| 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 | (pqac-00000004, pqac-00000005) |
| 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 | (pqac-00000004, pqac-00000005, pqac-00000001) |
| 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) | (pqac-00000004, pqac-00000005, pqac-00000000, pqac-00000001) |
| 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 | (pqac-00000005, pqac-00000006, pqac-00000004) |
| 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 | (pqac-00000005, pqac-00000004) |
| 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 | (pqac-00000007, pqac-00000001, pqac-00000000) |
| 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 | (pqac-00000005, pqac-00000007, pqac-00000010) |
| 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) | (pqac-00000004, pqac-00000005, pqac-00000002) |
| 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 | (pqac-00000005, pqac-00000004) |
| 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 | (pqac-00000005, pqac-00000002) |
| 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 | (pqac-00000011, pqac-00000009, pqac-00000000, pqac-00000001) |
| 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 | (pqac-00000005, pqac-00000004, pqac-00000000, pqac-00000001) |


*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.*