| domain | evidence-based finding | ontology/identifier suggestions | evidence level/limitations |
|---|---|---|---|
| Disease identity | Autosomal Dominant Nonsyndromic Hearing Loss 41 (DFNA41) is a rare Mendelian hearing-loss subtype defined from aggregated disease-level and pedigree-based human genetics data; OMIM identifier reported as 608224 (pqac-00000013, pqac-00000014) | OMIM: 608224; MONDO: not established from retrieved evidence; MeSH/ICD/Orphanet not confirmed in retrieved sources | Human primary evidence for disease existence and mapping; some cross-database identifiers unavailable in retrieved context |
| Causal gene/variant | The best-supported causal lesion is heterozygous P2RX2 c.178G>T, p.Val60Leu (p.V60L; NM_174873), identified in two unrelated Chinese families and absent from >7,000 controls (pqac-00000014) | P2RX2; HGNC gene symbol: P2RX2; variant: c.178G>T, p.Val60Leu | Human primary evidence is strong for this variant; broader allelic spectrum was not directly resolved from retrieved full primary reports |
| Inheritance | Inheritance is autosomal dominant with perfect cosegregation in the index pedigree, LOD score 13.3, and 100% penetrance among reported heterozygous carriers (pqac-00000014) | HP:0000006 Autosomal dominant inheritance | Human pedigree evidence strong, but penetrance estimate is based on a small number of families |
| Core phenotype | Affected individuals have bilateral, symmetrical, progressive sensorineural hearing loss, first detected at 12-20 years, ultimately involving all frequencies; severity reached about 60-70 dB by age 20 in the original family (pqac-00000013, pqac-00000014) | HP:0008619 Progressive hearing impairment; HP:0000407 Sensorineural hearing impairment; HP:0011453 Bilateral hearing impairment | Human primary evidence; natural-history estimates remain limited because only a few families are published |
| Audiometric pattern/symptoms | Hearing loss is typically high-frequency early, with high-frequency tinnitus reported; occupational noise exposure worsened high-frequency thresholds in mutation carriers (n=12 exposed vs n=9 unexposed, P=0.001) (pqac-00000013, pqac-00000014) | HP:0000366 Hearing impairment; HP:0000358 Tinnitus; HP:0001644 Dilated? not applicable; no exact HPO for noise susceptibility confirmed here | Human evidence for tinnitus/noise interaction comes from small family-based comparisons |
| Gene-environment interaction | DFNA41 shows a documented gene-environment interaction: moderate noise exposure exacerbates hearing loss in carriers, indicating increased susceptibility to noise-induced hearing loss (pqac-00000013, pqac-00000014, pqac-00000006) | Exposure concept: occupational noise; phenotype concept: noise-induced hearing loss susceptibility | Human evidence present but based on observational family histories rather than prospective exposure studies |
| Molecular function | P2X2 is an extracellular ATP-gated trimeric cation channel expressed in cochlear sensory and supporting tissues; the p.V60L change abolishes ATP-evoked inward current in homomeric channels and impairs permeability in heteromeric channels (pqac-00000013, pqac-00000014, pqac-00000008) | GO:0005230 extracellular ligand-gated ion channel activity; GO:0006811 ion transport | Human/in vitro evidence strong for loss of channel function; detailed downstream pathway mapping remains incomplete |
| Pathomechanism | The mutant receptor localizes to plasma membrane but is functionally defective, supporting a loss-of-function/gating defect rather than mislocalization; inferred disease chain is impaired purinergic cochlear adaptation and reduced protection from noise/age-related stress (pqac-00000002, pqac-00000008) | GO:0007166 cell surface receptor signaling pathway; GO:0050890 cognition? not applicable; inferred cochlear homeostasis terms | Mixed evidence: human cell assays plus model inference; some mechanistic steps remain inferred rather than directly proven in patients |
| Anatomy/cell types | P2X2 expression/localization has been shown in organ of Corti, inner and outer hair cells, supporting cells, spiral ganglion neurons, and epithelial lining of the cochlea; mouse KI work also found expression in crista ampullaris (pqac-00000015, pqac-00000011, pqac-00000013) | UBERON: cochlea, organ of Corti; CL: hair cell, supporting cell, spiral ganglion neuron | Primarily model/histologic evidence; exact human single-cell localization was not retrieved |
| Diagnostics | Recommended diagnosis is clinical audiologic assessment plus molecular confirmation by hearing-loss gene panel, WES, or targeted P2RX2 testing in the setting of dominant postlingual progressive SNHL and family history; temporal bone CT can be normal (pqac-00000014, pqac-00000020) | NCIT: Genetic Testing; audiology concepts: ABR/audiometry as applicable | Human evidence supports genetic confirmation; no DFNA41-specific formal guideline was retrieved |
| Current treatment | Current management is supportive: longitudinal audiologic follow-up, strict noise avoidance/protection, hearing aids, cochlear implantation when severity/function warrant it, and rehabilitation/genetic counseling (pqac-00000020, pqac-00000016) | NCIT: Hearing Aid Device; NCIT: Cochlear Implantation; NCIT: Genetic Counseling | Largely inferred from standard care for dominant progressive SNHL; no DFNA41-specific interventional outcome series retrieved |
| Approved therapies/trials | No approved molecular therapy specific to DFNA41 was identified, and no relevant registered interventional clinical trial was retrieved in the tool search (pqac-00000020) | NCIT: Gene Therapy (experimental only) | Evidence reflects search results, not proof of global absence; trial landscape can change rapidly |
| Mouse models | P2rx2-null mice develop progressive hearing loss and greater noise vulnerability; the P2rx2 V61L knock-in mouse recapitulates DFNA41-related auditory disease, with hearing loss beginning at postnatal day 21 and progressing to deafness by 6 months, plus vestibular dysfunction and inner hair cell/ribbon synapse abnormalities (pqac-00000001, pqac-00000005, pqac-00000012, pqac-00000015) | MGI mouse P2rx2 models; phenotype terms: hearing loss, vestibular dysfunction | Strong model evidence; disease onset is earlier and progression faster than in humans |
| Cellular models | Patient-derived non-integrative hiPSCs from urine samples and CRISPR-engineered homozygous/heterozygous P2RX2 p.V60L hiPSC lines were generated as mechanistic models for hereditary hearing loss (pqac-00000017) | iPSC disease model; P2RX2-mutated hiPSC | In vitro model only; no therapeutic efficacy in humans demonstrated |
| Recent translational development | A 2025 preclinical study used AAV2-delivered SaCas9/sgRNA allele-specific editing in adult P2rx2V61L/+ mice, with efficient mutant-selective editing, minimal detected off-target effects, no notable AAV integration in cochlear hair cells, and rescue of long-term auditory/vestibular function plus protection from noise hypersensitivity (pqac-00000020, pqac-00000019, pqac-00000018) | NCIT: CRISPR-Cas9 Genome Editing; NCIT: Adeno-Associated Virus Vector | Model-only, post-2024 preclinical evidence; not yet a human therapy or clinical trial |
| Evidence gaps | No robust disease-specific prevalence/incidence, survival, mortality, protective genetic modifiers, epigenetic biomarkers, or validated prognostic biomarkers were found in retrieved evidence (pqac-00000013, pqac-00000020) | Knowledge-base flag: data not available | Important to distinguish absence of evidence from evidence of absence |


*Table: This table condenses the most actionable evidence on DFNA41 across identity, genetics, phenotype, mechanism, diagnosis, treatment, and models. It distinguishes human primary findings from model-based and inferred information to support knowledge-base curation.*