| Domain | Established finding | Evidence type | Suggested ontology identifiers | Confidence / gap |
|---|---|---|---|---|
| Identity | Autosomal recessive nonsyndromic hearing loss 31 (DFNB31) is a Mendelian sensorineural hearing-loss disorder caused by biallelic **WHRN** variants. (pqac-00000000, pqac-00000004) | Aggregated disease–target resources; human genetic studies | **MONDO:0011767**; OMIM phenotype label: DFNB31; MeSH label: Hearing Loss, Sensorineural | High confidence for gene–disease relationship; dedicated ICD-10/ICD-11 codes are unavailable. |
| Core phenotype | Usually bilateral, congenital or prelingual, severe-to-profound sensorineural hearing loss; the canonical DFNB31 description emphasizes profound hearing loss with normal vision. (pqac-00000007) | Human pedigrees and literature synthesis | HPO: Sensorineural hearing impairment; Bilateral sensorineural hearing impairment; Congenital onset; Profound hearing impairment; Absent speech or delayed speech-and-language development | High confidence for hearing loss; exact frequencies and longitudinal progression rates are poorly quantified because reported cohorts are small. |
| Gene and protein | **WHRN** encodes whirlin, a cytoskeletal scaffolding protein with PDZ domains and a proline-rich region; the gene is located on chromosome 9q32–q34. (pqac-00000004, pqac-00000014) | Human genetics; molecular studies | HGNC label: WHRN; UniProt label: Whirlin; GO label: protein-containing complex scaffold activity | High confidence; transcript numbering and historical use of *DFNB31* as a gene symbol can complicate variant normalization. |
| Isoforms | Principal products include full-length whirlin with three PDZ domains, C-terminal whirlin containing the proline-rich region and PDZ3, and N-terminal forms containing PDZ1 and/or PDZ2. (pqac-00000001, pqac-00000004, pqac-00000007) | Mouse tissue expression, proteomics and molecular localization | Protein isoform labels: full-length whirlin, N-terminal whirlin, C-terminal whirlin; GO label: alternative mRNA splicing | High confidence in mice; exact expression and functional equivalence of every human transcript remain incompletely resolved. |
| Molecular mechanism | Loss of tip-localized whirlin disrupts the **MYO15A–WHRN–EPS8** elongation complex, leading to abnormally short and disorganized actin-rich stereocilia and impaired hair-cell mechanosensation. (pqac-00000001, pqac-00000002, pqac-00000003) | Biochemical interaction, localization and mouse-mutant evidence | GO: stereocilium organization; actin filament organization; sensory perception of sound; mechanosensory behavior; auditory receptor-cell stereocilium | High mechanistic confidence in model organisms; the complete causal sequence has not been directly observed in living human cochleae. |
| Anatomy and cell types | Primary disease sites are the cochlea and organ of Corti, particularly inner and outer hair-cell stereociliary bundles; whirlin also occurs in vestibular hair cells and, in long-isoform disease, photoreceptor periciliary regions. (pqac-00000001, pqac-00000003, pqac-00000005) | Mouse immunolocalization and functional studies | UBERON labels: cochlea, organ of Corti, inner ear, vestibular organ, retina; CL labels: inner hair cell, outer hair cell, vestibular hair cell, retinal photoreceptor cell; GO label: stereocilium | High confidence for cochlear localization; human vestibular involvement in isolated DFNB31 is insufficiently characterized. |
| Inheritance | Biallelic germline pathogenic variants produce autosomal recessive disease; heterozygous parents are generally clinically unaffected under the established human model. | Human segregation studies and Mendelian disease curation | HPO: Autosomal recessive inheritance; GENO label: germline allele | High confidence; penetrance is presumed high for severe biallelic loss-of-function genotypes, but formal penetrance estimates and verified human modifier genes are unavailable. |
| Pathogenic variants | Reported DFNB31-associated C-terminal truncating alleles include **p.Arg778Ter (R778X)** and **p.Gly808AspfsTer11 (G808DfsX11)**; pathogenic WHRN alleles also include other nonsense, frameshift and splice-disrupting variants. (pqac-00000006, pqac-00000007) | Human pedigrees, segregation and model comparison | Sequence Ontology labels: stop gained, frameshift variant, splice-region/splice-donor/splice-acceptor variant; ClinVar classification labels: pathogenic or likely pathogenic when criteria are met | Variant-level confidence must be assessed individually using current ClinVar/ACMG evidence, segregation and population frequency; no single founder allele explains most cases globally. |
| Distinction from USH2D | C-terminal variants that preserve a functional retinal N-terminal product tend to cause isolated DFNB31, whereas N-terminal variants disrupting full-length whirlin in ear and retina tend to cause moderate-to-severe hearing loss plus retinitis pigmentosa (USH2D). This is a useful but nonabsolute isoform-based correlation. (pqac-00000002, pqac-00000004, pqac-00000006, pqac-00000007) | Human genotype–phenotype observations plus allele-specific mouse models | MONDO label: Usher syndrome type 2D; HPO: Retinitis pigmentosa, Rod-cone dystrophy, Visual-field defect | Moderate confidence rather than a deterministic rule; retinal surveillance remains prudent after a WHRN diagnosis, especially for N-terminal or uncertain alleles. |
| Diagnosis | Confirm sensorineural hearing loss with newborn screening followed by diagnostic ABR, otoacoustic emissions and age-appropriate behavioral/pure-tone audiometry; establish etiology using a comprehensive hearing-loss panel including **WHRN**, with CNV analysis and segregation. Exome or genome sequencing is appropriate when panel testing is negative. | Standard genetic-hearing-loss practice; targeted sequencing studies; expert curation | LOINC labels: auditory brainstem response, otoacoustic emissions, pure-tone audiometry; NCIT labels: Genetic Testing, Whole Exome Sequencing, Whole Genome Sequencing | High confidence for the general workflow; no WHRN-specific biochemical biomarker, biopsy, metabolomic or epigenomic diagnostic is validated. |
| Additional evaluation | Ophthalmic history and baseline examination, with fundus imaging/OCT and electroretinography when indicated, help exclude evolving USH2D; vestibular testing is reasonable for imbalance or delayed motor milestones because mouse mutants show vestibular dysfunction. (pqac-00000005, pqac-00000012) | Human syndromic differential diagnosis; mouse vestibular evidence | HPO: Vestibular dysfunction, Abnormal electroretinogram; NCIT labels: Electroretinography, Optical Coherence Tomography, Vestibular Function Test | Retinal evaluation is clinically important; routine vestibular screening specifically for DFNB31 lacks disease-specific outcome data. |
| Current treatment | No approved WHRN-directed pharmacotherapy exists. Management uses hearing aids when residual hearing is aidable, cochlear implantation for severe-to-profound loss with inadequate aided benefit, and early speech-language, auditory-verbal or sign-language intervention. | Standard-of-care extrapolation from congenital genetic sensorineural hearing loss | NCIT labels: Hearing Aid, Cochlear Implantation, Speech Therapy, Auditory Rehabilitation | Strong general clinical support, but no DFNB31-specific controlled response rates or genotype-based implantation thresholds are available. |
| Experimental AAV8 therapy | Neonatal round-window delivery of AAV8 carrying 2,724-bp long **Whrn** cDNA restored whirlin expression, stereociliary length/bundle architecture and inner-hair-cell survival in whirler mice; however, it did **not** improve ABR hearing sensitivity at tested frequencies. Adult treatment did not restore stereociliary length or row number. (pqac-00000009, pqac-00000010, pqac-00000013) | Preclinical mouse gene-supplementation experiment | NCIT labels: Gene Therapy, Recombinant Adeno-Associated Viral Vector; NCBI Taxon: *Mus musculus*; GO label: stereocilium organization | Morphological rescue is reproducible evidence of target engagement, but functional efficacy was absent; there is no WHRN-targeted human clinical trial or approved therapy. |
| Epidemiology | Disease-specific prevalence, incidence, carrier frequency, sex ratio and geographic distribution have not been robustly estimated; WHRN appears to account for only a very small fraction of genetically diagnosed recessive hearing loss. | Rare-family reports and heterogeneous sequencing cohorts | Orphan disease label; epidemiology terms without disease-specific numerical identifiers | Major evidence gap: do not substitute prevalence estimates for all congenital hearing loss, all ARNSHL or Usher syndrome as DFNB31-specific statistics. |


*Table: Knowledge-base-ready summary of established WHRN-related DFNB31 findings, ontology mappings, evidence types, and major uncertainties. It separates isolated hearing loss from USH2D and morphological AAV8 rescue from functional hearing recovery.*