| Domain | Key finding | Evidence type | Evidence strength / limitations |
|---|---|---|---|
| Identifiers and nomenclature | **Hearing loss, autosomal dominant 84 (DFNA84)** refers to the ATP11A-associated disorder reported as **autosomal-dominant auditory neuropathy type 2 (AUNA2)**. Historical ATP11A families were mapped to **DFNA33 (13q34)**; DFNA33 and DFNA84/AUNA2 should not be treated as automatically interchangeable disease labels. | Curated disease nomenclature plus human linkage and molecular studies | Strong ATP11A–dominant hearing-loss association, but locus naming is historically inconsistent and should be retained with provenance. The German DFNA33 pedigree was later found to contain improbable haplotype assignments and was not resolved as ATP11A-related (pqac-00000004). |
| Causal lesion in AUNA2/DFNA84 | A heterozygous **5,500-bp germline deletion**, GRCh38 chr13:112877723–112883222, described as **ATP11A c.3327+1782del5500**, removes the alternative terminal coding exons 29a/29b. It causes aberrant use of an alternative last exon while the mutant transcript escapes nonsense-mediated decay (pqac-00000014). | Human four-generation pedigree; linkage, WGS, segregation, patient RNA, and in-vitro functional assays | Strong disease-specific evidence: deletion found at the linked locus and associated with the phenotype; stable biallelic RNA and altered splicing were demonstrated. Published evidence derives principally from one extended family, limiting genotype–phenotype generalization. |
| Human phenotype | Eleven individuals across four generations had predominantly **nonsyndromic, bilateral, symmetric, progressive auditory synaptopathy/neuropathy**. Neurologic examinations did not support generalized hereditary peripheral neuropathy; isolated comorbidities in individual relatives were not shown to be ATP11A manifestations (pqac-00000013, pqac-00000014). | Human family phenotyping | Strong for the core auditory phenotype within the pedigree; small sample and single-family ascertainment preclude reliable estimates of rare extracochlear manifestations. |
| Audiologic trajectory | Hearing can appear normal in the first decade although ABR is already abnormal. Typical recognized onset is **10–20 years**, initially affecting middle/high frequencies; loss becomes moderate in the third–fourth decades and can progress across all frequencies to severe/profound loss by approximately 40–50 years or later. TEOAEs are initially preserved and commonly disappear only with severe loss; ABR is abnormal or absent, and speech recognition declines with severity (pqac-00000013, pqac-00000014). | Serial and cross-sectional pure-tone audiometry, monosyllabic speech testing, TEOAE, cochlear microphonics, ABR, and cortical evoked potentials | Detailed disease-specific physiologic evidence. The available observations do not yield a validated annual threshold-shift rate or population-level penetrance estimate. |
| Quantitative audiology | At ages 7–16 years, hearing ranged from normal/abnormal to mild loss with speech recognition of **60–95%**, while ABR could already be pathologic or absent. At ages 38–41, moderate loss accompanied speech recognition of **0–42%** unaided; at ages 46–73, severe/profound loss accompanied **0%** unaided recognition. Hearing aids produced variable, generally limited gains (pqac-00000013, pqac-00000014). | Human clinical testing | Valuable within-family natural-history data, but based on approximately ten tested relatives at different ages rather than a prospective longitudinal cohort. |
| Molecular mechanism | ATP11A is a plasma-membrane P4-ATPase that, with the β-subunit CDC50A, flips phosphatidylserine and phosphatidylethanolamine from the exoplasmic to cytoplasmic leaflet. The AUNA2 mutant protein reached the plasma membrane normally but showed markedly diminished phosphatidylserine transport, supporting functional loss rather than trafficking failure (pqac-00000008, pqac-00000018, pqac-00000022). | Patient-informed HEK293/HEK293T expression, immunocytochemistry, surface biotinylation, and fluorescent-lipid uptake assay | Direct evidence for reduced mutant flippase activity. Downstream disruption of membrane stability, vesicle cycling, calcium handling, synaptic function, apoptosis, or phagocytic removal of auditory cells remains biologically plausible but substantially inferred rather than demonstrated in human cochlea (pqac-00000027, pqac-00000029). |
| Supporting ATP11A allelic families | A 2022 study reported a Newfoundland family and two Jewish Israeli families with variable bilateral progressive SNHL and distinct 3′ ATP11A variants, including **c.3322_3327+2dupGTCCAGGT**, predicted **p.Asn1110ValfsTer43**, and a cryptic-donor variant causing 153-bp intron retention. These were published under **DFNA33**, not as the original AUNA2/DFNA84 pedigree (pqac-00000001, pqac-00000002, pqac-00000006). | Human linkage/WGS, segregation, RT-PCR, cloning, Sanger sequencing, and minigene testing | Moderate-to-strong allelic support that ATP11A disruption causes dominant progressive hearing loss. Phenotypes were described as SNHL rather than fully documented auditory neuropathy, and some transcript/isoform consequences remained unresolved. |
| 2025 zebrafish model | CRISPR loss-of-function **atp11a** zebrafish with 5-bp or 7-bp deletions showed fewer stereocilia and inner-ear hair cells, including abnormalities in maculae and cristae, plus fewer cells in an otic neuromast. Reported stereocilia-analysis groups were wild type **n=17**, heterozygous **n=22**, and homozygous **n=7** (pqac-00000025). | ATP11A-specific vertebrate loss-of-function model | Strong support for a conserved requirement in ear/hair-cell maintenance, but it does not reproduce the exact human deletion or establish whether human disease is primarily hair-cell, synaptic, or neural. Homozygous fish effects may exceed those of heterozygous human disease. |
| Diagnosis | Confirm auditory neuropathy physiology using pure-tone and speech audiometry together with **ABR** and preserved **OAE and/or cochlear microphonics**, recognizing that emissions may disappear in advanced disease. Molecular evaluation should use a comprehensive hearing-loss panel with validated CNV/SV detection or WGS; suspected ATP11A variants require segregation and, where relevant, RNA/minigene studies because terminal-exon, intronic, and structural lesions can evade routine exome analysis (pqac-00000013, pqac-00000014, pqac-00000024, pqac-00000026). | Disease-specific audiology and genomic case-discovery evidence; standard clinical-genetics extrapolation | Strong rationale for combined physiologic and genomic testing. No ATP11A-specific diagnostic criteria, biochemical biomarker, or clinically validated RNA assay exists. |
| Treatment and trials | No approved disease-modifying ATP11A therapy and no ATP11A-targeted clinical trial were identified. Management is supportive: serial audiology, communication accommodations, speech/hearing rehabilitation, appropriately fitted hearing aids, and cochlear-implant evaluation when functional benefit is inadequate. In the reported family, hearing aids gave little benefit and three relatives met implantation criteria, but none had been implanted at assessment (pqac-00000013, pqac-00000014). | Human family experience plus general auditory-neuropathy practice | Disease-specific treatment evidence is very weak: there are no ATP11A pharmacotherapy, cochlear-implant outcome, gene-therapy, RNA-therapy, or editing trials. Proposed targeting of exposed phosphatidylserine remains speculative and preclinical (pqac-00000023). |
| Epidemiology and inheritance gaps | Transmission is autosomal dominant, implying a **50% recurrence risk** to each child of a heterozygous affected person. Disease-specific prevalence, incidence, carrier frequency, sex ratio, measured penetrance, de-novo rate, anticipation, germline mosaicism, and confirmed founder frequency are unavailable. A 99% penetrance value used in linkage analysis was a modeling assumption, not an empirical estimate (pqac-00000006). | Mendelian inference and sparse family reports | Inheritance pattern is strong; all population estimates are absent. Reported Newfoundland, Israeli, and German pedigrees cannot be used to calculate population prevalence or ethnic risk. |


*Table: Compact evidence appraisal for ATP11A-associated AUNA2/DFNA84, separating direct human and model findings from allelic support, clinical extrapolation, and unresolved nomenclature or epidemiology.*