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Hearing Loss Autosomal Dominant 84

Hearing Loss, Autosomal Dominant 84 (DFNA84): Disease-Characteristics Report

2026-09-04
Falcon MONDO:0030724 Model: Edison Scientific Literature 16 citations Prompt: disease_pathophysiology_research.md 1e7ea4ee817a

Hearing Loss, Autosomal Dominant 84 (DFNA84): Disease-Characteristics Report

Target category: rare Mendelian, autosomal-dominant hearing disorder
Core gene: ATP11A, encoding ATPase phospholipid-transporting 11A, a P4-type phospholipid flippase
Evidence cutoff: literature retrieved through 2025, with emphasis on 2023–2024 evidence. Because this is an exceptionally rare disorder, most disease-specific knowledge comes from one extended family, supplemented by allelic ATP11A families and model systems.

Executive summary and nomenclature caution

Hearing loss, autosomal dominant 84 is best understood as the ATP11A-associated disorder originally phenotyped as AUNA2, a slowly progressive, nonsyndromic auditory synaptopathy/auditory neuropathy. The defining pedigree contained 11 affected people over four generations. Hearing may appear normal in the first decade even though auditory-brainstem responses (ABRs) are already abnormal; clinically recognized loss usually begins at 10–20 years, initially affects middle and high frequencies, and can progress to severe or profound pan-frequency loss in later adulthood. Otoacoustic emissions (OAEs) and cochlear microphonics may initially be preserved but deteriorate in advanced disease (loh2021atp11acausesautosomaldominanta pages 22-25, loh2021atp11acausesautosomaldominanta pages 25-29).

A major curation issue is that other dominant ATP11A-associated families were published under the historical DFNA33 locus. Those families provide allelic support for ATP11A-related progressive hearing loss, but should not automatically be relabeled as the original DFNA84/AUNA2 pedigree. A 2023 reanalysis also found improbable haplotype assignments in the original German DFNA33 pedigree and did not resolve that family as ATP11A-related (pater2022autosomaldominantnonsyndromic pages 9-11, vona2023unravelinghaplotypeerrors pages 2-4).

The evidence base is summarized below.

Table (click to expand)
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 (vona2023unravelinghaplotypeerrors pages 2-4).
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 (loh2021atp11acausesautosomaldominanta pages 25-29). 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 (loh2021atp11acausesautosomaldominanta pages 22-25, loh2021atp11acausesautosomaldominanta pages 25-29). 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 (loh2021atp11acausesautosomaldominanta pages 22-25, loh2021atp11acausesautosomaldominanta pages 25-29). 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 (loh2021atp11acausesautosomaldominanta pages 22-25, loh2021atp11acausesautosomaldominanta pages 25-29). 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 (loh2021atp11acausesautosomaldominanta pages 1-7, loh2021atp11acausesautosomaldominanta pages 83-88, loh2021atp11acausesautosomaldominant pages 135-139). 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 (loh2021atp11acausesautosomaldominanta pages 135-139, loh2021atp11acausesautosomaldominant pages 123-126).
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 (pater2022autosomaldominantnonsyndromic pages 9-11, pater2021autosomaldominantnonsyndromic pages 1-5, pater2021autosomaldominantnonsyndromic pages 5-7). 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 (hawkeynoble2025thep4phospholipidflippase pages 14-18). 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 (loh2021atp11acausesautosomaldominanta pages 22-25, loh2021atp11acausesautosomaldominanta pages 25-29, pater2021autosomaldominantnonsyndromic pages 7-10, pater2019amultiomicapproach pages 154-158). 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 (loh2021atp11acausesautosomaldominanta pages 22-25, loh2021atp11acausesautosomaldominanta pages 25-29). 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 (pater2021autosomaldominantnonsyndromic pages 10-13).
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 (pater2021autosomaldominantnonsyndromic pages 5-7). 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.

1. Disease information

Definition

DFNA84/AUNA2 is a rare, postlingual, progressive, usually bilateral and symmetric sensorineural hearing disorder in which electrophysiology indicates impaired synchronous signaling at the inner-hair-cell synapse, spiral-ganglion neuron, or auditory nerve. It is described as nonsyndromic because generalized hereditary peripheral neuropathy or a reproducible extracochlear syndrome was not demonstrated in the defining family (loh2021atp11acausesautosomaldominanta pages 22-25, loh2021atp11acausesautosomaldominanta pages 25-29).

Identifiers and synonyms

  • Preferred label: Hearing loss, autosomal dominant 84.
  • Common symbols/names: DFNA84, AUNA2, autosomal-dominant auditory neuropathy type 2, ATP11A-related autosomal-dominant auditory synaptopathy/auditory neuropathy, ATP11A-related dominant nonsyndromic hearing loss.
  • Gene: ATP11A, chromosome 13q34.
  • Historical locus requiring provenance: DFNA33, OMIM 614211, was the locus label used in the 2022 ATP11A study; it is not necessarily synonymous with DFNA84 (pater2021autosomaldominantnonsyndromic pages 1-5, vona2023unravelinghaplotypeerrors pages 2-4).
  • OMIM/MONDO/Orphanet: The retrieved primary texts did not provide a reliably verifiable disease-entry number for DFNA84 or a dedicated MONDO/Orphanet identifier. A knowledge base should therefore map the disease label to ATP11A and retain AUNA2/DFNA84/DFNA33 assertions with source-specific provenance rather than infer an unverified identifier.
  • ICD-10/ICD-11/MeSH: There is no disease-specific billing code. Broader coding falls under sensorineural hearing loss or auditory neuropathy, with laterality and severity recorded separately.

The evidence is predominantly aggregated disease-level research data from pedigrees, audiological examinations, genomic studies, patient-derived RNA, and experimental cells—not routine EHR-derived individual-patient data.

2. Etiology

Causal factor

The initiating cause is a heterozygous germline ATP11A lesion. In the defining AUNA2 pedigree, WGS identified a 5,500-bp deletion at GRCh38 chr13:112877723–112883222, described as c.3327+1782del5500, removing alternative terminal coding exons 29a and 29b. The deletion produces aberrant terminal-exon use, but the mutant transcript remains stable rather than undergoing nonsense-mediated decay (loh2021atp11acausesautosomaldominanta pages 25-29, loh2021atp11acausesautosomaldominant pages 135-139).

Supporting dominant ATP11A alleles reported in other families include:

Risk factors

  • Genetic: A pathogenic heterozygous ATP11A allele and a positive autosomal-dominant family history are the principal known risk factors.
  • Environmental: Noise, ototoxic drugs, infections, and aging can independently worsen hearing, but no ATP11A-specific gene–environment interaction has been demonstrated.
  • Sex, lifestyle, occupational, infectious, or dietary risks: No disease-specific associations are known.

Protective factors

No protective ATP11A variants, modifier alleles, diets, drugs, or environmental exposures have been established. Hearing conservation—avoiding hazardous noise and unnecessary ototoxic medication—is prudent tertiary prevention but has not been shown to alter the genetic disease’s natural history.

3. Phenotypes

Core phenotypes and suggested HPO annotations

  1. Progressive sensorineural hearing impairment — HP:0000407, with progressive hearing impairment HP:0001730. Usually bilateral and symmetric; initially middle/high-frequency, later extending across frequencies. Severity ranges from normal behavioral thresholds in childhood to profound loss in older adults (loh2021atp11acausesautosomaldominanta pages 22-25, loh2021atp11acausesautosomaldominanta pages 25-29).
  2. Postlingual hearing impairment — HP:0008615. Typical recognized onset is 10–20 years, although electrophysiological abnormalities may precede symptoms (loh2021atp11acausesautosomaldominanta pages 25-29).
  3. Auditory neuropathy spectrum disorder — use the current HPO auditory-neuropathy term where available; operational phenotype is absent/pathologic ABR with initially preserved OAE and/or cochlear microphonics (loh2021atp11acausesautosomaldominanta pages 22-25).
  4. Abnormal auditory brainstem response — HP:0006958. In the family, ABR was absent or severely abnormal in most tested relatives, sometimes before measurable hearing loss (loh2021atp11acausesautosomaldominanta pages 22-25).
  5. Impaired speech discrimination — annotate with an HPO term for impaired speech discrimination/word recognition if supported by the deployed HPO release. Unaided monosyllabic recognition fell from 60–95% at ages 7–16 to 0–42% at ages 38–41 and 0% in several people aged 46–73 (loh2021atp11acausesautosomaldominanta pages 22-25, loh2021atp11acausesautosomaldominanta pages 25-29).
  6. Preserved then lost otoacoustic emissions. TEOAEs were detectable with normal through moderate loss and generally disappeared in severe/profound stages; this is a temporal biomarker rather than an invariant phenotype (loh2021atp11acausesautosomaldominanta pages 22-25, loh2021atp11acausesautosomaldominanta pages 25-29).

Frequency and severity

The core auditory phenotype occurred in all 11 clinically affected relatives in the defining pedigree. Exact population frequencies cannot be inferred. One seven-year-old had normal pure-tone hearing but pathological ABR; a ten-year-old had mild loss, 90% unaided recognition and absent ABR at 85 dB; a 38-year-old had moderate loss but only 15% word recognition; adults aged 46–73 had severe/profound loss and 0% unaided recognition (loh2021atp11acausesautosomaldominanta pages 22-25).

Quality-of-life impact

Disease-specific EQ-5D, SF-36, PROMIS, or hearing-quality-of-life scores have not been reported. Expected burdens include difficulty understanding speech—especially in noise—reduced educational or occupational communication, social isolation, and reliance on visual or assistive communication. In auditory neuropathy, temporal dyssynchrony can impair speech perception disproportionately to pure-tone thresholds (loh2021atp11acausesautosomaldominanta pages 19-22).

4. Genetic and molecular information

Gene and protein

ATP11A encodes a catalytic P4-ATPase α-subunit that partners with CDC50A/TMEM30A and uses ATP to translocate phosphatidylserine (PS) and phosphatidylethanolamine (PE) from the exoplasmic/luminal leaflet to the cytoplasmic leaflet, maintaining membrane-lipid asymmetry (loh2021atp11acausesautosomaldominanta pages 1-7, loh2021atp11acausesautosomaldominanta pages 29-32).

Suggested annotations include GO:0004012 phospholipid-translocating ATPase activity, GO:0045332 phospholipid translocation, GO:0097035 regulation of membrane lipid distribution, GO:0005886 plasma membrane, and GO:0016020 membrane; term identifiers should be checked against the current GO release before ingestion.

Variant mechanism

The defining deletion is germline and heterozygous. Patient RNA showed biallelic expression and aberrant splicing rather than simple transcript destruction. In HEK293/HEK293T assays, mutant ATP11A still reached the plasma membrane in a CDC50A-dependent manner but had markedly diminished PS-flipping activity, close to loss-of-function controls. The evidence therefore supports functional loss/hypomorphic activity, while dominant-negative action has not been excluded in the relevant cochlear cells (loh2021atp11acausesautosomaldominanta pages 83-88, loh2021atp11acausesautosomaldominant pages 135-139, loh2021atp11acausesautosomaldominanta pages 135-139).

Population frequency and ACMG classification

The defining 5.5-kb deletion was discovered by WGS and segregated with disease; a precise gnomAD-SV frequency was not supplied in the retrieved evidence. The Newfoundland cryptic-donor variant was absent from local controls and from 202 additional Newfoundland hearing-loss probands. The exon-28 duplication was classified as pathogenic in the 2022 study. By contrast, c.1221+5G>C remained a VUS in 2025 despite in-silico splice predictions and limited segregation information (pater2021autosomaldominantnonsyndromic pages 5-7, rosso2025unravelingthefunctional pages 5-7).

Modifiers, epigenetics, and chromosomal abnormalities

No validated modifier gene, epigenetic signature, anticipation mechanism, aneuploidy, translocation, or inversion is known. The causal 5.5-kb deletion is a submicroscopic structural variant, not a cytogenetically visible chromosomal abnormality.

5. Environmental information

No toxin, radiation exposure, pollutant, lifestyle factor, or infectious organism causes DFNA84. General hearing-health factors—unsafe noise, aminoglycosides, platinum chemotherapy, severe infections, and aging—may add independent cochlear injury, but ATP11A-specific interaction data are absent. The disorder is not infectious, contagious, or immune-mediated.

6. Mechanism and pathophysiology

Ordered causal chain

  1. A heterozygous terminal ATP11A deletion leads to aberrant terminal-exon splicing while allowing stable mutant RNA.
  2. Aberrant RNA results in an altered ATP11A C-terminus and reduced functional phospholipid-flippase activity.
  3. Reduced ATP11A activity leads to deficient inward translocation of PS, and possibly PE, at the plasma membrane; reduced PS transport is demonstrated in transfected cells (loh2021atp11acausesautosomaldominanta pages 1-7, loh2021atp11acausesautosomaldominant pages 135-139).
  4. Deficient lipid transport results in impaired membrane-lipid asymmetry. In inner-ear cells, this step is strongly biologically supported but not directly demonstrated in human tissue.
  5. Altered membrane asymmetry is inferred to lead to one or more branches:
    (a) disturbed synaptic vesicle exocytosis/endocytosis and Ca²⁺ handling at inner-hair-cell ribbon synapses;
    (b) altered membrane stability, stereociliary maintenance, and hair-cell survival;
    (c) externalized PS acting as an “eat-me” signal, promoting inappropriate phagocytic clearance or apoptosis;
    (d) impaired spiral-ganglion neurite maintenance or auditory-nerve synchrony (pater2021autosomaldominantnonsyndromic pages 10-13, loh2021atp11acausesautosomaldominant pages 123-126).
  6. Synaptic/neural dysfunction leads to abnormal or absent ABR despite initially preserved OAE/cochlear microphonics.
  7. Progressive cellular dysfunction or loss results in worsening speech discrimination, middle/high-frequency threshold elevation, later OAE loss, and ultimately severe/profound hearing impairment (loh2021atp11acausesautosomaldominanta pages 22-25, loh2021atp11acausesautosomaldominanta pages 25-29).

Upstream versus downstream evidence

The upstream sequence—structural variant, aberrant splicing, stable mutant protein, preserved membrane localization, and reduced PS transport—is experimentally supported. The exact downstream lesion in humans remains unresolved: the clinical physiology favors a synaptic/neural disorder, whereas zebrafish loss-of-function data demonstrate stereocilia and hair-cell abnormalities. Thus ATP11A deficiency may affect several cochlear compartments or shift from neural/synaptic dysfunction to secondary sensory-cell degeneration with age (loh2021atp11acausesautosomaldominant pages 135-139, hawkeynoble2025thep4phospholipidflippase pages 14-18).

Suggested biological-process terms include phospholipid translocation, establishment of membrane asymmetry, auditory receptor-cell maintenance, synaptic vesicle cycling, calcium-ion homeostasis, apoptotic signaling, neuron-projection maintenance, and sensory perception of sound. Suggested cell terms are inner hair cell, outer hair cell, Deiters cell, spiral ganglion neuron, and auditory sensory neuron. No DFNA84-specific immune, metabolic, methylomic, proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, or multi-omic disease signature has been established.

7. Anatomical structures affected

  • Primary organ/system: inner ear and auditory system; suggested UBERON:0001846 inner ear and UBERON:0002240 cochlea.
  • Key tissue: organ of Corti; suggested UBERON:0002227 if confirmed in the current release.
  • Likely cells: cochlear inner and outer hair cells, Deiters supporting cells, spiral-ganglion neurons, and auditory/vestibular ganglion neurons. Mouse expression supports these locations, but does not prove which cell initiates human disease (pater2021autosomaldominantnonsyndromic pages 10-13).
  • Subcellular compartment: ATP11A–CDC50A complex at the plasma membrane; the disease variant is trafficked to the membrane rather than retained in the endoplasmic reticulum (loh2021atp11acausesautosomaldominanta pages 83-88).
  • Laterality: predominantly bilateral and symmetric. Some ATP11A/DFNA33 families showed possible asymmetry, demonstrating broader allelic variability (pater2022autosomaldominantnonsyndromic pages 9-11).
  • Secondary organs: no reproducible renal, neurological, vestibular, visual, or systemic involvement has been established in DFNA84.

8. Temporal development

Behavioral hearing can be normal during the first decade, while ABR abnormalities may already be present. Recognized onset is usually insidious and postlingual at 10–20 years. Mild middle/high-frequency loss and speech difficulty progress through adolescence and early adulthood; moderate loss is typical by the third or fourth decade in the defining family, and severe/profound loss may occur from approximately 40–50 years onward. Low frequencies become involved later, producing broader or flat audiometric loss (loh2021atp11acausesautosomaldominanta pages 22-25, loh2021atp11acausesautosomaldominanta pages 25-29).

The condition is chronic and lifelong, without documented spontaneous remission or episodic relapses. There is no validated staging system or annual threshold-shift estimate. Early electrophysiological abnormality and retained sensory-cell function may constitute an intervention window, but this remains unproven.

9. Inheritance and population

Inheritance is autosomal dominant. A heterozygous affected person has a theoretical 50% chance per pregnancy of transmitting the variant. Both sexes are affected. The defining family showed vertical transmission across four generations; however, measured penetrance is unavailable. A 99% penetrance parameter used in linkage analysis was a modeling assumption, not an empirical estimate (pater2021autosomaldominantnonsyndromic pages 5-7, loh2021atp11acausesautosomaldominanta pages 22-25).

Disease-specific prevalence, incidence, carrier frequency, sex ratio, de-novo rate, germline-mosaicism rate, and age distribution are unknown. Families have been reported from Germany, Newfoundland/Northern-European ancestry, and Jewish Israeli families with roots in Afghanistan or Bukhara, Uzbekistan, but these observations do not establish ethnic susceptibility. The Newfoundland allele may be locally private; 202 additional local probands did not carry it (pater2022autosomaldominantnonsyndromic pages 9-11, pater2021autosomaldominantnonsyndromic pages 5-7).

There is no evidence of anticipation or a consanguinity effect. Founder effects remain possible but unproven.

10. Diagnostics

Clinical testing

A practical work-up should include:

  1. Otoscopy and tympanometry to exclude conductive disease.
  2. Pure-tone air- and bone-conduction audiometry, including high frequencies.
  3. Age-appropriate speech recognition and speech-in-noise testing.
  4. ABR, including waveform morphology, synchrony, and threshold.
  5. OAE and/or cochlear microphonics to identify preserved outer-hair-cell function. Preserved responses support auditory neuropathy early, but their absence in advanced disease does not exclude DFNA84 (loh2021atp11acausesautosomaldominanta pages 22-25, loh2021atp11acausesautosomaldominanta pages 25-29).
  6. Vestibular and neurological examination when clinically indicated, principally to exclude syndromic auditory neuropathy.

There is no blood biomarker, imaging signature, biopsy finding, or biochemical assay specific for DFNA84. MRI of the internal auditory canals/brain may exclude cochlear-nerve deficiency or acquired lesions, but is not diagnostic.

Genetic testing

The preferred first-line molecular test is a comprehensive hereditary-hearing-loss panel that includes ATP11A and validated exon-level CNV/structural-variant detection. If negative, WGS is particularly valuable because the defining deletion and noncanonical terminal-exon/intronic lesions can be missed by routine WES. Segregation testing should follow, and splice-region or terminal-exon variants may require patient RNA, full-length transcript analysis, or a minigene assay (pater2021autosomaldominantnonsyndromic pages 7-10, pater2019amultiomicapproach pages 154-158).

Single-gene ATP11A testing is reasonable when the family shows dominant auditory-neuropathy physiology or a known familial variant. CMA, karyotype, FISH, mitochondrial testing, and repeat-expansion testing are not primary tests unless another diagnosis is suspected. WES can identify coding variants but is less reliable for the structural and transcript-complex lesions already associated with ATP11A.

Differential diagnosis

Important genetic differentials include DIAPH3/AUNA1, OTOF, OPA1, ATP1A3, ATP1A1, PJVK/GSDME, PMP22, MPZ, and other auditory-neuropathy genes. Distinguishing features include recessive versus dominant inheritance, congenital versus postlingual onset, optic atrophy, ataxia, peripheral neuropathy, or syndromic manifestations. Conventional cochlear hearing-loss genes should also be considered because OAEs can disappear in advanced DFNA84.

Screening

Newborn OAE-only screening may be insufficient because auditory-neuropathy disorders can retain OAEs; ABR-based screening is more informative. In known families, cascade genetic testing and baseline ABR/OAE—even in apparently normal-hearing children—are appropriate. Prenatal and preimplantation genetic testing become technically possible after a familial pathogenic variant is established.

11. Outcome and prognosis

Life expectancy and mortality appear unaffected because the condition is nonsyndromic; no disease-specific survival statistics exist. The principal morbidity is progressive communication disability. Prognosis is variable but generally entails worsening thresholds and speech recognition over decades. ABR abnormality may precede perceived hearing difficulty and is therefore a plausible early prognostic marker, although no validated prediction model exists (loh2021atp11acausesautosomaldominanta pages 22-25, loh2021atp11acausesautosomaldominanta pages 25-29).

Recovery of lost native hearing has not been reported. Hearing aids may improve audibility but cannot directly restore neural synchrony. Older relatives in the defining family had little benefit; three met cochlear-implant criteria, but none had undergone implantation at the reported assessment, leaving ATP11A-specific implant outcomes unknown (loh2021atp11acausesautosomaldominanta pages 25-29).

12. Treatment

Current clinical management

There is no approved ATP11A-directed pharmacotherapy. Management is individualized and supportive:

  • serial audiology, including speech testing, ABR, and OAE where informative;
  • hearing conservation and avoidance of unnecessary ototoxic exposure;
  • appropriately fitted hearing aids when behavioral thresholds are elevated;
  • remote microphones, captioning, visual communication, educational/workplace accommodations, auditory-verbal or speech-language therapy;
  • cochlear-implant evaluation for severe functional impairment or inadequate aided speech understanding, after confirming cochlear-nerve integrity.

Suggested NCIT concepts include Hearing Aid Device, Cochlear Implantation, Audiologic Rehabilitation, Speech Therapy, and Genetic Counseling; exact NCIT codes should be validated against the release used by the knowledge base.

In general auditory neuropathy, cochlear implants may restore more synchronous neural activation when pathology is presynaptic, but outcome varies by genotype and lesion site. This principle cannot yet be converted into an ATP11A-specific response estimate (loh2021atp11acausesautosomaldominanta pages 22-25).

Experimental approaches

No ATP11A-specific gene replacement, gene editing, ASO, siRNA, cell therapy, or pharmacological trial was identified. Pharmacologically limiting externalized PS or restoring membrane asymmetry has been proposed, but remains speculative and preclinical (pater2021autosomaldominantnonsyndromic pages 10-13). Gene therapy successes in other forms of auditory neuropathy—particularly OTOF deficiency—should not be represented as evidence for ATP11A treatment.

13. Prevention

Primary prevention: The inherited variant cannot currently be prevented after conception. Reproductive options include genetic counseling, preimplantation genetic testing, prenatal diagnosis, donor gametes, and natural conception with or without testing.

Secondary prevention: Cascade testing, early ABR/OAE assessment, regular audiometry, prompt amplification or communication support, and monitoring of speech/language development can reduce avoidable developmental and social consequences.

Tertiary prevention: Hearing conservation, avoidance of excessive noise and unnecessary ototoxic medication, optimized assistive devices, rehabilitation, and timely cochlear-implant referral may limit disability. No vaccine, chemoprophylaxis, or disease-specific preventive drug is applicable.

14. Other species and natural disease

Relevant orthologs include Atp11a in mouse (Mus musculus, NCBI Taxonomy 10090) and zebrafish (Danio rerio, Taxonomy 7955). No naturally occurring ATP11A-associated veterinary hearing disorder, breed predisposition, zoonotic transmission, or cross-species infectious susceptibility was identified.

Conservation is supported by ATP11A expression in vertebrate auditory cells and by experimental zebrafish ear phenotypes. Comparative pathology suggests that membrane-lipid asymmetry is required for sensory-hair-cell and stereocilia maintenance, but the precise human auditory-neuropathy phenotype may require mammalian synaptic and neural physiology not captured by larval fish (hawkeynoble2025thep4phospholipidflippase pages 14-18).

15. Model organisms and experimental systems

Human-cell model

HEK293/HEK293T cells expressing wild-type or mutant human ATP11A with CDC50A demonstrated that the disease protein can reach the plasma membrane but has markedly reduced PS-flippase activity. This is the strongest direct functional evidence, although kidney-derived cells do not reproduce cochlear-cell architecture or auditory synapses (loh2021atp11acausesautosomaldominanta pages 83-88, loh2021atp11acausesautosomaldominant pages 135-139).

Zebrafish

A 2025 Journal of Cell Science study generated CRISPR loss-of-function atp11a alleles with 5-bp and 7-bp deletions. At 5 days post-fertilization, mutants showed fewer stereocilia and hair cells in inner-ear maculae/cristae and fewer cells in an otic neuromast. Stereocilia analyses included wild type n=17, heterozygotes n=22, and homozygotes n=7. This supports a conserved ear-maintenance requirement but is not an exact knock-in of the human variant (hawkeynoble2025thep4phospholipidflippase pages 14-18). Publication: May 2025, DOI/URL: https://doi.org/10.1242/jcs.263657.

Mouse and related models

Mouse expression data place Atp11a in inner and outer hair cells, Deiters cells, otic progenitors, and auditory/vestibular ganglion neurons, with postnatal upregulation. However, a validated mouse carrying the human DFNA84 deletion and reproducing its progressive auditory-neuropathy phenotype was not identified (pater2021autosomaldominantnonsyndromic pages 10-13). Phenotypes of other P4-ATPase models—such as Atp8a2- or Atp8b1-deficient mice—support roles in spiral-ganglion and hair-cell maintenance but are mechanistic analogies, not ATP11A disease models (pater2019amultiomicapproach pages 154-158).

Recent developments and authoritative interpretation

  • 2023: Chepurwar and colleagues published the ATP11A causal assignment for autosomal-dominant auditory neuropathy type 2 in Human Molecular Genetics, volume 32, pages 1083–1089; DOI/URL: https://doi.org/10.1093/hmg/ddac267. The key mechanistic conclusion is captured by the associated thesis abstract: the 5.5-kb deletion causes aberrant splicing without nonsense-mediated decay, and the mutant displays reduced PS-flipping activity while reaching the plasma membrane normally (loh2021atp11acausesautosomaldominanta pages 1-7).
  • 2023: Vona et al. revisited the historical DFNA33 pedigree and identified highly improbable double/triple recombination assignments, cautioning against automatically attributing the original German locus to ATP11A. Publication: August 2023, Frontiers in Genetics 14:1214736; DOI/URL: https://doi.org/10.3389/fgene.2023.1214736 (vona2023unravelinghaplotypeerrors pages 2-4).
  • 2023–2024: No new DFNA84 human cohort, penetrance estimate, treatment trial, or disease-specific omics study was found. This absence is scientifically important: proposed downstream pathways remain hypotheses rather than clinically validated therapeutic targets.
  • 2025: The zebrafish knockout study supplied the first strong ATP11A-specific vertebrate evidence for loss of ear hair cells and stereocilia, extending the mechanism from membrane transport assays to tissue maintenance (hawkeynoble2025thep4phospholipidflippase pages 14-18).

Exact source quotations available from retrieved abstracts/full text

“The causative mutation is a 5,500 bp deletion covering the last coding exon. This results in aberrant splicing with the use of an alternative last exon, without induction of nonsense-mediated mRNA decay.” (Disease-specific experimental thesis abstract.) (loh2021atp11acausesautosomaldominanta pages 1-7)

“A flippase activity assay … displays a hypoactivity of PS translocating function from the exoplasmic to the cytoplasmic leaflet of the plasma membrane in the presence of the mutation.” (Disease-specific in-vitro evidence.) (loh2021atp11acausesautosomaldominanta pages 1-7)

“We report a new DFNA gene, ATP11A, in a Newfoundland family with a variable form of bilateral sensorineural hearing loss.” (Allelic human evidence published as DFNA33, not the defining AUNA2 pedigree.) (pater2022autosomaldominantnonsyndromic pages 9-11)

Principal evidence limitations

The disorder’s phenotype, penetrance, and prognosis are based chiefly on one multigenerational family. There are no population prevalence data, prospective natural-history cohorts, validated biomarkers, ATP11A-specific cochlear-implant outcomes, or interventional trials. The precise affected human cell type remains unresolved, and claims involving apoptosis, phagocytosis, calcium dysregulation, synaptic-vesicle cycling, or neurite degeneration should be stored as inferred mechanisms, not established causal steps. Finally, disease-name harmonization must preserve the distinction between DFNA84/AUNA2 and ATP11A-associated families historically reported as DFNA33.

References

  1. (loh2021atp11acausesautosomaldominanta pages 22-25): SM von Loh. Atp11a causes autosomal-dominant progressive, non-syndromic auditory synaptopathy/auditory neuropathy. Unknown journal, 2021.

  2. (loh2021atp11acausesautosomaldominanta pages 25-29): SM von Loh. Atp11a causes autosomal-dominant progressive, non-syndromic auditory synaptopathy/auditory neuropathy. Unknown journal, 2021.

  3. (pater2022autosomaldominantnonsyndromic pages 9-11): Justin A. Pater, Cindy Penney, Darren D. O’Rielly, Anne Griffin, Lara Kamal, Zippora Brownstein, Barbara Vona, Chana Vinkler, Mordechai Shohat, Ortal Barel, Curtis R. French, Sushma Singh, Salem Werdyani, Taylor Burt, Nelly Abdelfatah, Jim Houston, Lance P. Doucette, Jessica Squires, Fabian Glaser, Nicole M. Roslin, Daniel Vincent, Pascale Marquis, Geoffrey Woodland, Touati Benoukraf, Alexia Hawkey-Noble, Karen B. Avraham, Susan G. Stanton, and Terry-Lynn Young. Autosomal dominant non-syndromic hearing loss maps to dfna33 (13q34) and co-segregates with splice and frameshift variants in atp11a, a phospholipid flippase gene. Human Genetics, 141:431-444, Mar 2022. URL: https://doi.org/10.1007/s00439-022-02444-x, doi:10.1007/s00439-022-02444-x. This article has 27 citations and is from a peer-reviewed journal.

  4. (vona2023unravelinghaplotypeerrors pages 2-4): Barbara Vona, Sabrina Regele, Aboulfazl Rad, Nicola Strenzke, Justin A. Pater, Katrin Neumann, Marc Sturm, Tobias B. Haack, and Antoinette G. Am Zehnhoff-Dinnesen. Unraveling haplotype errors in the dfna33 locus. Frontiers in Genetics, Aug 2023. URL: https://doi.org/10.3389/fgene.2023.1214736, doi:10.3389/fgene.2023.1214736. This article has 3 citations and is from a peer-reviewed journal.

  5. (loh2021atp11acausesautosomaldominanta pages 1-7): SM von Loh. Atp11a causes autosomal-dominant progressive, non-syndromic auditory synaptopathy/auditory neuropathy. Unknown journal, 2021.

  6. (loh2021atp11acausesautosomaldominanta pages 83-88): SM von Loh. Atp11a causes autosomal-dominant progressive, non-syndromic auditory synaptopathy/auditory neuropathy. Unknown journal, 2021.

  7. (loh2021atp11acausesautosomaldominant pages 135-139): SM von Loh. Atp11a causes autosomal-dominant progressive, non-syndromic auditory synaptopathy/auditory neuropathy. Unknown journal, 2021.

  8. (loh2021atp11acausesautosomaldominanta pages 135-139): SM von Loh. Atp11a causes autosomal-dominant progressive, non-syndromic auditory synaptopathy/auditory neuropathy. Unknown journal, 2021.

  9. (loh2021atp11acausesautosomaldominant pages 123-126): SM von Loh. Atp11a causes autosomal-dominant progressive, non-syndromic auditory synaptopathy/auditory neuropathy. Unknown journal, 2021.

  10. (pater2021autosomaldominantnonsyndromic pages 1-5): Justin Pater, Cindy Penney, Darren O’Rielly, Anne Griffin, Mordechai Shohat, Ortal Barel, Curtis R French, Sushma Singh, Salem Werdyani, Taylor Burt, Nelly Abdelfatah, Jim Houston, Lance Doucette, Jessica Squires, Nicole Roslin, Daniel Vincent, Pascale Marquis, Geoffrey Woodland, Susan Stanton, and Terry-Lynn Young. Autosomal dominant non-syndromic hearing loss maps to dfna33 (13q34) and co-segregates with splice site variants in atp11a, a phospholipid flippase gene. Unknown journal, May 2021. URL: https://doi.org/10.21203/rs.3.rs-530835/v1, doi:10.21203/rs.3.rs-530835/v1. This article has 0 citations.

  11. (pater2021autosomaldominantnonsyndromic pages 5-7): Justin Pater, Cindy Penney, Darren O’Rielly, Anne Griffin, Mordechai Shohat, Ortal Barel, Curtis R French, Sushma Singh, Salem Werdyani, Taylor Burt, Nelly Abdelfatah, Jim Houston, Lance Doucette, Jessica Squires, Nicole Roslin, Daniel Vincent, Pascale Marquis, Geoffrey Woodland, Susan Stanton, and Terry-Lynn Young. Autosomal dominant non-syndromic hearing loss maps to dfna33 (13q34) and co-segregates with splice site variants in atp11a, a phospholipid flippase gene. Unknown journal, May 2021. URL: https://doi.org/10.21203/rs.3.rs-530835/v1, doi:10.21203/rs.3.rs-530835/v1. This article has 0 citations.

  12. (hawkeynoble2025thep4phospholipidflippase pages 14-18): Alexia Hawkey-Noble, Cameron Tobin, Muhammad T. Ameen, Liam Osmond, Colby Gill, Christina S. Bottaro, Terry-Lynn Young, and Curtis R. French. The p4-phospholipid flippase atp11a is required for maintenance of eye and ear structure in zebrafish. May 2025. URL: https://doi.org/10.1242/jcs.263657, doi:10.1242/jcs.263657. This article has 0 citations and is from a domain leading peer-reviewed journal.

  13. (pater2021autosomaldominantnonsyndromic pages 7-10): Justin Pater, Cindy Penney, Darren O’Rielly, Anne Griffin, Mordechai Shohat, Ortal Barel, Curtis R French, Sushma Singh, Salem Werdyani, Taylor Burt, Nelly Abdelfatah, Jim Houston, Lance Doucette, Jessica Squires, Nicole Roslin, Daniel Vincent, Pascale Marquis, Geoffrey Woodland, Susan Stanton, and Terry-Lynn Young. Autosomal dominant non-syndromic hearing loss maps to dfna33 (13q34) and co-segregates with splice site variants in atp11a, a phospholipid flippase gene. Unknown journal, May 2021. URL: https://doi.org/10.21203/rs.3.rs-530835/v1, doi:10.21203/rs.3.rs-530835/v1. This article has 0 citations.

  14. (pater2019amultiomicapproach pages 154-158): J Pater. A multi-omic approach to genetic hearing loss in the newfoundland founder population. Unknown journal, 2019.

  15. (pater2021autosomaldominantnonsyndromic pages 10-13): Justin Pater, Cindy Penney, Darren O’Rielly, Anne Griffin, Mordechai Shohat, Ortal Barel, Curtis R French, Sushma Singh, Salem Werdyani, Taylor Burt, Nelly Abdelfatah, Jim Houston, Lance Doucette, Jessica Squires, Nicole Roslin, Daniel Vincent, Pascale Marquis, Geoffrey Woodland, Susan Stanton, and Terry-Lynn Young. Autosomal dominant non-syndromic hearing loss maps to dfna33 (13q34) and co-segregates with splice site variants in atp11a, a phospholipid flippase gene. Unknown journal, May 2021. URL: https://doi.org/10.21203/rs.3.rs-530835/v1, doi:10.21203/rs.3.rs-530835/v1. This article has 0 citations.

  16. (rosso2025unravelingthefunctional pages 5-7): Lara Emily Rosso, Giulia Pianigiani, Anna Morgan, Elisa Rubinato, Elisa Paccagnella, Stefania Lenarduzzi, Anita Wischmeijer, Beatrice Spedicati, and Giorgia Girotto. Unraveling the functional impact of splicing variants in inherited hearing disorders through minigene splicing assays. Sep 2025. URL: https://doi.org/10.3390/biomedicines13092245, doi:10.3390/biomedicines13092245. This article has 5 citations.

  17. (loh2021atp11acausesautosomaldominanta pages 19-22): SM von Loh. Atp11a causes autosomal-dominant progressive, non-syndromic auditory synaptopathy/auditory neuropathy. Unknown journal, 2021.

  18. (loh2021atp11acausesautosomaldominanta pages 29-32): SM von Loh. Atp11a causes autosomal-dominant progressive, non-syndromic auditory synaptopathy/auditory neuropathy. Unknown journal, 2021.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Table (click to expand)
Outcome Count
References checked 6
Resolved 6
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 6
On topic 5
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Table (click to expand)
Outcome Count
Terms checked 12
Resolved 11
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 0

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • GO:0004012 (GO_0004012) (1 mention) - replaced by GO:0140326

11 of 12 terms resolved to a current term; the rest could not be looked up either way.