Wonkam-Tingang 2020 rather than data it generated.
Vestibular Areflexia FREQUENT 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 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.
PMID:40859056 SUPPORT Other
"Variants in the CLIC5 gene, encoding Chloride Intracellular Channel 5, have been found to cause autosomal recessive hearing loss in humans, along with vestibular dysfunction, observed in some individuals and a related mouse model"
Graded PARTIAL because it qualifies the frequency claim rather than supporting it - vestibular dysfunction is observed in some individuals, not all, which is why this phenotype is FREQUENT rather than OBLIGATE.
🧬

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 (5 references)
PMID:24781754 SUPPORT 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 Human Clinical
"This study is the second report, worldwide, to describe CLIC5 involvement in human hearing impairment, and thus confirms CLIC5 as a novel non-syndromic hearing impairment gene that should be included in targeted diagnostic gene panels."
The independent replication that moved CLIC5 from a single-family finding to an accepted deafness gene.
PMID:40957967 SUPPORT 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.
+ 2 more references
🗃️

External Assertions

1
OMIM deafness, autosomal recessive 103 record
OMIM disease record OMIM:616042
The OMIM record MONDO:0014469 xrefs, and the identifier the DFNB103 literature uses when it names the disorder. Recorded here rather than under `mappings` because the `DiseaseMappings` class carries only ICD-10-CM, ICD-11, MONDO and NCIT slots.
Show evidence (1 reference)
PMID:40957967 SUPPORT Human Clinical
"Previously only two families were known with progressive autosomal recessive deafness 103 (DFNB103, OMIM616042) caused by pathogenic variants of the CLIC5 gene."
The disease name and its OMIM identifier used together in the primary literature.
💊

Medical Actions

1
Genetic Counselling with Audiologic and Vestibular Surveillance
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
Counselling for a recessive condition with a 25 percent sibling recurrence risk, and scheduled follow-up rather than a single assessment. Surveillance is the substantive part here: hearing is not congenitally impaired, newborn screening can be passed, and the loss then declines by several decibels per year, so a normal early audiogram is not a discharge. Vestibular testing is worth including because areflexia develops later than the hearing loss and is often asymptomatic.
Show evidence (2 references)
PMID:40957967 SUPPORT 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."
The quantified rate of decline, which is what makes scheduled rather than one-off audiometry the right recommendation.
PMID:40859056 SUPPORT Other
"Hearing loss in individuals with pathogenic variants in the CLIC5 gene is not congenital but emerges in early childhood, before the second decade of life, while vestibular areflexia, if present, generally develops later"
The two-stage natural history that determines what surveillance should look for and when. Graded OTHER: the sentence is this mouse study's introduction restating human findings from papers it cites, not evidence the study produced.
🔬

Diagnosis

1
CLIC5 on panels for postlingual progressive recessive hearing loss
DFNB103 is reached by exome sequencing or a targeted panel that contains CLIC5, after GJB2 has been excluded. The clinical prompt is a progressive postlingual sensorineural loss with vestibular signs, in a family pattern consistent with recessive inheritance and where newborn screening was passed. In the Sakha Republic the founder variant makes a single targeted test worthwhile in GJB2-negative patients before broader sequencing.
Show evidence (2 references)
PMID:33114113 SUPPORT Human Clinical
"confirms CLIC5 as a novel non-syndromic hearing impairment gene that should be included in targeted diagnostic gene panels"
The explicit recommendation to include the gene on panels.
PMID:40957967 SUPPORT Human Clinical
"In this study we present the novel truncating variant c.644 G > A p.(Trp215*) of this gene which was found in homozygous state among 22 patients with hearing loss (HL) from 16 unrelated families living in the Sakha Republic of Russia (Eastern Siberia)."
The founder allele and the population in which targeted testing for it is the efficient first step.
📈

Progression

3
Presymptomatic
Age: birth to about 8 years
Hearing is normal or near-normal at birth and the disease is not congenital, so a child with DFNB103 can pass newborn hearing screening. In the Siberian cohort the loss was detected at a mean of 7.9 years; in the Yakutia series the reported mean onset was 9.7 years. The founding Turkish family is the exception to the upper end, with onset in early childhood.
Show evidence (1 reference)
PMID:40859056 SUPPORT Other
"Hearing loss in individuals with pathogenic variants in the CLIC5 gene is not congenital but emerges in early childhood, before the second decade of life, while vestibular areflexia, if present, generally develops later"
The non-congenital start of the course. Graded OTHER because the sentence is this mouse study restating human findings it cites.
Progressive decline
Age: about 8 years to the second or third decade
Once detected the loss deteriorates at a measurable rate rather than in steps, which is what makes scheduled audiometry rather than a single audiogram the right surveillance. Vestibular areflexia, where it occurs, appears later than the hearing loss.
Show evidence (1 reference)
PMID:40957967 SUPPORT 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."
The rate of decline and the age band it ends in, from the only cohort large enough to measure either.
Profound deafness
Age: second or third decade onwards
The endpoint reached by the Siberian cohort. The founding Turkish family reached severe or profound loss earlier, before the second decade, so the age at endpoint varies between reported populations even on truncating alleles.
Show evidence (1 reference)
PMID:24781754 SUPPORT 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."
Graded PARTIAL because it qualifies the timing of this phase rather than confirming it: the founding family reached the endpoint a decade earlier than the Siberian cohort did.
📊

Prevalence

4
Yakutia (Sakha Republic), Eastern Siberia
Point Prevalence 2.7 per 100,000 1–9 per 100,000
The population-wide figure, 0.27 per 10,000 across a denominator of 958,528, converted to 2.7 per 100,000. Reported for the same founder allele under its earlier transcript numbering, c.1121G>A p.Trp374*.
Show evidence (1 reference)
DOI:10.25557/2073-7998.2019.10.36-48 SUPPORT 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 (209.3–418.5) >1 in 1,000
Local accumulation in one Arctic district, 31.39 plus or minus 10.46 per 10,000 converted to 313.9 per 100,000 with the reported standard error as the range - about 1 in 318, more than a hundred times the Yakutia-wide rate. The district is majority Even (53 percent), which is what makes this a founder effect rather than a sampling artefact.
Show evidence (2 references)
DOI:10.25557/2073-7998.2019.10.36-48 SUPPORT 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.
DOI:10.25557/2073-7998.2019.10.36-48 SUPPORT Human Clinical
"which referred to the Arctic group of districts where the majority of the population is represented by Evens (53%)"
The ethnic composition of the district carrying the accumulation, which is the founder-effect context for the local rate.
GJB2-negative hearing loss patients, Sakha Republic, Eastern Siberia
Unknown
The founder variant p.Trp215Ter was found homozygous in 9.9 percent of GJB2-negative hearing loss patients in the Sakha Republic. This is a diagnostic yield within an ascertained, GJB2-excluded patient group, not a population prevalence, and it does not generalise: the same variant was not detected in GJB2-negative patients of predominantly Russian descent. No rate_per_100000 or prevalence_class is recorded, because putting 9.9 percent in a population-rate slot would assert that a tenth of the Sakha population has DFNB103; the population figure is the separate Yakutia record above, roughly 3,700 times smaller. measure_type is UNKNOWN rather than CARRIER_FREQUENCY: the schema defines carrier frequency as the heterozygote rate, and these are homozygous affected patients, so no PrevalenceMeasureEnum value fits.
Show evidence (1 reference)
PMID:40957967 SUPPORT 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.
Worldwide outside the Siberian founder population
Cases In Literature Ultra Rare
Only two families were reported worldwide between 2015 and 2026, one Turkish and one Cameroonian.
Show evidence (1 reference)
PMID:40957967 SUPPORT Human Clinical
"Previously only two families were known with progressive autosomal recessive deafness 103 (DFNB103, OMIM616042) caused by pathogenic variants of the CLIC5 gene."
The size of the reported literature before the Siberian cohort.
🐁

Animal Models

2
Clic5 jitterbug mouse
The founding model and the reason CLIC5 was a candidate gene at all. jitterbug is a spontaneous recessive mutation, a 97 base pair intragenic deletion that causes exon 5 skipping with a frameshift and premature stop; western blot and immunohistochemistry confirm the protein is absent. Homozygotes have impaired hearing and vestibular dysfunction, dysmorphic stereocilia and progressive hair cell degeneration, and reduced radixin staining in the hair bundle. The 2014 follow-up on the same line established the fusion phenotype and the mislocalisation of radixin, taperin and PTPRQ.
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 This is where the mechanism was established. Stereocilia taper composition cannot be examined in living patients, so the jitterbug mouse is not corroborating a human observation; it is where the tethering claim was tested in the first place, and tested in both directions, since CLIC5 and radixin also fail to localise in myosin VI mutants. It is not the only mouse bearing on the claim - the independent Clic5-null line used in the 2025 gene-therapy study shows the same radixin dependence, and is curated separately below.
Limitations: A protein-null allele produced by exon skipping, against a human spectrum of nonsense, splice and missense alleles; the human missense allele in particular has residual protein that mislocalises rather than being absent, so it is not biochemically equivalent. The molecular partners were characterised partly in chicken and rat vestibular tissue rather than in mouse cochlea, so the complex is assembled from evidence across three species.
Readouts
Radixin immunostaining in hair bundles
Direction: DECREASED
Interpretation: The partner protein is lost from the bundle when CLIC5 is absent, which is the direct evidence that CLIC5 holds the complex in place.
Show evidence (1 reference)
PMID:17021174 SUPPORT 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: Three partners disperse out of the taper region, two of them before fusion is visible, so the complex disassembles first and the structure fails afterwards.
Show evidence (1 reference)
PMID:24285636 SUPPORT 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 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: The mouse time course is compressed relative to the human one - days to weeks against years - so the model reproduces the sequence of events but not their tempo. Whether the human loss reflects fusion at all is inference from the shared gene and shared progressive phenotype, since no human cochlear histology exists.
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 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 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 (2 references)
PMID:17021174 SUPPORT 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.
PMID:24781754 SUPPORT Other
"The orthologous mouse gene is mutated in the jitterbug mutant that exhibits progressive hearing impairment and vestibular dysfunction."
The human authors' own use of the mouse as the prior that made CLIC5 a credible candidate, so the model preceded and enabled the human discovery. Graded OTHER because the sentence reports neither this human study's clinical data nor a mouse experiment it ran - it is a citation of prior mouse work inside a human paper.
Clic5 knockout mouse treated with inner ear AAV
A gene-replacement experiment in a Clic5-null line with a well-characterised baseline: untreated homozygotes have auditory brainstem response thresholds shifted by about 40 dB at 4 weeks and no response at 8 weeks, circling behaviour from 4 weeks, and cochlear hair cell changes beginning between postnatal days 14 and 17. Utricle injection at postnatal day 0 of either a single-stranded or a self-complementary vector restored CLIC5 to the base of the stereocilia, normalised radixin localisation, prevented fusion and elongation, improved hair cell survival, and rescued auditory and vestibular function. The self-complementary vector achieved equivalent rescue at a titre an order of magnitude lower.
Species
Mouse
Genotype
Clic5 null, homozygous, treated at postnatal day 0 with AAV2/9-PHP.B carrying wild-type Clic5
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 The strongest available test of the tethering mechanism, because it runs the experiment forwards: restoring the protein restores its partner's localisation and prevents the structural failure. That is a stronger claim than any correlation between absence and phenotype.
Limitations: Treatment was given at postnatal day 0, before the mouse lesion begins between postnatal days 14 and 17, so this establishes prevention rather than reversal. Human DFNB103 is diagnosed after hearing loss has begun, typically around age 8, which is the equivalent of treating well after the mouse window has closed - the experiment does not address that situation. The rescue was also incomplete and unstable in the auditory system: treated thresholds remained significantly worse than controls at 12 weeks and deteriorated over time, particularly at high frequencies.
Readouts
Radixin localisation after CLIC5 restoration
Direction: RESTORED
Interpretation: Restoring CLIC5 restores its partner to the taper region, closing the causal loop between the adaptor and the complex.
Show evidence (1 reference)
PMID:40859056 SUPPORT 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.
Stereocilia morphology after treatment
Direction: RESTORED
Interpretation: Bundle morphology is held at normal rather than merely deteriorating more slowly: the fusion and elongation that follow loss of the tether do not occur.
Show evidence (1 reference)
PMID:40859056 SUPPORT 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 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 Hair Cell Degeneration partially recapitulates fidelity: moderate The untreated arm characterises the degeneration this node describes, in both the cochlea and the utricle, with a defined onset window between postnatal days 14 and 17 and no abnormality before that.
Limitations: Only partial with respect to the human disease, because the mouse loses hearing entirely by 8 weeks whereas patients decline over one to two decades. The vestibular phenotype is also more prominent in the mouse, where circling and hyperactivity are the defining behavioural signs, than in patients, where areflexia may be absent and is often asymptomatic when present.
Readouts
Auditory brainstem response threshold in untreated nulls
Direction: INCREASED
Interpretation: Thresholds rise, so the direction is INCREASED even though hearing falls: a shift of about 40 dB by four weeks and no response at all by eight, which is the untreated trajectory the rescue is measured against.
Show evidence (1 reference)
PMID:40859056 SUPPORT Model Organism
"In contrast, Clic5−/− mice exhibited ABR thresholds shifted by ~40 dB at 4 weeks, and no response was detected at 8 weeks"
The untreated auditory time course.
Show evidence (1 reference)
PMID:40859056 SUPPORT Model Organism
"No morphological changes were observed at P14, suggesting that the onset of hair cell defects occurs between P14 and P17"
The onset window for the cochlear lesion - nothing at P14, onset after it.
Show evidence (2 references)
PMID:40859056 SUPPORT Model Organism
"A key characteristic of the Clic5 mutant mouse phenotype is vestibular dysfunction, which translates to repetitive circling behavior, abnormal head movements, and overall balance dysfunction."
The vestibular behavioural phenotype that makes this line usable for the balance arm of the disease as well as the auditory arm.
PMID:40859056 SUPPORT Model Organism
"The ability to rescue auditory and vestibular function in Clic5-deficient mice may indicate potential applicability to humans."
Graded PARTIAL, matching the authors' own hedge. A neonatal prevention experiment in mice indicates possibility, not applicability.
{ }

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 progressive, postlingual autosomal recessive sensorineural hearing loss
  caused by biallelic loss of CLIC5, often accompanied by vestibular involvement, though
  not in every reported individual. It is not a congenital profound deafness: hearing
  begins mild in early childhood and deteriorates to severe or profound over the second
  and third decades, and vestibular areflexia, when present, tends to appear later still.

  CLIC5 is not a chloride channel in any functionally relevant sense here. It is a member
  of the chloride intracellular channel family that behaves as a cytoskeletal adaptor, and
  it occupies a very specific address: the taper region at the base of the stereocilium,
  not the tip. There it sits in an approximately one-to-one stoichiometry with radixin and
  works with taperin, PTPRQ and myosin VI to pin the plasma membrane to the underlying
  actin core. The mechanism this entry curates is the failure of that pinning.

  What follows from a base-of-bundle adhesion defect is different from what follows from a
  tip defect, and the mouse shows it. Stereocilia in CLIC5-deficient mice do not simply
  shorten; they fuse with one another from postnatal day 10 onwards, and radixin, taperin
  and PTPRQ disperse out of the taper region rather than staying put - PTPRQ and radixin
  already before fusion is visible, which is what makes the mislocalisation causal rather
  than a consequence of the fusion. Loss of a membrane-to-actin tether at the base lets
  adjacent membranes come together.

  DFNB103 was defined in one Turkish family in 2015 and confirmed in a Cameroonian family
  in 2020, and until 2026 those were the only two. A founder truncating variant has since
  been found homozygous in 22 patients from 16 unrelated families in the Sakha Republic of
  Eastern Siberia, accounting for about one in ten GJB2-negative hearing loss patients
  there and traced to a single origin about 2,500 years ago. The disease went from an
  ultra-rare curiosity to a population-level cause in one region.

  There is now a proof of concept for treatment. Inner ear delivery of wild-type Clic5 by
  adeno-associated virus in neonatal Clic5-null mice prevented stereocilia fusion,
  restored radixin localisation, improved hair cell survival and rescued both auditory and
  vestibular function. Two features of that result are worth holding onto: the vestibular
  rescue was durable to 12 weeks while auditory thresholds drifted back up despite
  transgene expression remaining robust, and the injections were done at postnatal day 0,
  well before the mouse phenotype begins - neither of which maps cleanly onto a human
  disease that declares itself in childhood.
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.
  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.
  - 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: >-
      Textbook recessive segregation in a non-consanguineous family, which is stronger
      evidence for the inheritance mode than a homozygous consanguineous pedigree alone.
pathophysiology:
- name: CLIC5 Loss of Function
  description: >-
    Biallelic CLIC5 alleles that abolish or cripple the protein. The reported human
    spectrum is a nonsense variant p.Cys32Ter in the founding Turkish family, a compound
    heterozygous pair in the Cameroonian family consisting of a missense p.L75P and a
    canonical donor splice-site variant, and a founder nonsense variant p.Trp215Ter in
    Eastern Siberia. Even the one missense allele behaves as a loss of function in cells:
    expressed CLIC5A p.L75P forms perinuclear aggregates instead of distributing evenly in
    the cytoplasm, and fails to produce the thin filopodia-like membrane protrusions the
    wild-type protein induces.
  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: DIRECT
  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.
  - 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: "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.
  - 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: >-
      Functional confirmation that the missense allele mislocalises, so the human allelic
      spectrum is uniformly loss of function rather than mixed.
  - 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: "Furthermore, cells transfected with the wild-type CLIC5A formed thin membrane filopodia-like protrusions which were absent in the CLIC5A mutant expressing and control cells."
    explanation: >-
      A membrane-protrusion assay in which the mutant behaves like empty vector, which is
      the closest cell-based analogue of the stereocilia phenotype.
- name: Loss of Membrane-Actin Tethering at the Stereocilia Taper
  description: >-
    CLIC5 concentrates at the base of hair cell stereocilia, in the taper region, and not
    at the tips. Mass spectrometry of chicken utricle stereocilia puts it there at roughly
    a one-to-one molar ratio with radixin, and biochemical assays show it interacts with
    ezrin-radixin-moesin proteins, with taperin and possibly with myosin VI. The proposed
    job of the complex is to hold the plasma membrane against the underlying actin core at
    the point where the stereocilium narrows.

    In CLIC5-deficient mice, radixin immunostaining at the bundle is reduced, and radixin,
    taperin and PTPRQ are all mislocalised in fused stereocilia. The timing is what makes
    this the primary lesion rather than a byproduct: PTPRQ and radixin are already
    dispersed before any fusion is visible. The dependency also runs the other way, since
    CLIC5 and radixin fail to localise properly in myosin VI mutant mice, so the complex is
    mutually stabilising rather than hierarchical.
  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
  molecular_functions:
  - preferred_term: actin filament binding
    term:
      id: GO:0051015
      label: actin filament binding
    modifier: DECREASED
  downstream:
  - target: Progressive Stereocilia Fusion and Bundle Distortion
    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: "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.
  - 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: >-
      The subcellular address. Base rather than tip is the whole reason DFNB103 looks
      unlike the tip-complex deafness genes.
  - 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: >-
      Quantitative stoichiometry with radixin, which is what makes the association a
      structural partnership rather than a passing interaction.
  - 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: >-
      The timing evidence: partner mislocalisation precedes the structural failure, so it
      is upstream of it rather than a consequence.
  - 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.
  - 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: >-
      The dependency measured in the other direction, which is what the description means
      by mutually stabilising rather than hierarchical: losing myosin VI mislocalises
      CLIC5, just as losing CLIC5 mislocalises radixin.
  - 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: >-
      An independent line of evidence for the functional importance of the taper complex:
      deleting only the CLIC5-binding region of a partner protein causes hearing loss
      without visible morphological change, so the complex matters functionally and not
      only structurally.
- name: Progressive Stereocilia Fusion and Bundle Distortion
  description: >-
    The structural failure. Without the taper tether, adjacent stereocilia fuse. In the
    cochlea the fusion affects inner hair cells across all regions and outer hair cells
    most severely at the apex.

    The reported onset differs between the two mouse lines and they should not be read as
    one time course. In the jitterbug line, which carries an exon-skipping frameshift,
    fusion is described from postnatal day 10 onwards. In the Clic5-null line used for the
    gene therapy work, no cochlear abnormality is detectable at day 14 and the defects are
    established by day 17, with the vestibular change running slightly ahead - elongated
    utricular bundles from day 15, thickened by day 17. Both agree that the lesion has a
    defined postnatal onset rather than being present from birth, which is the structural
    counterpart of the postlingual, progressive human course; the P14-to-P17 window used
    by the therapeutic-window discussion and by the AAV model limitations is the null
    line's, not the jitterbug line's.
  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: DIRECT
  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.
  - 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 cells are the more extensively affected cochlear population - fusion
      across all regions, against outer hair cell fusion that is worst apically - which is
      why both cell types are annotated on this node.
  - 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: The vestibular structural counterpart and its onset in an independent Clic5-null line.
- name: Progressive Hair Cell Degeneration
  description: >-
    Hair cells are lost after the bundles fail. The founding mouse description reports
    dysmorphic stereocilia together with progressive hair cell degeneration, and the
    vestibular hair cell count in Clic5-null mice is reduced by 12 weeks. Because
    degeneration follows rather than accompanies the structural lesion, there is a period
    in which cells are still present with damaged bundles, and that interval is where the
    gene therapy result sits.
  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 two histological findings and their ordering in the founding mouse description.
  - 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: "Similar to cochlear hair cells of Clic5−/− mice, VHCs also showed progressive degeneration, characterized by elongated stereocilia bundles at 12 weeks of age"
    explanation: Progressive vestibular hair cell degeneration in an independent null line.
phenotypes:
- name: Progressive Sensorineural Hearing Impairment
  category: Auditory
  description: >-
    Bilateral, symmetrical sensorineural hearing loss that begins mild and deteriorates.
    In the founding family onset was in early childhood and hearing progressed from mild
    to severe or profound before the second decade. The Siberian founder cohort quantifies
    the rate: about 7 dB lost per year across the speech frequencies, reaching profound
    deafness in the second or third decade, with severity across the cohort ranging from
    moderate to profound.
  frequency: OBLIGATE
  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.
  - 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 and severity range in the largest cohort. The symmetry is worth recording
      rather than assuming: it is the opposite of what the DFNA7 literature reports, where
      asymmetry is common enough that it has been proposed as a diagnostic prompt.
  - 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.
- name: Bilateral Sensorineural Hearing Impairment
  category: Auditory
  description: >-
    Both ears are affected. Every DFNB103 patient with a reported audiogram has bilateral
    disease, and the Siberian cohort adds that the two ears are usually matched rather than
    merely both involved.
  frequency: VERY_FREQUENT
  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.
  - 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.
  notes: >-
    VERY_FREQUENT rather than OBLIGATE because no reported series states laterality for
    every patient - the Turkish founding family's cached abstract does not say - so what is
    established is that no unilateral case has been described, not that none exists.
- name: High and Mid-Frequency Hearing Impairment
  category: Auditory
  description: >-
    Audiograms in the Siberian cohort mostly show a downsloping configuration with
    pronounced loss of high and mid frequencies.
  frequency: FREQUENT
  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: The audiometric configuration in the only cohort large enough to describe one.
  notes: >-
    Bound to HP:0001757 for the high-frequency component. The mid-frequency involvement
    reported alongside it is carried in the description rather than by a second binding,
    because the source describes one downsloping audiogram shape rather than two separable
    findings.
- name: Postlingual Sensorineural Hearing Impairment
  category: Auditory
  description: >-
    Onset is after speech acquisition in most patients, at a mean of about 8 years in the
    Siberian cohort. This matters practically: a child with DFNB103 can pass newborn
    hearing screening, and the diagnosis is made on a later audiogram rather than at birth.
  frequency: FREQUENT
  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.
  - 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: >-
      The denominator behind the frequency grade: 19 of 26 homozygotes, which is 73 percent
      and so FREQUENT rather than VERY_FREQUENT.
  - reference: PMID:40859056
    reference_title: "AAV gene therapy rescues hearing and balance in a model of CLIC5 deafness."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Hearing loss in individuals with pathogenic variants in the CLIC5 gene is not congenital but emerges in early childhood, before the second decade of life, while vestibular areflexia, if present, generally develops later"
    explanation: >-
      The non-congenital onset stated explicitly, together with the later timing of the
      vestibular component. Graded OTHER rather than HUMAN_CLINICAL: this is a mouse AAV
      study, and the sentence is its introduction restating human findings it cites from
      Seco 2015 and Wonkam-Tingang 2020 rather than data it generated.
- name: Vestibular Areflexia
  category: Vestibular
  description: >-
    Absent vestibular responses accompany the hearing loss in the founding family, and
    vestibular dysfunction is the other half of the CLIC5 phenotype in every species where
    it has been looked for. It is described as developing later than the hearing loss, and
    it is not documented in every reported family, so it is neither obligate nor
    incidental.
  frequency: FREQUENT
  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.
  - reference: PMID:40859056
    reference_title: "AAV gene therapy rescues hearing and balance in a model of CLIC5 deafness."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Variants in the CLIC5 gene, encoding Chloride Intracellular Channel 5, have been found to cause autosomal recessive hearing loss in humans, along with vestibular dysfunction, observed in some individuals and a related mouse model"
    explanation: >-
      Graded PARTIAL because it qualifies the frequency claim rather than supporting it -
      vestibular dysfunction is observed in some individuals, not all, which is why this
      phenotype is FREQUENT rather than OBLIGATE.
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 population-wide figure, 0.27 per 10,000 across a denominator of 958,528, converted
    to 2.7 per 100,000. Reported for the same founder allele under its earlier transcript
    numbering, c.1121G>A p.Trp374*.
  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.
- population: Eveno-Bytantaysky national district, Arctic Yakutia
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 313.9
  rate_low: 209.3
  rate_high: 418.5
  notes: >-
    Local accumulation in one Arctic district, 31.39 plus or minus 10.46 per 10,000
    converted to 313.9 per 100,000 with the reported standard error as the range - about
    1 in 318, more than a hundred times the Yakutia-wide rate. The district is majority
    Even (53 percent), which is what makes this a founder effect rather than a sampling
    artefact.
  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.
  - 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: "which referred to the Arctic group of districts where the majority of the population is represented by Evens (53%)"
    explanation: >-
      The ethnic composition of the district carrying the accumulation, which is the
      founder-effect context for the local rate.
- population: GJB2-negative hearing loss patients, Sakha Republic, Eastern Siberia
  measure_type: UNKNOWN
  notes: >-
    The founder variant p.Trp215Ter was found homozygous in 9.9 percent of GJB2-negative
    hearing loss patients in the Sakha Republic. This is a diagnostic yield within an
    ascertained, GJB2-excluded patient group, not a population prevalence, and it does not
    generalise: the same variant was not detected in GJB2-negative patients of
    predominantly Russian descent. No rate_per_100000 or prevalence_class is recorded,
    because putting 9.9 percent in a population-rate slot would assert that a tenth of the
    Sakha population has DFNB103; the population figure is the separate Yakutia record
    above, roughly 3,700 times smaller. measure_type is UNKNOWN rather than
    CARRIER_FREQUENCY: the schema defines carrier frequency as the heterozygote rate, and
    these are homozygous affected patients, so no PrevalenceMeasureEnum value fits.
  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.
- population: Worldwide outside the Siberian founder population
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Only two families were reported worldwide between 2015 and 2026, one Turkish and one
    Cameroonian.
  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: "Previously only two families were known with progressive autosomal recessive deafness 103 (DFNB103, OMIM616042) caused by pathogenic variants of the CLIC5 gene."
    explanation: The size of the reported literature before the Siberian cohort.
progression:
- phase: Presymptomatic
  age_range: birth to about 8 years
  notes: >-
    Hearing is normal or near-normal at birth and the disease is not congenital, so a
    child with DFNB103 can pass newborn hearing screening. In the Siberian cohort the
    loss was detected at a mean of 7.9 years; in the Yakutia series the reported mean
    onset was 9.7 years. The founding Turkish family is the exception to the upper end,
    with onset in early childhood.
  evidence:
  - reference: PMID:40859056
    reference_title: "AAV gene therapy rescues hearing and balance in a model of CLIC5 deafness."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Hearing loss in individuals with pathogenic variants in the CLIC5 gene is not congenital but emerges in early childhood, before the second decade of life, while vestibular areflexia, if present, generally develops later"
    explanation: >-
      The non-congenital start of the course. Graded OTHER because the sentence is this
      mouse study restating human findings it cites.
- phase: Progressive decline
  age_range: about 8 years to the second or third decade
  notes: >-
    Once detected the loss deteriorates at a measurable rate rather than in steps, which
    is what makes scheduled audiometry rather than a single audiogram the right
    surveillance. Vestibular areflexia, where it occurs, appears later than the hearing
    loss.
  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: >-
      The rate of decline and the age band it ends in, from the only cohort large enough
      to measure either.
- phase: Profound deafness
  age_range: second or third decade onwards
  notes: >-
    The endpoint reached by the Siberian cohort. The founding Turkish family reached
    severe or profound loss earlier, before the second decade, so the age at endpoint
    varies between reported populations even on truncating alleles.
  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: >-
      Graded PARTIAL because it qualifies the timing of this phase rather than confirming
      it: the founding family reached the endpoint a decade earlier than the Siberian
      cohort did.
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: >-
    The OMIM record MONDO:0014469 xrefs, and the identifier the DFNB103 literature uses
    when it names the disorder. Recorded here rather than under `mappings` because the
    `DiseaseMappings` class carries only ICD-10-CM, ICD-11, MONDO and NCIT slots.
  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: "Previously only two families were known with progressive autosomal recessive deafness 103 (DFNB103, OMIM616042) caused by pathogenic variants of the CLIC5 gene."
    explanation: The disease name and its OMIM identifier used together in the primary literature.
genetic:
- name: CLIC5
  notes: >-
    CLIC5 on 6p21.1 encodes chloride intracellular channel 5, originally isolated from
    microvilli in complex with actin-binding proteins including ezrin. Despite the family
    name, its role in the ear is as a membrane-cytoskeletal adaptor at the stereocilia
    taper rather than as an ion channel. It is expressed elsewhere - in glomerular
    podocytes and endothelium, and in myoblasts - which is the background to the isolated
    report of mild renal dysfunction in one patient. In hair cells its expression is
    directly regulated by miR-96 and miR-182 of the miR-183 family, through a conserved
    binding site in its 3-prime untranslated region.

    The Siberian founder allele p.Trp215Ter is the only CLIC5 variant so far shown to reach
    appreciable population frequency anywhere; haplotype analysis over 730,000 genome-wide
    SNP markers places its origin around 78 generations ago.

    That allele appears in the literature under two names and they are the same variant:
    Pshennikova 2019 calls it c.1121G>A p.(Trp374*) and the 2026 Siberian cohort paper
    calls it c.644G>A p.(Trp215*). The offsets differ by exactly 477 nucleotides and 159
    codons, which is the shift between the two CLIC5 transcripts, not a second Siberian
    allele.
  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.
  - 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: "This study is the second report, worldwide, to describe CLIC5 involvement in human hearing impairment, and thus confirms CLIC5 as a novel non-syndromic hearing impairment gene that should be included in targeted diagnostic gene panels."
    explanation: >-
      The independent replication that moved CLIC5 from a single-family finding to an
      accepted deafness gene.
  - 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.
  - 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: OTHER
    snippet: "The encoded protein associates with actin-based cytoskeletal structures and may play a role in multiple processes including hair cell stereocilia formation, myoblast proliferation, and glomerular podocyte and endothelial cell maintenance."
    explanation: >-
      The gene's expression outside the ear, which is the reason the renal observation is
      biologically plausible rather than dismissible. Graded OTHER because the sentence is
      this paper's introductory summary of prior gene-function knowledge, not a clinical
      observation from the Cameroonian family it studied.
  - 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
    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: >-
      Identifies a direct upstream regulator of CLIC5 dosage, mapped to a specific
      conserved binding site. Recorded because DFNB103 is a dosage-loss disease, so
      anything that sets CLIC5 expression level is a candidate modifier.
diagnosis:
- name: CLIC5 on panels for postlingual progressive recessive hearing loss
  description: >-
    DFNB103 is reached by exome sequencing or a targeted panel that contains CLIC5, after
    GJB2 has been excluded. The clinical prompt is a progressive postlingual sensorineural
    loss with vestibular signs, in a family pattern consistent with recessive inheritance
    and where newborn screening was passed. In the Sakha Republic the founder variant makes
    a single targeted test worthwhile in GJB2-negative patients before broader sequencing.
  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: "confirms CLIC5 as a novel non-syndromic hearing impairment gene that should be included in targeted diagnostic gene panels"
    explanation: The explicit recommendation to include the gene on panels.
  - 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 this study we present the novel truncating variant c.644 G > A p.(Trp215*) of this gene which was found in homozygous state among 22 patients with hearing loss (HL) from 16 unrelated families living in the Sakha Republic of Russia (Eastern Siberia)."
    explanation: >-
      The founder allele and the population in which targeted testing for it is the
      efficient first step.
treatments:
- name: Genetic Counselling with Audiologic and Vestibular Surveillance
  description: >-
    Counselling for a recessive condition with a 25 percent sibling recurrence risk, and
    scheduled follow-up rather than a single assessment. Surveillance is the substantive
    part here: hearing is not congenitally impaired, newborn screening can be passed, and
    the loss then declines by several decibels per year, so a normal early audiogram is not
    a discharge. Vestibular testing is worth including because areflexia develops later
    than the hearing loss and is often asymptomatic.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  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: >-
      The quantified rate of decline, which is what makes scheduled rather than one-off
      audiometry the right recommendation.
  - reference: PMID:40859056
    reference_title: "AAV gene therapy rescues hearing and balance in a model of CLIC5 deafness."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Hearing loss in individuals with pathogenic variants in the CLIC5 gene is not congenital but emerges in early childhood, before the second decade of life, while vestibular areflexia, if present, generally develops later"
    explanation: >-
      The two-stage natural history that determines what surveillance should look for and
      when. Graded OTHER: the sentence is this mouse study's introduction restating human
      findings from papers it cites, not evidence the study produced.
  notes: >-
    No DFNB103-specific report of hearing amplification, cochlear implantation or
    vestibular rehabilitation was found in the reviewed literature, so none is curated here
    even though all three are standard in progressive severe-to-profound sensorineural
    hearing loss with vestibular failure. This is a deliberate scoping decision rather than
    a judgement that they are inappropriate. Gene replacement is likewise not curated as a
    treatment: the AAV work is preclinical and is recorded under animal_models, where its
    limitations can be stated alongside it.
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 founding model and the reason CLIC5 was a candidate gene at all. jitterbug is a
    spontaneous recessive mutation, a 97 base pair intragenic deletion that causes exon 5
    skipping with a frameshift and premature stop; western blot and immunohistochemistry
    confirm the protein is absent. Homozygotes have impaired hearing and vestibular
    dysfunction, dysmorphic stereocilia and progressive hair cell degeneration, and reduced
    radixin staining in the hair bundle. The 2014 follow-up on the same line established
    the fusion phenotype and the mislocalisation of radixin, taperin and PTPRQ.
  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: >-
      This is where the mechanism was established. Stereocilia taper composition cannot be
      examined in living patients, so the jitterbug mouse is not corroborating a human
      observation; it is where the tethering claim was tested in the first place, and
      tested in both directions, since CLIC5 and radixin also fail to localise in myosin VI
      mutants. It is not the only mouse bearing on the claim - the independent Clic5-null
      line used in the 2025 gene-therapy study shows the same radixin dependence, and is
      curated separately below.
    limitations: >-
      A protein-null allele produced by exon skipping, against a human spectrum of
      nonsense, splice and missense alleles; the human missense allele in particular has
      residual protein that mislocalises rather than being absent, so it is not
      biochemically equivalent. The molecular partners were characterised partly in chicken
      and rat vestibular tissue rather than in mouse cochlea, so the complex is assembled
      from evidence across three species.
    readouts:
    - name: Radixin immunostaining in hair bundles
      target: Loss of Membrane-Actin Tethering at the Stereocilia Taper
      direction: DECREASED
      interpretation: >-
        The partner protein is lost from the bundle when CLIC5 is absent, which is the
        direct evidence that CLIC5 holds the complex in place.
      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.
    - name: Taper-region localisation of radixin, taperin and PTPRQ
      target: Loss of Membrane-Actin Tethering at the Stereocilia Taper
      direction: ALTERED
      interpretation: >-
        Three partners disperse out of the taper region, two of them before fusion is
        visible, so the complex disassembles first and the structure fails afterwards.
      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.
    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.
  - 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: >-
      The mouse time course is compressed relative to the human one - days to weeks against
      years - so the model reproduces the sequence of events but not their tempo. Whether
      the human loss reflects fusion at all is inference from the shared gene and shared
      progressive phenotype, since no human cochlear histology exists.
    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.
    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.
  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.
  - reference: PMID:24781754
    reference_title: "Progressive hearing loss and vestibular dysfunction caused by a homozygous nonsense mutation in CLIC5."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The orthologous mouse gene is mutated in the jitterbug mutant that exhibits progressive hearing impairment and vestibular dysfunction."
    explanation: >-
      The human authors' own use of the mouse as the prior that made CLIC5 a credible
      candidate, so the model preceded and enabled the human discovery. Graded OTHER
      because the sentence reports neither this human study's clinical data nor a mouse
      experiment it ran - it is a citation of prior mouse work inside a human paper.
- name: Clic5 knockout mouse treated with inner ear AAV
  species: Mouse
  genotype: Clic5 null, homozygous, treated at postnatal day 0 with AAV2/9-PHP.B carrying wild-type Clic5
  publication: PMID:40859056
  description: >-
    A gene-replacement experiment in a Clic5-null line with a well-characterised baseline:
    untreated homozygotes have auditory brainstem response thresholds shifted by about
    40 dB at 4 weeks and no response at 8 weeks, circling behaviour from 4 weeks, and
    cochlear hair cell changes beginning between postnatal days 14 and 17. Utricle
    injection at postnatal day 0 of either a single-stranded or a self-complementary vector
    restored CLIC5 to the base of the stereocilia, normalised radixin localisation,
    prevented fusion and elongation, improved hair cell survival, and rescued auditory and
    vestibular function. The self-complementary vector achieved equivalent rescue at a
    titre an order of magnitude lower.
  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: >-
      The strongest available test of the tethering mechanism, because it runs the
      experiment forwards: restoring the protein restores its partner's localisation and
      prevents the structural failure. That is a stronger claim than any correlation
      between absence and phenotype.
    limitations: >-
      Treatment was given at postnatal day 0, before the mouse lesion begins between
      postnatal days 14 and 17, so this establishes prevention rather than reversal. Human
      DFNB103 is diagnosed after hearing loss has begun, typically around age 8, which is
      the equivalent of treating well after the mouse window has closed - the experiment
      does not address that situation. The rescue was also incomplete and unstable in the
      auditory system: treated thresholds remained significantly worse than controls at
      12 weeks and deteriorated over time, particularly at high frequencies.
    readouts:
    - name: Radixin localisation after CLIC5 restoration
      target: Loss of Membrane-Actin Tethering at the Stereocilia Taper
      direction: RESTORED
      interpretation: >-
        Restoring CLIC5 restores its partner to the taper region, closing the causal loop
        between the adaptor and the complex.
      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.
    - name: Stereocilia morphology after treatment
      target: Loss of Membrane-Actin Tethering at the Stereocilia Taper
      direction: RESTORED
      interpretation: >-
        Bundle morphology is held at normal rather than merely deteriorating more slowly:
        the fusion and elongation that follow loss of the tether do not occur.
      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.
    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.
  - target: Progressive Hair Cell Degeneration
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      The untreated arm characterises the degeneration this node describes, in both the
      cochlea and the utricle, with a defined onset window between postnatal days 14 and
      17 and no abnormality before that.
    limitations: >-
      Only partial with respect to the human disease, because the mouse loses hearing
      entirely by 8 weeks whereas patients decline over one to two decades. The vestibular
      phenotype is also more prominent in the mouse, where circling and hyperactivity are
      the defining behavioural signs, than in patients, where areflexia may be absent and
      is often asymptomatic when present.
    readouts:
    - name: Auditory brainstem response threshold in untreated nulls
      target: Progressive Hair Cell Degeneration
      direction: INCREASED
      interpretation: >-
        Thresholds rise, so the direction is INCREASED even though hearing falls: a shift
        of about 40 dB by four weeks and no response at all by eight, which is the
        untreated trajectory the rescue is measured against.
      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 contrast, Clic5−/− mice exhibited ABR thresholds shifted by ~40 dB at 4 weeks, and no response was detected at 8 weeks"
        explanation: The untreated auditory time course.
    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: "No morphological changes were observed at P14, suggesting that the onset of hair cell defects occurs between P14 and P17"
      explanation: The onset window for the cochlear lesion - nothing at P14, onset after it.
  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: "A key characteristic of the Clic5 mutant mouse phenotype is vestibular dysfunction, which translates to repetitive circling behavior, abnormal head movements, and overall balance dysfunction."
    explanation: >-
      The vestibular behavioural phenotype that makes this line usable for the balance arm
      of the disease as well as the auditory arm.
  - 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: "The ability to rescue auditory and vestibular function in Clic5-deficient mice may indicate potential applicability to humans."
    explanation: >-
      Graded PARTIAL, matching the authors' own hedge. A neonatal prevention experiment in
      mice indicates possibility, not applicability.
discussions:
- discussion_id: clic5_therapeutic_window_timing
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Gene replacement prevents the CLIC5 phenotype when given at birth in mice, before the
    lesion starts. Human DFNB103 is diagnosed on an audiogram at around age 8, after
    stereocilia fusion would already have occurred. Can restoring CLIC5 rescue a bundle
    that has already fused, or only protect one that has not?
  attaches_to:
  - animal_models#Clic5 knockout mouse treated with inner ear AAV
  - pathophysiology#Progressive Stereocilia Fusion and Bundle Distortion
  - treatments#Genetic Counselling with Audiologic and Vestibular Surveillance
  rationale: >-
    The rescue experiment is genuinely encouraging and it does not answer the question a
    patient would ask. Injections were given at postnatal day 0. The cochlear lesion
    begins between postnatal days 14 and 17. So what was demonstrated is that a hair cell
    which has never lost its taper complex can be kept intact, which is a prevention
    result. Nobody has injected a mouse after fusion has begun.

    The human timing makes this the central question rather than a detail. DFNB103 is not
    congenital, hearing is normal or near-normal at birth, and detection is at a mean of
    about 8 years - by which time the equivalent mouse would be long past the treatment
    window used. Any clinical translation therefore depends on an experiment that has not
    been done, and the founder cohort in the Sakha Republic, where the genotype is known
    and the population is identifiable, is exactly the setting where presymptomatic
    genetic diagnosis in infancy would be feasible if the answer turned out to be that
    only prevention works.

    There is a second, more specific worry inside the same result. Vestibular rescue was
    stable to 12 weeks while auditory thresholds deteriorated over the same period even
    though transgene expression remained robust and hair cell morphology looked
    unchanged. Something is failing in the treated cochlea that is neither loss of
    transgene nor visible loss of cells, and until that is understood the durability of
    any human auditory benefit is unpredictable.
  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 authors state plainly that treatment preceded the lesion. That is the mismatch
      with human diagnostic timing.
  - 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.
  - 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: >-
      Rules out the two obvious explanations for the auditory drift, which is what makes it
      an open mechanistic question rather than a technical shortfall.
  - reference: PMID:40859056
    reference_title: "AAV gene therapy rescues hearing and balance in a model of CLIC5 deafness."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Hearing loss in individuals with pathogenic variants in the CLIC5 gene is not congenital but emerges in early childhood, before the second decade of life, while vestibular areflexia, if present, generally develops later"
    explanation: >-
      The human timing that the neonatal mouse experiment does not correspond to. Graded
      OTHER because the sentence is this mouse study restating human findings it cites.
  proposed_experiments:
  - experiment_id: exp_dfnb103_delayed_aav_after_fusion_onset
    name: Delayed AAV delivery after stereocilia fusion has begun
    description: >-
      Deliver the same self-complementary Clic5 vector to Clic5-null mice at postnatal
      days 21 and 42, after fusion is established, with auditory brainstem response,
      distortion product otoacoustic emission, open-field circling and scanning electron
      microscopy at matched endpoints against the postnatal day 0 arm and untreated
      controls. Include a group in which transgene expression is confirmed but bundles are
      imaged before and after to distinguish arrest of progression from structural repair.
    would_support:
    - pathophysiology#Progressive Stereocilia Fusion and Bundle Distortion
    supporting_outcome:
    - >-
      Delayed treatment arrests further threshold loss and stabilises bundle morphology
      relative to untreated nulls, which would mean the tethering defect is continuously
      required and a post-diagnosis human intervention is coherent.
    would_refute:
    - pathophysiology#Progressive Stereocilia Fusion and Bundle Distortion
    refuting_outcome:
    - >-
      Delayed treatment restores CLIC5 protein and partner localisation but changes
      neither thresholds nor bundle morphology, which would mean fusion is irreversible
      once formed and would confine any therapeutic strategy to presymptomatic infants
      identified by genotype.
- 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: >-
    One patient in the founding Turkish family had mild renal dysfunction, and the authors
    were careful to describe the gene as involved in hearing, vestibular and possibly mild
    renal dysfunction rather than asserting the last. That hedge has largely dropped out of
    subsequent descriptions, which now call the disease nonsyndromic without qualification.

    The observation deserves better than to be forgotten, because CLIC5 has an established
    role outside the ear in glomerular podocyte and endothelial cell maintenance. A
    podocyte adaptor protein whose loss produces a membrane-cytoskeletal failure in one
    specialised cell type has an obvious reason to do something similar in another. A
    single patient with mild dysfunction is weak evidence, but it is evidence pointing at a
    mechanism rather than a chance finding.

    What is missing is measurement. Neither the Cameroonian family nor the 22 Siberian
    patients have reported renal assessment, and the Siberian founder cohort is now large
    enough and genotypically homogeneous enough that urinalysis and estimated glomerular
    filtration rate against matched heterozygous relatives would settle the question
    cheaply. If a subclinical renal phenotype exists, DFNB103 patients need monitoring that
    nobody currently offers them; if it does not, the founding hedge can be retired on
    evidence rather than by attrition.
  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: >-
      Graded PARTIAL: a single patient with a mild finding, which is the entire human basis
      for the question.
  - 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 authors' own hedged wording, preserved here because later descriptions drop it
      and the hedge is the accurate statement of what is known.
  - 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: OTHER
    snippet: "The encoded protein associates with actin-based cytoskeletal structures and may play a role in multiple processes including hair cell stereocilia formation, myoblast proliferation, and glomerular podocyte and endothelial cell maintenance."
    explanation: >-
      The biological reason the renal observation is plausible: the same class of
      membrane-cytoskeletal role in a different specialised cell type. Graded OTHER, not
      HUMAN_CLINICAL, because it is background prose summarising prior gene-function
      knowledge - grading it as clinical evidence would imply human podocyte data that
      this gap says does not exist.
📚

References & Deep Research

Deep Research

1
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)
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  • 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)

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  • 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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