Hearing Loss Autosomal Dominant 84

Mendelian MONDO:0030724 Pathograph 11 Show in embeddings browser Autosomal Dominant Nonsyndromic Hearing Loss

DFNA84 is dominantly inherited, postlingual, slowly progressive bilateral sensorineural hearing loss caused by heterozygous variants in ATP11A, a class-6 P4-ATPase that flips phosphatidylserine and phosphatidylethanolamine from the outer to the inner leaflet of the plasma membrane. It is the first Mendelian phenotype attributed to this flippase. Two things make the entry worth curating beyond "another DFNA locus". The first is where the variants sit. Every reported disease allele affects the C-terminal region or the 3' end of the gene rather than the catalytic core - a cryptic-splice-site substitution retaining 153 bp of intron in the 3' UTR, an 8 bp duplication at the exon 28 boundary producing p.Asn1110Valfs43Ter, a 5.5 kb deletion removing the last coding exon, a further 3' UTR deletion of more than 5 kb, and a +5 splice-donor variant activating a cryptic site in intron 12. Several of these lie outside the coding sequence of the MANE select transcript and are only interpretable once alternative ATP11A isoforms are considered, which is why in silico pipelines anchored on MANE missed them. Functionally the alleles converge: the mammalian P4-ATPase C-terminus governs folding, activity and localisation, and the AUNA2 deletion allele was shown directly to abolish phosphatidylserine flippase activity. The second is that the same gene produces two clinically distinguishable auditory phenotypes. The Newfoundland and Israeli families have nonsyndromic sensorineural hearing loss (DFNA84); a large German family with a 5.5 kb deletion has autosomal dominant auditory neuropathy type 2 (AUNA2), in which outer hair cell amplification is preserved and it is sound encoding by inner hair cells and auditory nerve fibres that fails. Atp11a is expressed in auditory nerve fibres, their synaptic contacts and the cochlear nucleus in mice, and it is also a Deiters cell defining gene in the organ of Corti - so the gene sits on both sides of the hair cell/neuron divide, which is a plausible substrate for the split presentation rather than an explanation for it. The disease mechanism is explicitly unresolved in the primary literature. Haploinsufficiency and dominant negative action are both on the table, the C-terminally altered protein is made rather than simply lost, and homozygous Atp11a deletion is embryonic lethal in mice so the null is not the human situation. What is established is the phenotype: slow progression with onset typically in the first or second decade, high frequencies worst, with marked intrafamilial variability in onset, configuration and symmetry. There is a specific therapeutic hook. If loss of flipping leaves phosphatidylserine exposed on the outer leaflet, the affected cells carry a phagocytic "eat me" signal, and surface phosphatidylserine is an established pharmacological target - so the discovery paper argues ATP11A hearing loss could in principle be druggable. That is a proposal, not a result, and is curated here as a knowledge gap rather than as a treatment.

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1
Inheritance
5
Pathophys.
4
Phenotypes
3
Gaps
11
Pathograph
1
Genes
3
Medical Actions
2
Subtypes
2
Models
7
References
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Deep Research
🏷

Classifications

Harrison's Part
NEUROLOGIC
👪

Inheritance

1
Autosomal dominant HP:0000006
Heterozygous ATP11A variants segregating with hearing loss over multiple generations. In the Israeli families the exon 28 duplication co-segregated fully across five affected and three unaffected members; in the Newfoundland kindred linkage to 13q34 reached a LOD of 4.77 under a dominant model. Penetrance is high but expressivity is variable, and at least one report describes obligate young adult carriers who are not yet symptomatic.
Autosomal dominant inheritance
Show evidence (3 references)
PMID:35278131 SUPPORT Human Clinical
"The duplication co-segregates fully with dominant hearing loss in five affected and three unaffected family members."
Full dominant co-segregation of the exon 28 duplication in the Israeli family.
PMID:35278131 SUPPORT Human Clinical
"The proband (PID IV-7) presented at age 13 years with a progressive, sloping, bilateral SNHL and a family history consistent with autosomal dominant inheritance."
The dominant family history in the discovery kindred.
PMID:41007806 SUPPORT Human Clinical
"Segregation analysis in the offspring of the proband revealed that both children inherited the variant from their mother."
Vertical transmission to two clinically unaffected adult offspring, which is the reduced/age-dependent penetrance that makes carrier surveillance necessary.
◆

Subtypes

2
DFNA84 - nonsyndromic progressive sensorineural hearing loss
The nonsyndromic presentation, described in a six-generation Newfoundland kindred and in two unrelated Jewish Israeli families. Bilateral, progressive, high-frequency predominant sensorineural hearing loss with variable onset and audiogram configuration and no reported extra-auditory involvement.
Show evidence (1 reference)
PMID:35278131 SUPPORT Human Clinical
"We report a new DFNA gene, ATP11A, in a Newfoundland family with a variable form of bilateral sensorineural hearing loss (SNHL)."
The founding description of the nonsyndromic ATP11A phenotype.
AUNA2 - autosomal dominant auditory neuropathy type 2 MONDO:0957279
ATP11A hgnc:13552 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in ATP11A (hgnc:13552). hgnc:13552 is a gene from the HUGO Gene Nomenclature Committee.
A large German family carrying a 5.5 kb ATP11A deletion presents instead as auditory synaptopathy/neuropathy: outer hair cell cochlear amplification is preserved while sound encoding by inner hair cells and/or auditory nerve fibres is disrupted. Curated here as a subtype of the same gene-disease entity rather than as a separate disease because the causal allele class, the locus and the flippase mechanism are shared; the difference is which cochlear compartment carries the deficit. The clinical course was described in this family six years before the gene was found: first symptoms in the second decade, moderate hearing loss by the fourth decade, and profound impairment in the older members, with no involvement of other organ systems. The same study excluded the AUNA1 locus and mapped the family to 13q34 (and 12q24), which is the linkage result the later whole-genome sequencing resolved to ATP11A.
Show evidence (5 references)
PMID:36300302 SUPPORT Human Clinical
"Auditory synaptopathy/neuropathy (AS/AN) is a distinct type of sensorineural hearing loss in which the cochlear sensitivity to sound (i.e. active cochlear amplification by outer hair cells) is preserved whereas sound encoding by inner hair cells and/or auditory nerve fibers is disrupted owing to..."
Defines the auditory-neuropathy presentation that distinguishes this subtype.
PMID:36300302 SUPPORT Human Clinical
"By whole-genome sequencing, we now detected a 5500 bp deletion in ATP11A on chromosome 13q34 segregating with the phenotype in this family."
The causal allele in the AUNA2 family, at the same locus as the DFNA84 alleles.
PMID:28601886 SUPPORT Human Clinical
"Affected family members developed their first symptoms in their second decade. Moderate hearing loss in the fourth decade then progressed to profound hearing impairment in older family members."
The natural history of the AUNA2 presentation, from the clinical description of the family published before the causal gene was identified.
+ 2 more references
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Discussions and Knowledge Gaps

3
Does a heterozygous C-terminal ATP11A allele cause hearing loss by halving flippase dose, or by the altered protein interfering with the wild-type protein?
KNOWLEDGE GAP atp11a_dominance_mechanism
Attached to
pathophysiology#Loss of Phosphatidylserine Flippase Activity pathophysiology#ATP11A C-Terminal and 3' Region Variants
Every reported allele leaves a protein that is made and C-terminally altered rather than absent, and the C-terminus is where folding, activity regulation and localisation are controlled. That is the classic setup for dominant-negative action, but it is equally compatible with the altered protein being degraded and the phenotype reflecting haploinsufficiency. The discovery paper names both possibilities and chooses neither. The question is not academic. If the mechanism is haploinsufficiency, dose restoration - gene addition or upregulation of the wild-type allele - is the therapeutic route. If it is dominant-negative, adding wild-type protein may not help and allele-specific silencing is needed instead. The available models do not settle it: the mouse null is embryonic lethal, the conditional knockout is a null in the targeted cells, and the zebrafish alleles are coding loss-of-function rather than C-terminal. A model carrying a knock-in of a patient C-terminal allele in the heterozygous state is the missing reagent.
Show evidence (3 references)
PMID:35278131 SUPPORT Human Clinical
"The disease mechanism, how variants in the ATP11A gene cause hearing loss, is unclear."
The authors state the gap directly.
PMID:35278131 SUPPORT Human Clinical
"It is likely that pathogenic splicing variants act via dominant-negative or haploinsufficiency mechanism."
The two candidate mechanisms, left unresolved.
PMID:35278131 SUPPORT Model Organism
"deletion of in atp11a in mice results in lethality during embryogenesis"
Why the constitutive mouse null cannot answer the question, and why a heterozygous knock-in is the reagent that would.
Is phosphatidylserine actually externalised on cochlear cells in ATP11A-related hearing loss, and would blocking the resulting phagocytic signal preserve hearing?
KNOWLEDGE GAP atp11a_ps_exposure_druggability
Attached to
pathophysiology#Loss of Plasma Membrane Phospholipid Asymmetry treatments#
The discovery paper's therapeutic proposal has two links, and only the first is established. That ATP11A flips phosphatidylserine inward, and that a disease allele abolishes that activity, is demonstrated. That the consequence in the cochlea is surface phosphatidylserine marking hair cells or spiral ganglion neurons for phagocytic clearance is an inference from general phospholipid biology - no cochlear phosphatidylserine-exposure measurement has been reported in any ATP11A model, human or animal. The proposal is nonetheless worth recording, because unlike most deafness genes it names a druggable intermediate rather than requiring gene replacement: surface phosphatidylserine has established pharmacological ligands. The experiment that would move this from proposal to hypothesis is a direct one - stain cochlear or hair-cell membranes from an ATP11A model for outer-leaflet phosphatidylserine and ask whether it is increased. The zebrafish mutants and the conditional mouse both exist and neither has been used this way.
Show evidence (3 references)
PMID:35278131 SUPPORT INDIRECT Human Clinical
"Phagocytic signals such as PS at the cell surface are known pharmaceutical targets"
The druggability half of the proposal. Marked INDIRECT because it is a statement about phosphatidylserine as a target class generally, not about the cochlea.
PMID:35278131 SUPPORT INDIRECT Human Clinical
"the deregulation of transport could redistribute PS to the extracellular side of plasma membrane flagging cells for their recognition, phagocytosis, and ultimate degradation by phagocytes"
The mechanistic half, stated by the authors in the conditional as a future direction rather than as a result.
PMID:35278131 SUPPORT Human Clinical
"Limitations of this study include a lack of insight as to protein function, specifically with respect to hearing loss."
The authors' own statement that the cochlear functional link is missing.
Is the historical DFNA33 locus the same entity as DFNA84, or was the original mapping wrong?
KNOWLEDGE GAP dfna33_locus_disposition
Attached to
disease#Hearing Loss Autosomal Dominant 84
The discovery kindred for DFNA84 linked to 13q34, the interval mapped in 2009 as DFNA33 in a German family, and the discovery paper closes by saying the original DFNA33 family should be sequenced to settle whether ATP11A is DFNA33. That was attempted. A member of the original family was genome-sequenced; the ATP11A variant found was deep intronic and spliced normally, and re-examination of the published haplotypes turned up two double recombination events and one triple - a pattern the authors read as genotyping error rather than biology. So the disposition of DFNA33 is unresolved in a specific way that matters for this entry: the shared 13q34 coordinates are not evidence that DFNA33 and DFNA84 are one disease, and DFNA84 should be treated as resting on its own families rather than inheriting the DFNA33 kindred's phenotype description. Nothing here casts doubt on ATP11A as the DFNA84 gene.
Show evidence (4 references)
PMID:37671045 SUPPORT Human Clinical
"The DFNA33 locus was mapped in 2009 and coincidentally contains ATP11A, a gene recently associated with autosomal dominant hearing loss and auditory neuropathy type 2."
The coincidence of coordinates that prompted the re-analysis.
PMID:37671045 REFUTE Human Clinical
"We identified a deep intronic variant in ATP11A that showed evidence of functionally normal splicing."
Refutes the proposal that ATP11A is the DFNA33 gene, at least via the variant found in the re-ascertained family member.
PMID:37671045 SUPPORT Human Clinical
"we re-assessed haplotypes from the originally published DFNA33 family and identified two double recombination events and one triple recombination event in the pedigree, a highly unlikely occurrence, especially at this scale"
The evidence that the original DFNA33 interval itself is unreliable.
+ 1 more reference
⚙

Pathophysiology

5
ATP11A C-Terminal and 3' Region Variants
Every established disease allele disturbs the C-terminal region or the 3' end of ATP11A rather than its catalytic core. The Newfoundland allele (chr13:113534963G>A) creates a cryptic donor site that retains 153 bp of intron in the 3' UTR; the Israeli allele c.3322_3327+2dupGTCCAGGT extends exon 28 by 8 bp and truncates the protein 82 residues before its normal end; the German AUNA2 allele deletes 5.5 kb spanning the last coding exon; and a fourth family carries a further 3' UTR deletion of more than 5 kb. One further allele, c.1221+5G>C, activates a cryptic donor 44 bp into intron 12 and is the exception on both counts - it lies in the middle of the gene rather than the 3' region, and it is a variant of uncertain significance rather than an established DFNA84 allele. It is listed here because the minigene result below is real, not because it extends the C-terminal pattern. Two curation-relevant points follow. First, several alleles do not touch the coding sequence of the MANE select transcript at all and are only interpretable against alternative ATP11A isoforms, so a MANE-anchored pipeline scores them benign. Second, the C-terminal region of a mammalian P4-ATPase is not inert: it governs folding, activity regulation, and calcium-dependent endocytosis or polarised plasma-membrane localisation, so a shortened and differently charged tail is a plausible functional lesion even where the transport domains are intact.
ATP11A hgnc:13552 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ATP11A (hgnc:13552). hgnc:13552 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Loss of Phosphatidylserine Flippase Activity
Show evidence (6 references)
PMID:42371110 SUPPORT Human Clinical
"To date, only three pathogenic ATP11A variants have been reported in association with HL, all affecting the C-terminal region of the protein."
The allelic spectrum converges on the C-terminal region.
PMID:35278131 SUPPORT Human Clinical
"RNA studies verified in silico predictions, revealing the retention of 153 bp of intron in the 3' UTR of several ATP11A isoforms."
Experimental confirmation of the splicing consequence of the Newfoundland allele.
PMID:35278131 SUPPORT Human Clinical
"the insertion is predicted to extend exon 28 by 8 bp, including the 2 intronic nucleotides (gt), followed by the 6 last exonic nucleotides (GTCCAG), leading to a frame shift at amino acid 1110 (82 amino acids before the end of the protein) and a stop codon 43 amino acids downstream, p.Asn1110Valfs43Ter"
The C-terminal truncation produced by the recurrent Israeli allele.
+ 3 more references
Loss of Phosphatidylserine Flippase Activity
ATP11A is a class-6 P4-ATPase whose substrate specificity is for phosphatidylserine and phosphatidylethanolamine. The AUNA2 deletion allele was tested directly and the C-terminally altered protein lost flippase activity for phosphatidylserine, and the 2026 multi-family analysis reads the whole allelic series the same way. Whether the heterozygous state acts by haploinsufficiency or by dominant-negative interference with wild-type protein is stated as unresolved by the discovery paper and is not settled here.
phosphatidylserine flippase activity GO:0140346 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased phosphatidylserine flippase activity (GO:0140346). GO:0140346 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Loss of Plasma Membrane Phospholipid Asymmetry
Show evidence (3 references)
PMID:36300302 SUPPORT In Vitro
"ATP11A carrying the altered C-terminus loses its flippase activity for phosphatidylserine."
Direct functional demonstration that a disease allele abolishes the flippase activity.
PMID:42371110 SUPPORT Human Clinical
"Functionally, all reported ATP11A variants appear to converge on a loss of normal ATP11A flippase activity, resulting in defective phospholipid transport and disruption of cell membrane homeostasis."
Convergence of the allelic series onto one functional lesion.
PMID:35278131 SUPPORT Human Clinical
"It is likely that pathogenic splicing variants act via dominant-negative or haploinsufficiency mechanism."
The authors leave the dominance mechanism open; this entry records the flippase deficit without committing to which of the two produces it.
Loss of Plasma Membrane Phospholipid Asymmetry
Eukaryotic plasma membranes hold phosphatidylserine and phosphatidylethanolamine on the inner leaflet, an asymmetry that is generated and maintained by ATP-dependent flipping and that underpins membrane potential, curvature, stability and domain organisation. Losing ATP11A flipping is expected to leave phosphatidylserine on the outer leaflet. The downstream consequence proposed by the discovery paper is that exposed phosphatidylserine is the canonical "eat me" signal, marking the cell for recognition and phagocytic clearance. That step is a mechanistic proposal drawn from general phospholipid biology and has not been demonstrated in cochlear tissue, which is why it is carried in this node's description and in the therapeutic knowledge gap rather than as its own asserted node.
aminophospholipid translocation GO:0140331 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased aminophospholipid translocation (GO:0140331). GO:0140331 is a biological process from the Gene Ontology. ↓ DECREASED regulation of membrane lipid distribution GO:0097035 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased regulation of membrane lipid distribution (GO:0097035). GO:0097035 is a biological process from the Gene Ontology. ↓ DECREASED
plasma membrane GO:0005886 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves plasma membrane (GO:0005886). GO:0005886 is a cellular component from the Gene Ontology.
Downstream
Cochlear Hair Cell and Supporting Cell Dysfunction
Auditory Nerve and Spiral Ganglion Dysfunction
Show evidence (3 references)
PMID:35278131 SUPPORT Human Clinical
"ATP11A is a type of P4-ATPase that transports (flip) phospholipids from the outer to inner leaflet of cell membranes to maintain asymmetry."
The normal function whose loss defines this node.
PMID:35278131 SUPPORT INDIRECT Human Clinical
"Haploinsufficiency of ATP11A, the phospholipid flippase that specially transports phosphatidylserine (PS) and phosphatidylethanolamine (PE), could leave cells with PS/PE at the extracellular side vulnerable to phagocytic degradation."
The proposed consequence of losing asymmetry. Marked INDIRECT because the authors state it as an inference from flippase biology, not as an observation in cochlear tissue.
PMID:40223426 SUPPORT Other
"This asymmetry helps to establish membrane properties such as resting potential, shape, permeability and stability"
Why asymmetry matters cell-biologically. Graded OTHER because the quoted sentence is background review rather than a result of any study arm.
Cochlear Hair Cell and Supporting Cell Dysfunction
ATP11A is expressed in the sensory epithelium of the organ of Corti. Single-cell and long-read RNA-seq places the murine Atp11a exon corresponding to the short human ATP11A-203 isoform in inner hair cells, outer hair cells and Deiters cells, and identifies Atp11a as a Deiters cell defining gene with a marked postnatal rise in expression - a timing that fits a postlingual, progressive disease rather than a developmental one. The direct structural evidence is from zebrafish rather than from human cochlea: loss-of-function atp11a mutants have reduced stereocilia counts across four of the five larval otic sensory patches and fewer hair cells in one lateral-line neuromast. Conformance to the sensorineural hair cell loss module is asserted at that module's sensory-epithelium-insult node and not at its mechanotransduction-failure-and-death node, because no study has shown hair-cell mechanotransduction failure or hair-cell death for any ATP11A allele; the zebrafish result is a structural stereocilia count. Nothing links ATP11A to the module's ionic-homeostasis and oxidative-stress node either, so that step is left out rather than assumed. Of the two biological processes the module node carries, only GO:0007605 is reproduced here. GO:0050910, detection of mechanical stimulus involved in sensory perception of sound, is deliberately omitted for the same reason the conformance target is the insult node rather than the mechanotransduction node: no ATP11A study demonstrates a mechanotransduction defect. The single observation in the vicinity is a Yo-Pro-1 uptake difference in one zebrafish lateral-line neuromast, which the authors themselves read as either cell loss or loss of mechanotransduction capacity without deciding between them, and which is not a cochlear hair cell.
cochlear inner hair cell CL:0000589 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlear inner hair cell (CL:0000589). CL:0000589 is a cell type from the Cell Ontology. cochlear outer hair cell CL:0000601 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlear outer hair cell (CL:0000601). CL:0000601 is a cell type from the Cell Ontology. Deiters cell CL:0000635 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Deiters cell, annotated with Deiter's cell (CL:0000635). CL:0000635 is a cell type from the Cell Ontology.
sensory perception of sound GO:0007605 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal sensory perception of sound (GO:0007605). GO:0007605 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Animal models
atp11a loss-of-function zebrafish Zebrafish partially recapitulates Reproduces a sensory hair-cell structural deficit on loss of the orthologue, in both the otic sensory patches and one lateral-line neuromast.
Downstream
Progressive Bilateral Sensorineural Hearing Loss
Show evidence (2 references)
PMID:35278131 SUPPORT Model Organism
"Atp11a was identified as a Deiter cell defining gene that exhibits moderate expression during mouse embryonic development, followed by a marked increase in expression after birth"
Cell-type expression and its postnatal timing in mouse cochlea, which is the expression basis for locating the lesion in the organ of Corti.
PMID:40223426 SUPPORT Model Organism
"A reduction in stereocilia number, as evidenced by phalloidin staining, was observed in the medial crista, posterior crista, posterior macula and anterior macula of homozygous atp11a mutants"
Structural hair-bundle deficit on loss of the orthologue.
Auditory Nerve and Spiral Ganglion Dysfunction
In the AUNA2 presentation the deficit is neural rather than in the cochlear amplifier. Atp11a is expressed in auditory nerve fibres, their synaptic contacts and the cochlear nucleus in mice, and conditional Atp11a knockout mice show a progressive fall in the spiral ganglion neuron compound action potential. This is the pathophysiological branch that separates the AUNA2 subtype from the nonsyndromic DFNA84 presentation; both derive from the same flippase deficit and it is not known what determines which one a given family develops. This node deliberately does not declare conformance to the sensorineural hair cell loss module's "Cochlear Amplification Loss and Spiral Ganglion Neuron Degeneration" node. That module node derives spiral ganglion degeneration from hair-cell loss and lost cochlear amplification; in AUNA2 outer hair cell amplification is explicitly preserved and the neural deficit is primary, so conforming here would assert the opposite of what the source reports.
spiral ganglion neuron CL:0011113 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves spiral ganglion neuron (CL:0011113). CL:0011113 is a cell type from the Cell Ontology.
Animal models
Conditional Atp11a knockout mouse Mouse recapitulates Reproduces the progressive neural encoding deficit that defines the human AUNA2 presentation.
Downstream
Progressive Bilateral Sensorineural Hearing Loss
Show evidence (1 reference)
PMID:36300302 SUPPORT Model Organism
"Atp11a is expressed in fibers and synaptic contacts of the auditory nerve and in the cochlear nucleus in mice, and conditional Atp11a knockout mice show a progressive reduction of the spiral ganglion neuron compound action potential, recapitulating the human phenotype of AN."
Expression in the auditory nerve plus a conditional knockout that reproduces the progressive neural deficit.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Hearing Loss Autosomal Dominant 84 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

4
Progressive Bilateral Sensorineural Hearing Loss OBLIGATE Auditory HP:0000408 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive sensorineural hearing impairment (HP:0000408). HP:0000408 is a phenotype from the Human Phenotype Ontology.
Graded OBLIGATE because it is definitional for the entity rather than because a proportion was counted: DFNA84 is diagnosed by an ATP11A variant segregating with dominant progressive SNHL, so an unaffected carrier is recorded as non-penetrant rather than as an affected individual lacking the feature.
Show evidence (2 references)
PMID:35278131 SUPPORT Human Clinical
"Splice variants in the 3' region of ATP11A cause a bilateral, progressive SNHL with variable onset and configuration."
The authors' summary of the phenotype across all three of their families.
PMID:41007806 SUPPORT Human Clinical
"ATP11A is associated with autosomal dominant deafness-84 (DFNA84; MIM #619810), an NSHL form, characterized by a slow progression, typically with onset in the first or second decade of life."
An independent statement of the natural history, and the sentence that pins the DFNA84 designation to OMIM 619810 and to this gene.
High-Frequency Sensorineural Hearing Impairment Auditory HP:0001757 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High-frequency sensorineural hearing impairment (HP:0001757). HP:0001757 is a phenotype from the Human Phenotype Ontology.
No frequency band is asserted. The audiometric detail comes from single probands in separate papers, and combining them would count different patients toward one denominator.
Show evidence (2 references)
PMID:35278131 SUPPORT Human Clinical
"At the age of 39 years, she had normal low and mid-frequency hearing to 1 kHz and a sloping audiogram showing severe bilateral high-frequency SNHL."
The sloping high-frequency configuration in the Family A proband.
PMID:41007806 SUPPORT Human Clinical
"which revealed a moderate-to-severe, bilateral, symmetric sensorineural HL, predominantly affecting the high frequencies, particularly at 4000 and 8000 Hz"
The same configuration in an unrelated proband carrying a different ATP11A splice allele.
Postlingual Sensorineural Hearing Impairment Auditory HP:0008596 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Postlingual sensorineural hearing impairment (HP:0008596). HP:0008596 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41007806 SUPPORT Human Clinical
"characterized by a slow progression, typically with onset in the first or second decade of life"
The usual postlingual onset window for DFNA84.
PMID:41007806 SUPPORT Human Clinical
"The proband, a 57-year-old female, underwent her first audiological assessment at the age of 54"
The late end of the ascertainment range in a molecularly confirmed carrier.
Intrafamilial Variability in Onset and Audiogram Configuration Auditory HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Bound to the generic HP:0000407 on purpose. HP:0003828 "Variable expressivity" is the natural fit for what this phenotype records, but it sits under the clinical-modifier branch rather than under HP:0000118, so it is outside the PhenotypeTerm dynamic enum and fails term validation. The specificity is carried in the preferred_term-level phenotype name and description instead.
Show evidence (2 references)
PMID:35278131 SUPPORT Human Clinical
"Of note, the intrafamilial variability among individuals in Family A with respect to onset could be explained by"
The authors flag intrafamilial variability explicitly. The quote stops before their numbered list of three candidate explanations, which is reproduced in this phenotype's description.
PMID:35278131 SUPPORT Human Clinical
"Comparison of audiograms (right ear series) of six family members show variable severity in the 3rd decade"
Six same-generation relatives at comparable ages with markedly different thresholds.
🧬

Genetic Associations

1
ATP11A
Gene: ATP11A hgnc:13552 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ATP11A (hgnc:13552). hgnc:13552 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal dominant
Show evidence (2 references)
PMID:35278131 SUPPORT Human Clinical
"this study documents the first association of ATP11A with a highly penetrant Mendelian phenotype"
Establishes ATP11A as a Mendelian deafness gene.
PMID:35278131 SUPPORT Model Organism
"The ATP11A protein specifically transports phosphatidylserine (PS) and phosphatidylethanolamine (PE) across cell membranes, is ubiquitously expressed in various tissues and deletion of in atp11a in mice results in lethality during embryogenesis"
Substrate specificity, expression breadth, and the embryonic lethality of the mouse null that constrains which model systems can address the heterozygous disease.
🗃️

External Assertions

1
OMIM DFNA84
OMIM disease record OMIM:619810
OMIM phenotype entry for deafness, autosomal dominant 84 (ATP11A-related). The MIM number is quoted in the evidence for this entry via PMID:41007806.
💊

Medical Actions

3
Hearing Amplification
Platform: Device
Hearing aids are the mainstay while thresholds remain aidable. There is no disease-modifying therapy for DFNA84, and fitting is driven by the audiogram rather than the genotype. One reported ATP11A carrier began using aids in her twenties and is now being considered for cochlear implantation.
Mechanism Target:
Progressive Bilateral Sensorineural Hearing Loss — Symptomatic amplification; it does not act on the flippase deficit.
Cochlear Implantation
Action: cochlear device implantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cochlear device implantation, annotated with Surgical Procedure (NCIT:C15329), qualified as medical device cochlear implant. NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Device
Considered when hearing loss reaches the severe-to-profound range and amplification is no longer sufficient. In the auditory-neuropathy presentation the calculus is different from ordinary sensorineural loss, since outer hair cell function is preserved and the lesion is neural, and no ATP11A-specific implant outcome data have been published.
Mechanism Target:
Progressive Bilateral Sensorineural Hearing Loss — Bypasses the sensory deficit; does not address the underlying flippase lesion.
Show evidence (1 reference)
PMID:41007806 SUPPORT Human Clinical
"Currently, cochlear implantation (CI) represents the standard treatment for severe-to-profound hearing loss."
The standard-of-care statement this treatment records; it is not ATP11A-specific.
Genetic Counseling and Cascade Testing
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Platform: Behavioral / lifestyle
Dominant inheritance with high penetrance but late and variable onset makes cascade testing informative and makes the result actionable only as surveillance. In one reported family both adult offspring of an affected proband were found to carry the allele while still asymptomatic.
Show evidence (1 reference)
PMID:41007806 SUPPORT Human Clinical
"the children of the patient carrying a heterozygous splicing variant in ATP11A were found to carry the same variant, despite not yet showing HL"
Cascade testing identifying presymptomatic carriers, which is what makes surveillance possible.
🔬

Diagnosis

3
Isoform-aware genome or exome sequencing
Molecular diagnosis requires an analysis that does not stop at the MANE select transcript. Two of the reported alleles sit in the 3' UTR of the MANE transcript and were assigned significance only after the short and long ATP11A isoforms were considered, and one was passed over by in silico splicing prediction entirely. Linkage or haplotype reduction in a large kindred remains a practical way to shrink the candidate list before this analysis.
Show evidence (2 references)
PMID:35278131 SUPPORT Human Clinical
"Given the complexity in genomes, a comprehensive bioinformatics pipeline targeting all known transcripts is essential as is the need to experimentally validate in silico predictions in patient-derived tissues."
The authors' explicit methodological conclusion, which is the diagnostic recommendation.
PMID:42371110 SUPPORT Human Clinical
"In silico analysis also did not predict its impact on splicing."
A reported disease allele that prediction tools scored as benign.
Minigene splicing assay for candidate ATP11A splice alleles
Because the recurrent finding is a non-canonical splice-region variant of uncertain significance, an in vitro splicing assay is the step that converts a prediction into evidence. Minigene assays have been applied to two ATP11A alleles - one confirming that the exon 28 duplication adds 8 bp without disturbing the splice pattern, the other confirming that c.1221+5G>C activates a cryptic donor. Note the limitation the authors themselves raise: a minigene reports on a construct, not on the patient's tissue.
Show evidence (2 references)
PMID:41007806 SUPPORT In Vitro
"The functional studies with minigene assays confirmed this observation and showed that the tested variants induced both exon skipping and activation"
The assay converts predicted splicing effects into demonstrated ones.
PMID:41007806 SUPPORT In Vitro
"results obtained from minigene assays should be interpreted with caution and ideally validated using patient-derived RNA"
The authors' own caveat on the assay's standing as evidence.
Audiological surveillance of asymptomatic carriers
Because onset is postlingual and variable, a carrier identified by cascade testing may be years from symptoms. Periodic audiometry, rather than reassurance, is what the reported management of such carriers consists of.
Show evidence (1 reference)
PMID:41007806 SUPPORT Human Clinical
"periodic audiological evaluations were recommended to monitor for the potential onset of hearing impairment"
The surveillance actually recommended for the presymptomatic carriers in that family.
📊

Prevalence

1
Worldwide, published families
Cases In Literature Ultra Rare
Six families in total as of the 2026 literature: the Newfoundland kindred and two Jewish Israeli families (Pater 2022), the German AUNA2 family (Chepurwar 2023), a fourth family with a 3' UTR deletion (2026 multi-family series), and an Italian family with a VUS-grade intron 12 splice allele. Everything this entry says about natural history rests on that base, which is why no phenotype frequency band is asserted from pooled counts.
Show evidence (1 reference)
PMID:42371110 SUPPORT Human Clinical
"To date, only three pathogenic ATP11A variants have been reported in association with HL, all affecting the C-terminal region of the protein."
The published pathogenic-allele total before this series added a fourth.
🐁

Animal Models

2
atp11a loss-of-function zebrafish
CRISPR-generated loss-of-function alleles in the zebrafish orthologue, phenotyped in the larval inner ear and lateral line. Two independent alleles show the same phenotype, which is the control against CRISPR off-target effects. Heterozygotes have an intermediate but statistically significant stereocilia deficit, which is the feature that makes this model relevant to a dominant human disease rather than only to a null.
Species
Zebrafish
Genotype
atp11a nl1005 and nl1007 CRISPR loss-of-function alleles, heterozygous and homozygous
Genes
ATP11A hgnc:13552 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns ATP11A (hgnc:13552). hgnc:13552 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:40223426
Pathograph links
Cochlear Hair Cell and Supporting Cell Dysfunction partially recapitulates fidelity: moderate Reproduces a sensory hair-cell structural deficit on loss of the orthologue, in both the otic sensory patches and one lateral-line neuromast.
Limitations: Zebrafish have no cochlea, no organ of Corti and no Deiters cells, so the model cannot speak to the cell type the human expression data implicate most strongly. The phenotype is a larval structural count, not a hearing threshold, and no auditory function was measured. The alleles are coding loss-of-function, whereas every human disease allele alters the C-terminus or 3' end - so the model tests loss of the protein rather than the specific lesion patients carry. The same animals have an independent light-dependent photoreceptor phenotype absent from the human disease.
Readouts
Stereocilia count in otic sensory patches
Direction: DECREASED
Interpretation: Phalloidin-stained hair bundle counts fall in four of the five larval otic sensory patches in homozygotes, with an intermediate significant reduction in heterozygotes.
Show evidence (1 reference)
PMID:40223426 SUPPORT Model Organism
"Intermediate phenotypes, that were also statistically significant, were observed in heterozygous animals."
The gene-dosage sensitivity that makes the heterozygous fish informative about a dominant human disease.
Lateral-line neuromast hair cell count
Direction: DECREASED
Interpretation: Reduced in the O1 neuromast in homozygotes and heterozygotes, but unchanged in SO1-SO3 - so the deficit is not a global hair-cell loss.
Show evidence (1 reference)
PMID:40223426 SUPPORT Model Organism
"we observed a reduction in the number of hair cells in the O1 neuromast in both homozygous and heterozygous mutant larvae; however, analysis of other neuromasts (SO1, SO2 and SO3), showed no phenotype compared to wild-type siblings"
Records the negative result alongside the positive one, which bounds how far the hair-cell claim extends.
Show evidence (2 references)
PMID:40223426 SUPPORT Model Organism
"We demonstrate that mutant atp11a zebrafish display a reduced number of stereocilia in the larval ear and a reduced number of hair cells in some sensory neuromasts, indicating that these fish represent an ideal model for studying atp11a-attributable hearing loss."
The authors' own claim for the model's relevance to ATP11A hearing loss.
+ 1 more reference
Show evidence (1 reference)
PMID:40223426 SUPPORT Model Organism
"Phenotypes are present in two different alleles of atp11a"
Two independent alleles give the same phenotype, which is what allows the result to be attributed to atp11a loss rather than to CRISPR off-target effects.
Conditional Atp11a knockout mouse
A conditional knockout generated to test the AUNA2 mechanism; constitutive deletion is embryonic lethal, which is why conditional deletion was required. The readout is a progressive fall in the spiral ganglion neuron compound action potential, matching the neural rather than cochlear-amplifier lesion of auditory neuropathy.
Species
Mouse
Genotype
Conditional Atp11a knockout
Genes
ATP11A hgnc:13552 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns ATP11A (hgnc:13552). hgnc:13552 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:36300302
Pathograph links
Auditory Nerve and Spiral Ganglion Dysfunction recapitulates fidelity: moderate Reproduces the progressive neural encoding deficit that defines the human AUNA2 presentation.
Limitations: A conditional knockout is a null in the targeted cells, whereas the human allele is a heterozygous C-terminal deletion producing an altered protein - so the model tests absence of ATP11A rather than the dominant action of the patient allele. Only the abstract is available for this report, so the deletion driver, timing and cochlear histology cannot be assessed from the cached record.
Readouts
Spiral ganglion neuron compound action potential
Direction: DECREASED
Interpretation: Progressive decline, the electrophysiological signature of auditory neuropathy.
Show evidence (1 reference)
PMID:36300302 SUPPORT Model Organism
"conditional Atp11a knockout mice show a progressive reduction of the spiral ganglion neuron compound action potential"
The measurement itself and its direction.
Show evidence (1 reference)
PMID:36300302 SUPPORT Model Organism
"conditional Atp11a knockout mice show a progressive reduction of the spiral ganglion neuron compound action potential, recapitulating the human phenotype of AN"
The authors' recapitulation claim, with the specific electrophysiological readout.
Show evidence (1 reference)
PMID:36300302 SUPPORT Model Organism
"By combining whole-genome sequencing, immunohistochemistry, in vitro functional assays and generation of a mouse model, we could thus identify a partial deletion of ATP11A as the genetic cause of AUNA2."
The mouse model is one of the four lines of evidence the gene-disease claim rests on.
{ }

Source YAML

click to show 
name: Hearing Loss Autosomal Dominant 84
category: Mendelian
creation_date: "2026-09-03T00:00:00Z"
synonyms:
- DFNA84
- deafness, autosomal dominant 84
- ATP11A-related hearing loss
- autosomal dominant deafness-84
description: >-
  DFNA84 is dominantly inherited, postlingual, slowly progressive bilateral sensorineural
  hearing loss caused by heterozygous variants in ATP11A, a class-6 P4-ATPase that flips
  phosphatidylserine and phosphatidylethanolamine from the outer to the inner leaflet of
  the plasma membrane. It is the first Mendelian phenotype attributed to this flippase.

  Two things make the entry worth curating beyond "another DFNA locus". The first is
  where the variants sit. Every reported disease allele affects the C-terminal region or
  the 3' end of the gene rather than the catalytic core - a cryptic-splice-site
  substitution retaining 153 bp of intron in the 3' UTR, an 8 bp duplication at the exon
  28 boundary producing p.Asn1110Valfs43Ter, a 5.5 kb deletion removing the last coding
  exon, a further 3' UTR deletion of more than 5 kb, and a +5 splice-donor variant
  activating a cryptic site in intron 12. Several of these lie outside the coding sequence
  of the MANE select transcript and are only interpretable once alternative ATP11A
  isoforms are considered, which is why in silico pipelines anchored on MANE missed them.
  Functionally the alleles converge: the mammalian P4-ATPase C-terminus governs folding,
  activity and localisation, and the AUNA2 deletion allele was shown directly to abolish
  phosphatidylserine flippase activity.

  The second is that the same gene produces two clinically distinguishable auditory
  phenotypes. The Newfoundland and Israeli families have nonsyndromic sensorineural
  hearing loss (DFNA84); a large German family with a 5.5 kb deletion has autosomal
  dominant auditory neuropathy type 2 (AUNA2), in which outer hair cell amplification is
  preserved and it is sound encoding by inner hair cells and auditory nerve fibres that
  fails. Atp11a is expressed in auditory nerve fibres, their synaptic contacts and the
  cochlear nucleus in mice, and it is also a Deiters cell defining gene in the organ of
  Corti - so the gene sits on both sides of the hair cell/neuron divide, which is a
  plausible substrate for the split presentation rather than an explanation for it.

  The disease mechanism is explicitly unresolved in the primary literature. Haploinsufficiency
  and dominant negative action are both on the table, the C-terminally altered protein is
  made rather than simply lost, and homozygous Atp11a deletion is embryonic lethal in mice
  so the null is not the human situation. What is established is the phenotype: slow
  progression with onset typically in the first or second decade, high frequencies worst,
  with marked intrafamilial variability in onset, configuration and symmetry.

  There is a specific therapeutic hook. If loss of flipping leaves phosphatidylserine
  exposed on the outer leaflet, the affected cells carry a phagocytic "eat me" signal, and
  surface phosphatidylserine is an established pharmacological target - so the discovery
  paper argues ATP11A hearing loss could in principle be druggable. That is a proposal,
  not a result, and is curated here as a knowledge gap rather than as a treatment.
disease_term:
  preferred_term: hearing loss, autosomal dominant 84
  term:
    id: MONDO:0030724
    label: hearing loss, autosomal dominant 84
parents:
- Autosomal Dominant Nonsyndromic Hearing Loss
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
references:
- reference: PMID:35278131
  title: "Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene."
- reference: PMID:36300302
  title: A mutation in ATP11A causes autosomal-dominant auditory neuropathy type 2.
- reference: PMID:28601886
  title: "AUNA2: A Novel Type of Non-Syndromic Slowly Progressive Auditory Synaptopathy/Auditory Neuropathy with Autosomal-Dominant Inheritance."
- reference: PMID:37671045
  title: Unraveling haplotype errors in the DFNA33 locus.
- reference: PMID:40223426
  title: The P4-phospholipid flippase Atp11a is required for maintenance of eye and ear structure in zebrafish.
- reference: PMID:41007806
  title: "Unraveling the Functional Impact of Splicing Variants in Inherited Hearing Disorders Through Minigene Splicing Assays."
- reference: PMID:42371110
  title: Integrative genetic and functional analysis of autosomal dominant hearing loss in 108 multigenerational families.
external_assertions:
- name: OMIM DFNA84
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:619810
  description: >-
    OMIM phenotype entry for deafness, autosomal dominant 84 (ATP11A-related). The MIM
    number is quoted in the evidence for this entry via PMID:41007806.
notes: >-
  Literature base. A PubMed sweep run on 2026-09-04 for ATP11A crossed with hearing loss,
  deafness, auditory, cochlea, DFNA84 and 13q34 returns six ATP11A hearing-loss reports,
  all of which are cited here, plus PMID:28601886, the pre-gene clinical description of the
  AUNA2 family, which was added to the AUNA2 subtype as a result. "DFNA84" as a query
  string returns nothing indexed. A falcon deep-research report was also generated and is
  committed at research/Hearing_Loss_Autosomal_Dominant_84-deep-research-falcon.md. It
  introduced no reference the entry was missing: every indexed source in its citation list
  resolves to a paper already cited here - the Research Square preprint
  DOI:10.21203/rs.3.rs-530835/v1 is the preprint of PMID:35278131, and its remaining DOIs
  are PMID:36300302, PMID:37671045, PMID:40223426 and PMID:41007806. Its only other two
  sources are unindexed dissertations (von Loh 2021; Pater 2019) with no PMID or DOI. The
  manual sweep and the retrieval pass therefore agree that the citable literature base is
  complete, which is a stronger statement of completeness than either check alone. One
  preflight warning on that report is a false positive worth recording, because it will
  recur for every audiology entry curated from a deep-research report: preflight-dr flags
  "ABR" as a rival gene symbol - hgnc:81 is a real gene called ABR - but every occurrence
  of ABR in this report and in this entry is the auditory brainstem response. The report also
  suggests GO:0004012, which is obsolete and replaced by GO:0140326; it was treated as a
  lead and not bound, and this entry binds GO:0140346, GO:0140331, GO:0097035 and
  GO:0005886 instead.

  GeneReviews. PMID:20301607, the Genetic Hearing Loss Overview, is cached and is tagged
  GeneReviews in sibling hearing-loss entries, but it is deliberately not tagged here. Its
  cached record is abstract-only - the body is the chapter's six-point statement of scope
  and nothing more - and contains no occurrence of ATP11A, DFNA84 or AUNA2, so tagging it
  would produce a tagged-but-not-mined reference. There is no ATP11A-specific GeneReviews
  chapter; the entity was first described in 2022. This paragraph records the negative so
  it is auditable rather than looking like an omission.

  AUNA2 and kb/disorders/Auditory_Neuropathy.yaml. The AUNA2 subtype below is also carried
  as a subtype of Auditory_Neuropathy, bound to the same MONDO:0957279 term and citing the
  same PMID:36300302 finding. That is deliberate overlap along two different axes - this
  entry groups by gene and allelic mechanism, Auditory_Neuropathy groups by the
  audiological presentation - and neither is a duplicate of the other. If the two are ever
  reconciled, the gene-side pathophysiology lives here and the audiological
  differential lives there.
inheritance:
- name: Autosomal dominant
  description: >-
    Heterozygous ATP11A variants segregating with hearing loss over multiple generations.
    In the Israeli families the exon 28 duplication co-segregated fully across five
    affected and three unaffected members; in the Newfoundland kindred linkage to 13q34
    reached a LOD of 4.77 under a dominant model. Penetrance is high but expressivity is
    variable, and at least one report describes obligate young adult carriers who are not
    yet symptomatic.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:35278131
    reference_title: "Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The duplication co-segregates fully with dominant hearing loss in five affected and three unaffected family members."
    explanation: Full dominant co-segregation of the exon 28 duplication in the Israeli family.
  - reference: PMID:35278131
    reference_title: "Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proband (PID IV-7) presented at age 13 years with a progressive, sloping, bilateral SNHL and a family history consistent with autosomal dominant inheritance."
    explanation: The dominant family history in the discovery kindred.
  - reference: PMID:41007806
    reference_title: "Unraveling the Functional Impact of Splicing Variants in Inherited Hearing Disorders Through Minigene Splicing Assays."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Segregation analysis in the offspring of the proband revealed that both children inherited the variant from their mother."
    explanation: >-
      Vertical transmission to two clinically unaffected adult offspring, which is the
      reduced/age-dependent penetrance that makes carrier surveillance necessary.
has_subtypes:
- name: DFNA84
  display_name: DFNA84 - nonsyndromic progressive sensorineural hearing loss
  description: >-
    The nonsyndromic presentation, described in a six-generation Newfoundland kindred and
    in two unrelated Jewish Israeli families. Bilateral, progressive, high-frequency
    predominant sensorineural hearing loss with variable onset and audiogram configuration
    and no reported extra-auditory involvement.
  evidence:
  - reference: PMID:35278131
    reference_title: "Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a new DFNA gene, ATP11A, in a Newfoundland family with a variable form of bilateral sensorineural hearing loss (SNHL)."
    explanation: The founding description of the nonsyndromic ATP11A phenotype.
- name: AUNA2
  display_name: AUNA2 - autosomal dominant auditory neuropathy type 2
  subtype_term:
    preferred_term: auditory neuropathy, autosomal dominant 2
    term:
      id: MONDO:0957279
      label: auditory neuropathy, autosomal dominant 2
  review_notes: >-
    The same subtype, bound to the same MONDO term and citing the same PMID:36300302
    finding, is also carried in kb/disorders/Auditory_Neuropathy.yaml. See the top-level
    notes of this entry for why both are kept.
  description: >-
    A large German family carrying a 5.5 kb ATP11A deletion presents instead as auditory
    synaptopathy/neuropathy: outer hair cell cochlear amplification is preserved while
    sound encoding by inner hair cells and/or auditory nerve fibres is disrupted. Curated
    here as a subtype of the same gene-disease entity rather than as a separate disease
    because the causal allele class, the locus and the flippase mechanism are shared; the
    difference is which cochlear compartment carries the deficit.

    The clinical course was described in this family six years before the gene was found:
    first symptoms in the second decade, moderate hearing loss by the fourth decade, and
    profound impairment in the older members, with no involvement of other organ systems.
    The same study excluded the AUNA1 locus and mapped the family to 13q34 (and 12q24),
    which is the linkage result the later whole-genome sequencing resolved to ATP11A.
  genes:
  - preferred_term: ATP11A
    term:
      id: hgnc:13552
      label: ATP11A
  evidence:
  - reference: PMID:36300302
    reference_title: A mutation in ATP11A causes autosomal-dominant auditory neuropathy type 2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Auditory synaptopathy/neuropathy (AS/AN) is a distinct type of sensorineural hearing loss in which the cochlear sensitivity to sound (i.e. active cochlear amplification by outer hair cells) is preserved whereas sound encoding by inner hair cells and/or auditory nerve fibers is disrupted owing to genetic or environmental factors."
    explanation: Defines the auditory-neuropathy presentation that distinguishes this subtype.
  - reference: PMID:36300302
    reference_title: A mutation in ATP11A causes autosomal-dominant auditory neuropathy type 2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By whole-genome sequencing, we now detected a 5500 bp deletion in ATP11A on chromosome 13q34 segregating with the phenotype in this family."
    explanation: The causal allele in the AUNA2 family, at the same locus as the DFNA84 alleles.
  - reference: PMID:28601886
    reference_title: "AUNA2: A Novel Type of Non-Syndromic Slowly Progressive Auditory Synaptopathy/Auditory Neuropathy with Autosomal-Dominant Inheritance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected family members developed their first symptoms in their second decade. Moderate hearing loss in the fourth decade then progressed to profound hearing impairment in older family members."
    explanation: >-
      The natural history of the AUNA2 presentation, from the clinical description of the
      family published before the causal gene was identified.
  - reference: PMID:28601886
    reference_title: "AUNA2: A Novel Type of Non-Syndromic Slowly Progressive Auditory Synaptopathy/Auditory Neuropathy with Autosomal-Dominant Inheritance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By means of linkage analyses, the AUNA1 locus was excluded, and putatively linked regions on chromosomal bands 12q24 and 13q34 were identified as likely carrying the second locus for autosomal-dominant AS/AN (AUNA2)."
    explanation: >-
      The linkage result that placed AUNA2 at 13q34, which the later whole-genome
      sequencing resolved to ATP11A.
  - reference: PMID:28601886
    reference_title: "AUNA2: A Novel Type of Non-Syndromic Slowly Progressive Auditory Synaptopathy/Auditory Neuropathy with Autosomal-Dominant Inheritance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "AUNA2 is associated with a slowly progressive postlingual hearing loss without any evidence for additional symptoms in other organ systems."
    explanation: That the AUNA2 presentation is nonsyndromic, which is what keeps it a subtype here rather than a separate syndromic entity.
pathophysiology:
- name: ATP11A C-Terminal and 3' Region Variants
  description: >-
    Every established disease allele disturbs the C-terminal region or the 3' end of ATP11A
    rather than its catalytic core. The Newfoundland allele (chr13:113534963G>A) creates a
    cryptic donor site that retains 153 bp of intron in the 3' UTR; the Israeli allele
    c.3322_3327+2dupGTCCAGGT extends exon 28 by 8 bp and truncates the protein 82 residues
    before its normal end; the German AUNA2 allele deletes 5.5 kb spanning the last coding
    exon; and a fourth family carries a further 3' UTR deletion of more than 5 kb. One
    further allele, c.1221+5G>C, activates a cryptic donor 44 bp into intron 12 and is the
    exception on both counts - it lies in the middle of the gene rather than the 3' region,
    and it is a variant of uncertain significance rather than an established DFNA84 allele.
    It is listed here because the minigene result below is real, not because it extends the
    C-terminal pattern.

    Two curation-relevant points follow. First, several alleles do not touch the coding
    sequence of the MANE select transcript at all and are only interpretable against
    alternative ATP11A isoforms, so a MANE-anchored pipeline scores them benign. Second,
    the C-terminal region of a mammalian P4-ATPase is not inert: it governs folding,
    activity regulation, and calcium-dependent endocytosis or polarised plasma-membrane
    localisation, so a shortened and differently charged tail is a plausible functional
    lesion even where the transport domains are intact.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: ATP11A
    term:
      id: hgnc:13552
      label: ATP11A
  downstream:
  - target: Loss of Phosphatidylserine Flippase Activity
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:42371110
    reference_title: Integrative genetic and functional analysis of autosomal dominant hearing loss in 108 multigenerational families.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, only three pathogenic ATP11A variants have been reported in association with HL, all affecting the C-terminal region of the protein."
    explanation: The allelic spectrum converges on the C-terminal region.
  - reference: PMID:35278131
    reference_title: "Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RNA studies verified in silico predictions, revealing the retention of 153 bp of intron in the 3' UTR of several ATP11A isoforms."
    explanation: Experimental confirmation of the splicing consequence of the Newfoundland allele.
  - reference: PMID:35278131
    reference_title: "Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the insertion is predicted to extend exon 28 by 8 bp, including the 2 intronic nucleotides (gt), followed by the 6 last exonic nucleotides (GTCCAG), leading to a frame shift at amino acid 1110 (82 amino acids before the end of the protein) and a stop codon 43 amino acids downstream, p.Asn1110Valfs43Ter"
    explanation: The C-terminal truncation produced by the recurrent Israeli allele.
  - reference: PMID:35278131
    reference_title: "Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "As the C-terminus region of ATP11A has been shown to be critical for Ca2+-dependent endocytosis or polarized localization at the plasma membrane"
    explanation: >-
      Why a C-terminal lesion is functionally consequential even when the transport domains
      are intact. Graded COMPUTATIONAL because the sentence introduces the authors'
      AlphaFold modelling of the wild-type and mutant tails.
  - reference: PMID:42371110
    reference_title: Integrative genetic and functional analysis of autosomal dominant hearing loss in 108 multigenerational families.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Variants located outside the coding regions of MANE select transcripts may disrupt coding exons in alternative isoforms, which could be relevant for inner ear function."
    explanation: The interpretation trap specific to this gene's disease alleles.
  - reference: PMID:41007806
    reference_title: "Unraveling the Functional Impact of Splicing Variants in Inherited Hearing Disorders Through Minigene Splicing Assays."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "selection of a cryptic splice site that causes partial intron retention was seen in ATP11A and OTOF (c.5533+12G>T) cases"
    explanation: >-
      Minigene confirmation that the ATP11A allele activates a cryptic donor site and
      retains part of the intron. The earlier version of this item quoted the sentence-level
      result for c.1221+5G>C and stopped mid-token at the typographic prime in "5'ss"; that
      quote was not propositional and its stated justification (validator normalisation of
      the prime glyph) is not documented in conf/reference_validator_config.yaml. This
      quote is the authors' summary of the same result, contains no prime character and
      names ATP11A explicitly.
- name: Loss of Phosphatidylserine Flippase Activity
  description: >-
    ATP11A is a class-6 P4-ATPase whose substrate specificity is for phosphatidylserine and
    phosphatidylethanolamine. The AUNA2 deletion allele was tested directly and the
    C-terminally altered protein lost flippase activity for phosphatidylserine, and the
    2026 multi-family analysis reads the whole allelic series the same way. Whether the
    heterozygous state acts by haploinsufficiency or by dominant-negative interference with
    wild-type protein is stated as unresolved by the discovery paper and is not settled
    here.
  biological_scale: MOLECULAR
  molecular_functions:
  - preferred_term: phosphatidylserine flippase activity
    modifier: DECREASED
    term:
      id: GO:0140346
      label: phosphatidylserine flippase activity
  downstream:
  - target: Loss of Plasma Membrane Phospholipid Asymmetry
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:36300302
    reference_title: A mutation in ATP11A causes autosomal-dominant auditory neuropathy type 2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "ATP11A carrying the altered C-terminus loses its flippase activity for phosphatidylserine."
    explanation: Direct functional demonstration that a disease allele abolishes the flippase activity.
  - reference: PMID:42371110
    reference_title: Integrative genetic and functional analysis of autosomal dominant hearing loss in 108 multigenerational families.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Functionally, all reported ATP11A variants appear to converge on a loss of normal ATP11A flippase activity, resulting in defective phospholipid transport and disruption of cell membrane homeostasis."
    explanation: Convergence of the allelic series onto one functional lesion.
  - reference: PMID:35278131
    reference_title: "Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is likely that pathogenic splicing variants act via dominant-negative or haploinsufficiency mechanism."
    explanation: >-
      The authors leave the dominance mechanism open; this entry records the flippase
      deficit without committing to which of the two produces it.
- name: Loss of Plasma Membrane Phospholipid Asymmetry
  description: >-
    Eukaryotic plasma membranes hold phosphatidylserine and phosphatidylethanolamine on the
    inner leaflet, an asymmetry that is generated and maintained by ATP-dependent flipping
    and that underpins membrane potential, curvature, stability and domain organisation.
    Losing ATP11A flipping is expected to leave phosphatidylserine on the outer leaflet.

    The downstream consequence proposed by the discovery paper is that exposed
    phosphatidylserine is the canonical "eat me" signal, marking the cell for recognition
    and phagocytic clearance. That step is a mechanistic proposal drawn from general
    phospholipid biology and has not been demonstrated in cochlear tissue, which is why it
    is carried in this node's description and in the therapeutic knowledge gap rather than
    as its own asserted node.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: aminophospholipid translocation
    modifier: DECREASED
    term:
      id: GO:0140331
      label: aminophospholipid translocation
  - preferred_term: regulation of membrane lipid distribution
    modifier: DECREASED
    term:
      id: GO:0097035
      label: regulation of membrane lipid distribution
  cellular_components:
  - preferred_term: plasma membrane
    term:
      id: GO:0005886
      label: plasma membrane
  downstream:
  - target: Cochlear Hair Cell and Supporting Cell Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Auditory Nerve and Spiral Ganglion Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:35278131
    reference_title: "Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ATP11A is a type of P4-ATPase that transports (flip) phospholipids from the outer to inner leaflet of cell membranes to maintain asymmetry."
    explanation: The normal function whose loss defines this node.
  - reference: PMID:35278131
    reference_title: "Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Haploinsufficiency of ATP11A, the phospholipid flippase that specially transports phosphatidylserine (PS) and phosphatidylethanolamine (PE), could leave cells with PS/PE at the extracellular side vulnerable to phagocytic degradation."
    explanation: >-
      The proposed consequence of losing asymmetry. Marked INDIRECT because the authors
      state it as an inference from flippase biology, not as an observation in cochlear
      tissue.
  - reference: PMID:40223426
    reference_title: The P4-phospholipid flippase Atp11a is required for maintenance of eye and ear structure in zebrafish.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This asymmetry helps to establish membrane properties such as resting potential, shape, permeability and stability"
    explanation: >-
      Why asymmetry matters cell-biologically. Graded OTHER because the quoted sentence is
      background review rather than a result of any study arm.
- name: Cochlear Hair Cell and Supporting Cell Dysfunction
  conforms_to: "sensorineural_hair_cell_loss#Cochlear Sensory Epithelium Insult"
  description: >-
    ATP11A is expressed in the sensory epithelium of the organ of Corti. Single-cell and
    long-read RNA-seq places the murine Atp11a exon corresponding to the short human
    ATP11A-203 isoform in inner hair cells, outer hair cells and Deiters cells, and
    identifies Atp11a as a Deiters cell defining gene with a marked postnatal rise in
    expression - a timing that fits a postlingual, progressive disease rather than a
    developmental one.

    The direct structural evidence is from zebrafish rather than from human cochlea:
    loss-of-function atp11a mutants have reduced stereocilia counts across four of the five
    larval otic sensory patches and fewer hair cells in one lateral-line neuromast.

    Conformance to the sensorineural hair cell loss module is asserted at that module's
    sensory-epithelium-insult node and not at its mechanotransduction-failure-and-death
    node, because no study has shown hair-cell mechanotransduction failure or hair-cell
    death for any ATP11A allele; the zebrafish result is a structural stereocilia count.
    Nothing links ATP11A to the module's ionic-homeostasis and oxidative-stress node
    either, so that step is left out rather than assumed.

    Of the two biological processes the module node carries, only GO:0007605 is reproduced
    here. GO:0050910, detection of mechanical stimulus involved in sensory perception of
    sound, is deliberately omitted for the same reason the conformance target is the insult
    node rather than the mechanotransduction node: no ATP11A study demonstrates a
    mechanotransduction defect. The single observation in the vicinity is a Yo-Pro-1
    uptake difference in one zebrafish lateral-line neuromast, which the authors themselves
    read as either cell loss or loss of mechanotransduction capacity without deciding
    between them, and which is not a cochlear hair cell.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: sensory perception of sound
    term:
      id: GO:0007605
      label: sensory perception of sound
    modifier: ABNORMAL
  cell_types:
  - preferred_term: cochlear inner hair cell
    term:
      id: CL:0000589
      label: cochlear inner hair cell
  - preferred_term: cochlear outer hair cell
    term:
      id: CL:0000601
      label: cochlear outer hair cell
  - preferred_term: Deiters cell
    term:
      id: CL:0000635
      label: Deiter's cell
  downstream:
  - target: Progressive Bilateral Sensorineural Hearing Loss
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:35278131
    reference_title: "Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Atp11a was identified as a Deiter cell defining gene that exhibits moderate expression during mouse embryonic development, followed by a marked increase in expression after birth"
    explanation: >-
      Cell-type expression and its postnatal timing in mouse cochlea, which is the
      expression basis for locating the lesion in the organ of Corti.
  - reference: PMID:40223426
    reference_title: The P4-phospholipid flippase Atp11a is required for maintenance of eye and ear structure in zebrafish.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "A reduction in stereocilia number, as evidenced by phalloidin staining, was observed in the medial crista, posterior crista, posterior macula and anterior macula of homozygous atp11a mutants"
    explanation: Structural hair-bundle deficit on loss of the orthologue.
- name: Auditory Nerve and Spiral Ganglion Dysfunction
  description: >-
    In the AUNA2 presentation the deficit is neural rather than in the cochlear amplifier.
    Atp11a is expressed in auditory nerve fibres, their synaptic contacts and the cochlear
    nucleus in mice, and conditional Atp11a knockout mice show a progressive fall in the
    spiral ganglion neuron compound action potential. This is the pathophysiological branch
    that separates the AUNA2 subtype from the nonsyndromic DFNA84 presentation; both derive
    from the same flippase deficit and it is not known what determines which one a given
    family develops.

    This node deliberately does not declare conformance to the sensorineural hair cell loss
    module's "Cochlear Amplification Loss and Spiral Ganglion Neuron Degeneration" node.
    That module node derives spiral ganglion degeneration from hair-cell loss and lost
    cochlear amplification; in AUNA2 outer hair cell amplification is explicitly preserved
    and the neural deficit is primary, so conforming here would assert the opposite of what
    the source reports.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: spiral ganglion neuron
    term:
      id: CL:0011113
      label: spiral ganglion neuron
  downstream:
  - target: Progressive Bilateral Sensorineural Hearing Loss
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:36300302
    reference_title: A mutation in ATP11A causes autosomal-dominant auditory neuropathy type 2.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Atp11a is expressed in fibers and synaptic contacts of the auditory nerve and in the cochlear nucleus in mice, and conditional Atp11a knockout mice show a progressive reduction of the spiral ganglion neuron compound action potential, recapitulating the human phenotype of AN."
    explanation: >-
      Expression in the auditory nerve plus a conditional knockout that reproduces the
      progressive neural deficit.
phenotypes:
- name: Progressive Bilateral Sensorineural Hearing Loss
  category: Auditory
  description: >-
    The defining feature: bilateral sensorineural hearing loss that worsens over time.
    Progression is slow, and severity within a single family at a comparable age varies
    widely - the discovery paper compares six relatives all in their third decade with
    markedly different thresholds.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Progressive sensorineural hearing impairment
    term:
      id: HP:0000408
      label: Progressive sensorineural hearing impairment
  notes: >-
    Graded OBLIGATE because it is definitional for the entity rather than because a
    proportion was counted: DFNA84 is diagnosed by an ATP11A variant segregating with
    dominant progressive SNHL, so an unaffected carrier is recorded as non-penetrant rather
    than as an affected individual lacking the feature.
  evidence:
  - reference: PMID:35278131
    reference_title: "Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Splice variants in the 3' region of ATP11A cause a bilateral, progressive SNHL with variable onset and configuration."
    explanation: The authors' summary of the phenotype across all three of their families.
  - reference: PMID:41007806
    reference_title: "Unraveling the Functional Impact of Splicing Variants in Inherited Hearing Disorders Through Minigene Splicing Assays."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ATP11A is associated with autosomal dominant deafness-84 (DFNA84; MIM #619810), an NSHL form, characterized by a slow progression, typically with onset in the first or second decade of life."
    explanation: >-
      An independent statement of the natural history, and the sentence that pins the
      DFNA84 designation to OMIM 619810 and to this gene.
- name: High-Frequency Sensorineural Hearing Impairment
  category: Auditory
  description: >-
    High frequencies are worst affected, with low and mid frequencies relatively preserved
    early. Two Israeli probands had normal hearing to 1 kHz with a sloping high-frequency
    loss above it; a further reported proband had moderate-to-severe symmetric loss
    concentrated at 4000 and 8000 Hz.
  phenotype_term:
    preferred_term: High-frequency sensorineural hearing impairment
    term:
      id: HP:0001757
      label: High-frequency sensorineural hearing impairment
  notes: >-
    No frequency band is asserted. The audiometric detail comes from single probands in
    separate papers, and combining them would count different patients toward one
    denominator.
  evidence:
  - reference: PMID:35278131
    reference_title: "Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At the age of 39 years, she had normal low and mid-frequency hearing to 1 kHz and a sloping audiogram showing severe bilateral high-frequency SNHL."
    explanation: The sloping high-frequency configuration in the Family A proband.
  - reference: PMID:41007806
    reference_title: "Unraveling the Functional Impact of Splicing Variants in Inherited Hearing Disorders Through Minigene Splicing Assays."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "which revealed a moderate-to-severe, bilateral, symmetric sensorineural HL, predominantly affecting the high frequencies, particularly at 4000 and 8000 Hz"
    explanation: The same configuration in an unrelated proband carrying a different ATP11A splice allele.
- name: Postlingual Sensorineural Hearing Impairment
  category: Auditory
  description: >-
    Onset is after speech acquisition. Reported ages at presentation range from 13 years in
    the discovery proband to a first audiological assessment at 54 years in an
    independently reported family, and one obligate carrier pair in their twenties remained
    asymptomatic at the time of testing.
  phenotype_term:
    preferred_term: Postlingual sensorineural hearing impairment
    term:
      id: HP:0008596
      label: Postlingual sensorineural hearing impairment
  evidence:
  - reference: PMID:41007806
    reference_title: "Unraveling the Functional Impact of Splicing Variants in Inherited Hearing Disorders Through Minigene Splicing Assays."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterized by a slow progression, typically with onset in the first or second decade of life"
    explanation: The usual postlingual onset window for DFNA84.
  - reference: PMID:41007806
    reference_title: "Unraveling the Functional Impact of Splicing Variants in Inherited Hearing Disorders Through Minigene Splicing Assays."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proband, a 57-year-old female, underwent her first audiological assessment at the age of 54"
    explanation: The late end of the ascertainment range in a molecularly confirmed carrier.
- name: Intrafamilial Variability in Onset and Audiogram Configuration
  category: Auditory
  description: >-
    Relatives carrying the same allele differ in age at onset, audiogram shape and
    inter-ear symmetry. The discovery paper offers three non-exclusive explanations for the
    onset spread within one family - genuine variability of the allele, later ascertainment
    in older generations who predate newborn screening, and anticipation - and does not
    choose between them. One older carrier had a dead right ear against a
    moderate-to-profound sloping left ear, which the authors treat as within the range of
    the phenotype rather than as evidence of a second cause.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  notes: >-
    Bound to the generic HP:0000407 on purpose. HP:0003828 "Variable expressivity" is the
    natural fit for what this phenotype records, but it sits under the clinical-modifier
    branch rather than under HP:0000118, so it is outside the PhenotypeTerm dynamic enum
    and fails term validation. The specificity is carried in the preferred_term-level
    phenotype name and description instead.
  evidence:
  - reference: PMID:35278131
    reference_title: "Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of note, the intrafamilial variability among individuals in Family A with respect to onset could be explained by"
    explanation: >-
      The authors flag intrafamilial variability explicitly. The quote stops before their
      numbered list of three candidate explanations, which is reproduced in this
      phenotype's description.
  - reference: PMID:35278131
    reference_title: "Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Comparison of audiograms (right ear series) of six family members show variable severity in the 3rd decade"
    explanation: Six same-generation relatives at comparable ages with markedly different thresholds.
prevalence:
- population: Worldwide, published families
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Six families in total as of the 2026 literature: the Newfoundland kindred and two Jewish
    Israeli families (Pater 2022), the German AUNA2 family (Chepurwar 2023), a fourth family
    with a 3' UTR deletion (2026 multi-family series), and an Italian family with a VUS-grade
    intron 12 splice allele. Everything this entry says about natural history rests on that
    base, which is why no phenotype frequency band is asserted from pooled counts.
  evidence:
  - reference: PMID:42371110
    reference_title: Integrative genetic and functional analysis of autosomal dominant hearing loss in 108 multigenerational families.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, only three pathogenic ATP11A variants have been reported in association with HL, all affecting the C-terminal region of the protein."
    explanation: The published pathogenic-allele total before this series added a fourth.
genetic:
- name: ATP11A
  notes: >-
    ATP11A (13q34) encodes a class-6 P4-ATPase phospholipid flippase specific for
    phosphatidylserine and phosphatidylethanolamine. It is ubiquitously expressed and
    homozygous deletion is embryonic lethal in mice, so the human heterozygous disease state
    is not modelled by the null. Seventeen transcripts are annotated and the disease alleles
    are distributed across them, which is why isoform-aware interpretation matters here more
    than for most deafness genes.
  gene_term:
    preferred_term: ATP11A
    term:
      id: hgnc:13552
      label: ATP11A
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  relationship_type: CAUSATIVE
  evidence:
  - reference: PMID:35278131
    reference_title: "Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "this study documents the first association of ATP11A with a highly penetrant Mendelian phenotype"
    explanation: Establishes ATP11A as a Mendelian deafness gene.
  - reference: PMID:35278131
    reference_title: "Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The ATP11A protein specifically transports phosphatidylserine (PS) and phosphatidylethanolamine (PE) across cell membranes, is ubiquitously expressed in various tissues and deletion of in atp11a in mice results in lethality during embryogenesis"
    explanation: >-
      Substrate specificity, expression breadth, and the embryonic lethality of the mouse
      null that constrains which model systems can address the heterozygous disease.
diagnosis:
- name: Isoform-aware genome or exome sequencing
  description: >-
    Molecular diagnosis requires an analysis that does not stop at the MANE select
    transcript. Two of the reported alleles sit in the 3' UTR of the MANE transcript and
    were assigned significance only after the short and long ATP11A isoforms were
    considered, and one was passed over by in silico splicing prediction entirely. Linkage
    or haplotype reduction in a large kindred remains a practical way to shrink the
    candidate list before this analysis.
  evidence:
  - reference: PMID:35278131
    reference_title: "Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Given the complexity in genomes, a comprehensive bioinformatics pipeline targeting all known transcripts is essential as is the need to experimentally validate in silico predictions in patient-derived tissues."
    explanation: The authors' explicit methodological conclusion, which is the diagnostic recommendation.
  - reference: PMID:42371110
    reference_title: Integrative genetic and functional analysis of autosomal dominant hearing loss in 108 multigenerational families.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In silico analysis also did not predict its impact on splicing."
    explanation: A reported disease allele that prediction tools scored as benign.
- name: Minigene splicing assay for candidate ATP11A splice alleles
  description: >-
    Because the recurrent finding is a non-canonical splice-region variant of uncertain
    significance, an in vitro splicing assay is the step that converts a prediction into
    evidence. Minigene assays have been applied to two ATP11A alleles - one confirming that
    the exon 28 duplication adds 8 bp without disturbing the splice pattern, the other
    confirming that c.1221+5G>C activates a cryptic donor. Note the limitation the authors
    themselves raise: a minigene reports on a construct, not on the patient's tissue.
  evidence:
  - reference: PMID:41007806
    reference_title: "Unraveling the Functional Impact of Splicing Variants in Inherited Hearing Disorders Through Minigene Splicing Assays."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The functional studies with minigene assays confirmed this observation and showed that the tested variants induced both exon skipping and activation"
    explanation: The assay converts predicted splicing effects into demonstrated ones.
  - reference: PMID:41007806
    reference_title: "Unraveling the Functional Impact of Splicing Variants in Inherited Hearing Disorders Through Minigene Splicing Assays."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "results obtained from minigene assays should be interpreted with caution and ideally validated using patient-derived RNA"
    explanation: The authors' own caveat on the assay's standing as evidence.
- name: Audiological surveillance of asymptomatic carriers
  description: >-
    Because onset is postlingual and variable, a carrier identified by cascade testing may
    be years from symptoms. Periodic audiometry, rather than reassurance, is what the
    reported management of such carriers consists of.
  evidence:
  - reference: PMID:41007806
    reference_title: "Unraveling the Functional Impact of Splicing Variants in Inherited Hearing Disorders Through Minigene Splicing Assays."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "periodic audiological evaluations were recommended to monitor for the potential onset of hearing impairment"
    explanation: The surveillance actually recommended for the presymptomatic carriers in that family.
treatments:
- name: Hearing Amplification
  description: >-
    Hearing aids are the mainstay while thresholds remain aidable. There is no
    disease-modifying therapy for DFNA84, and fitting is driven by the audiogram rather than
    the genotype. One reported ATP11A carrier began using aids in her twenties and is now
    being considered for cochlear implantation.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: hearing aid fitting
  notes: >-
    No term: is bound. NCIT was searched for a hearing-aid clinical action and has device
    terms (for example NCIT:C183182 Hearing Aid) but no amplification-fitting procedure
    reachable from NCIT:C25218 Clinical Intervention or Procedure, which is the root the
    TreatmentTerm enum requires. Binding a device term in that slot is the error the
    cochlear-implant convention in CLAUDE.md exists to prevent, so the slot is left
    unbound rather than filled with a broader action that says less than the free text.
  target_mechanisms:
  - target: Progressive Bilateral Sensorineural Hearing Loss
    description: Symptomatic amplification; it does not act on the flippase deficit.
- name: Cochlear Implantation
  description: >-
    Considered when hearing loss reaches the severe-to-profound range and amplification is
    no longer sufficient. In the auditory-neuropathy presentation the calculus is different
    from ordinary sensorineural loss, since outer hair cell function is preserved and the
    lesion is neural, and no ATP11A-specific implant outcome data have been published.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: cochlear device implantation
    term:
      id: NCIT:C15329
      label: Surgical Procedure
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: cochlear implant
        term:
          id: NCIT:C157820
          label: Cochlear Implant
  target_mechanisms:
  - target: Progressive Bilateral Sensorineural Hearing Loss
    description: Bypasses the sensory deficit; does not address the underlying flippase lesion.
  evidence:
  - reference: PMID:41007806
    reference_title: "Unraveling the Functional Impact of Splicing Variants in Inherited Hearing Disorders Through Minigene Splicing Assays."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Currently, cochlear implantation (CI) represents the standard treatment for severe-to-profound hearing loss."
    explanation: The standard-of-care statement this treatment records; it is not ATP11A-specific.
- name: Genetic Counseling and Cascade Testing
  description: >-
    Dominant inheritance with high penetrance but late and variable onset makes cascade
    testing informative and makes the result actionable only as surveillance. In one
    reported family both adult offspring of an affected proband were found to carry the
    allele while still asymptomatic.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:41007806
    reference_title: "Unraveling the Functional Impact of Splicing Variants in Inherited Hearing Disorders Through Minigene Splicing Assays."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the children of the patient carrying a heterozygous splicing variant in ATP11A were found to carry the same variant, despite not yet showing HL"
    explanation: Cascade testing identifying presymptomatic carriers, which is what makes surveillance possible.
animal_models:
- name: atp11a loss-of-function zebrafish
  species: Zebrafish
  genotype: atp11a nl1005 and nl1007 CRISPR loss-of-function alleles, heterozygous and homozygous
  publication: PMID:40223426
  description: >-
    CRISPR-generated loss-of-function alleles in the zebrafish orthologue, phenotyped in the
    larval inner ear and lateral line. Two independent alleles show the same phenotype,
    which is the control against CRISPR off-target effects. Heterozygotes have an
    intermediate but statistically significant stereocilia deficit, which is the feature
    that makes this model relevant to a dominant human disease rather than only to a null.
  genes:
  - preferred_term: ATP11A
    term:
      id: hgnc:13552
      label: ATP11A
  modeled_mechanisms:
  - target: Cochlear Hair Cell and Supporting Cell Dysfunction
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces a sensory hair-cell structural deficit on loss of the orthologue, in both
      the otic sensory patches and one lateral-line neuromast.
    limitations: >-
      Zebrafish have no cochlea, no organ of Corti and no Deiters cells, so the model cannot
      speak to the cell type the human expression data implicate most strongly. The
      phenotype is a larval structural count, not a hearing threshold, and no auditory
      function was measured. The alleles are coding loss-of-function, whereas every human
      disease allele alters the C-terminus or 3' end - so the model tests loss of the
      protein rather than the specific lesion patients carry. The same animals have an
      independent light-dependent photoreceptor phenotype absent from the human disease.
    evidence:
    - reference: PMID:40223426
      reference_title: The P4-phospholipid flippase Atp11a is required for maintenance of eye and ear structure in zebrafish.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We demonstrate that mutant atp11a zebrafish display a reduced number of stereocilia in the larval ear and a reduced number of hair cells in some sensory neuromasts, indicating that these fish represent an ideal model for studying atp11a-attributable hearing loss."
      explanation: The authors' own claim for the model's relevance to ATP11A hearing loss.
    - reference: PMID:40223426
      reference_title: The P4-phospholipid flippase Atp11a is required for maintenance of eye and ear structure in zebrafish.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Loss of hair cell stereocilia in the ear is observed in atp11a mutant zebrafish, in agreement with hearing loss in human individuals and mouse models"
      explanation: The correspondence the authors draw to the human and murine phenotypes.
    readouts:
    - name: Stereocilia count in otic sensory patches
      target: Cochlear Hair Cell and Supporting Cell Dysfunction
      direction: DECREASED
      interpretation: >-
        Phalloidin-stained hair bundle counts fall in four of the five larval otic sensory
        patches in homozygotes, with an intermediate significant reduction in heterozygotes.
      evidence:
      - reference: PMID:40223426
        reference_title: The P4-phospholipid flippase Atp11a is required for maintenance of eye and ear structure in zebrafish.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Intermediate phenotypes, that were also statistically significant, were observed in heterozygous animals."
        explanation: >-
          The gene-dosage sensitivity that makes the heterozygous fish informative about a
          dominant human disease.
    - name: Lateral-line neuromast hair cell count
      target: Cochlear Hair Cell and Supporting Cell Dysfunction
      direction: DECREASED
      interpretation: >-
        Reduced in the O1 neuromast in homozygotes and heterozygotes, but unchanged in
        SO1-SO3 - so the deficit is not a global hair-cell loss.
      evidence:
      - reference: PMID:40223426
        reference_title: The P4-phospholipid flippase Atp11a is required for maintenance of eye and ear structure in zebrafish.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "we observed a reduction in the number of hair cells in the O1 neuromast in both homozygous and heterozygous mutant larvae; however, analysis of other neuromasts (SO1, SO2 and SO3), showed no phenotype compared to wild-type siblings"
        explanation: >-
          Records the negative result alongside the positive one, which bounds how far the
          hair-cell claim extends.
  evidence:
  - reference: PMID:40223426
    reference_title: The P4-phospholipid flippase Atp11a is required for maintenance of eye and ear structure in zebrafish.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Phenotypes are present in two different alleles of atp11a"
    explanation: >-
      Two independent alleles give the same phenotype, which is what allows the result to be
      attributed to atp11a loss rather than to CRISPR off-target effects.
- name: Conditional Atp11a knockout mouse
  species: Mouse
  genotype: Conditional Atp11a knockout
  publication: PMID:36300302
  description: >-
    A conditional knockout generated to test the AUNA2 mechanism; constitutive deletion is
    embryonic lethal, which is why conditional deletion was required. The readout is a
    progressive fall in the spiral ganglion neuron compound action potential, matching the
    neural rather than cochlear-amplifier lesion of auditory neuropathy.
  genes:
  - preferred_term: ATP11A
    term:
      id: hgnc:13552
      label: ATP11A
  modeled_mechanisms:
  - target: Auditory Nerve and Spiral Ganglion Dysfunction
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the progressive neural encoding deficit that defines the human AUNA2
      presentation.
    limitations: >-
      A conditional knockout is a null in the targeted cells, whereas the human allele is a
      heterozygous C-terminal deletion producing an altered protein - so the model tests
      absence of ATP11A rather than the dominant action of the patient allele. Only the
      abstract is available for this report, so the deletion driver, timing and cochlear
      histology cannot be assessed from the cached record.
    evidence:
    - reference: PMID:36300302
      reference_title: A mutation in ATP11A causes autosomal-dominant auditory neuropathy type 2.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "conditional Atp11a knockout mice show a progressive reduction of the spiral ganglion neuron compound action potential, recapitulating the human phenotype of AN"
      explanation: The authors' recapitulation claim, with the specific electrophysiological readout.
    readouts:
    - name: Spiral ganglion neuron compound action potential
      target: Auditory Nerve and Spiral Ganglion Dysfunction
      direction: DECREASED
      interpretation: Progressive decline, the electrophysiological signature of auditory neuropathy.
      evidence:
      - reference: PMID:36300302
        reference_title: A mutation in ATP11A causes autosomal-dominant auditory neuropathy type 2.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "conditional Atp11a knockout mice show a progressive reduction of the spiral ganglion neuron compound action potential"
        explanation: The measurement itself and its direction.
  evidence:
  - reference: PMID:36300302
    reference_title: A mutation in ATP11A causes autosomal-dominant auditory neuropathy type 2.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "By combining whole-genome sequencing, immunohistochemistry, in vitro functional assays and generation of a mouse model, we could thus identify a partial deletion of ATP11A as the genetic cause of AUNA2."
    explanation: The mouse model is one of the four lines of evidence the gene-disease claim rests on.
discussions:
- discussion_id: atp11a_dominance_mechanism
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does a heterozygous C-terminal ATP11A allele cause hearing loss by halving flippase
    dose, or by the altered protein interfering with the wild-type protein?
  attaches_to:
  - pathophysiology#Loss of Phosphatidylserine Flippase Activity
  - pathophysiology#ATP11A C-Terminal and 3' Region Variants
  rationale: >-
    Every reported allele leaves a protein that is made and C-terminally altered rather than
    absent, and the C-terminus is where folding, activity regulation and localisation are
    controlled. That is the classic setup for dominant-negative action, but it is equally
    compatible with the altered protein being degraded and the phenotype reflecting
    haploinsufficiency. The discovery paper names both possibilities and chooses neither.

    The question is not academic. If the mechanism is haploinsufficiency, dose restoration -
    gene addition or upregulation of the wild-type allele - is the therapeutic route. If it
    is dominant-negative, adding wild-type protein may not help and allele-specific
    silencing is needed instead. The available models do not settle it: the mouse null is
    embryonic lethal, the conditional knockout is a null in the targeted cells, and the
    zebrafish alleles are coding loss-of-function rather than C-terminal. A model carrying a
    knock-in of a patient C-terminal allele in the heterozygous state is the missing
    reagent.
  evidence:
  - reference: PMID:35278131
    reference_title: "Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disease mechanism, how variants in the ATP11A gene cause hearing loss, is unclear."
    explanation: The authors state the gap directly.
  - reference: PMID:35278131
    reference_title: "Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is likely that pathogenic splicing variants act via dominant-negative or haploinsufficiency mechanism."
    explanation: The two candidate mechanisms, left unresolved.
  - reference: PMID:35278131
    reference_title: "Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "deletion of in atp11a in mice results in lethality during embryogenesis"
    explanation: >-
      Why the constitutive mouse null cannot answer the question, and why a heterozygous
      knock-in is the reagent that would.
- discussion_id: atp11a_ps_exposure_druggability
  kind: KNOWLEDGE_GAP
  prompt: >-
    Is phosphatidylserine actually externalised on cochlear cells in ATP11A-related hearing
    loss, and would blocking the resulting phagocytic signal preserve hearing?
  attaches_to:
  - pathophysiology#Loss of Plasma Membrane Phospholipid Asymmetry
  - treatments#
  rationale: >-
    The discovery paper's therapeutic proposal has two links, and only the first is
    established. That ATP11A flips phosphatidylserine inward, and that a disease allele
    abolishes that activity, is demonstrated. That the consequence in the cochlea is surface
    phosphatidylserine marking hair cells or spiral ganglion neurons for phagocytic
    clearance is an inference from general phospholipid biology - no cochlear
    phosphatidylserine-exposure measurement has been reported in any ATP11A model, human or
    animal.

    The proposal is nonetheless worth recording, because unlike most deafness genes it names
    a druggable intermediate rather than requiring gene replacement: surface
    phosphatidylserine has established pharmacological ligands. The experiment that would
    move this from proposal to hypothesis is a direct one - stain cochlear or hair-cell
    membranes from an ATP11A model for outer-leaflet phosphatidylserine and ask whether it
    is increased. The zebrafish mutants and the conditional mouse both exist and neither has
    been used this way.
  evidence:
  - reference: PMID:35278131
    reference_title: "Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Phagocytic signals such as PS at the cell surface are known pharmaceutical targets"
    explanation: >-
      The druggability half of the proposal. Marked INDIRECT because it is a statement about
      phosphatidylserine as a target class generally, not about the cochlea.
  - reference: PMID:35278131
    reference_title: "Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "the deregulation of transport could redistribute PS to the extracellular side of plasma membrane flagging cells for their recognition, phagocytosis, and ultimate degradation by phagocytes"
    explanation: >-
      The mechanistic half, stated by the authors in the conditional as a future direction
      rather than as a result.
  - reference: PMID:35278131
    reference_title: "Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Limitations of this study include a lack of insight as to protein function, specifically with respect to hearing loss."
    explanation: The authors' own statement that the cochlear functional link is missing.
- discussion_id: dfna33_locus_disposition
  kind: KNOWLEDGE_GAP
  prompt: >-
    Is the historical DFNA33 locus the same entity as DFNA84, or was the original mapping
    wrong?
  attaches_to:
  - disease#Hearing Loss Autosomal Dominant 84
  rationale: >-
    The discovery kindred for DFNA84 linked to 13q34, the interval mapped in 2009 as DFNA33
    in a German family, and the discovery paper closes by saying the original DFNA33 family
    should be sequenced to settle whether ATP11A is DFNA33. That was attempted. A member of
    the original family was genome-sequenced; the ATP11A variant found was deep intronic and
    spliced normally, and re-examination of the published haplotypes turned up two double
    recombination events and one triple - a pattern the authors read as genotyping error
    rather than biology.

    So the disposition of DFNA33 is unresolved in a specific way that matters for this entry:
    the shared 13q34 coordinates are not evidence that DFNA33 and DFNA84 are one disease,
    and DFNA84 should be treated as resting on its own families rather than inheriting the
    DFNA33 kindred's phenotype description. Nothing here casts doubt on ATP11A as the DFNA84
    gene.
  evidence:
  - reference: PMID:37671045
    reference_title: Unraveling haplotype errors in the DFNA33 locus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The DFNA33 locus was mapped in 2009 and coincidentally contains ATP11A, a gene recently associated with autosomal dominant hearing loss and auditory neuropathy type 2."
    explanation: The coincidence of coordinates that prompted the re-analysis.
  - reference: PMID:37671045
    reference_title: Unraveling haplotype errors in the DFNA33 locus.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a deep intronic variant in ATP11A that showed evidence of functionally normal splicing."
    explanation: >-
      Refutes the proposal that ATP11A is the DFNA33 gene, at least via the variant found in
      the re-ascertained family member.
  - reference: PMID:37671045
    reference_title: Unraveling haplotype errors in the DFNA33 locus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we re-assessed haplotypes from the originally published DFNA33 family and identified two double recombination events and one triple recombination event in the pedigree, a highly unlikely occurrence, especially at this scale"
    explanation: The evidence that the original DFNA33 interval itself is unreliable.
  - reference: PMID:35278131
    reference_title: "Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It will be important, if possible, for the original German family used to map DFNA33 be sequenced to be certain that ATP11A is DFNA33."
    explanation: The question as originally posed, which the later study then attempted to answer.
📚

References & Deep Research

References

7
PMID:35278131
Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene.
No top-level findings curated for this source.
PMID:36300302
A mutation in ATP11A causes autosomal-dominant auditory neuropathy type 2.
No top-level findings curated for this source.
PMID:28601886
AUNA2: A Novel Type of Non-Syndromic Slowly Progressive Auditory Synaptopathy/Auditory Neuropathy with Autosomal-Dominant Inheritance.
No top-level findings curated for this source.
PMID:37671045
Unraveling haplotype errors in the DFNA33 locus.
No top-level findings curated for this source.
PMID:40223426
The P4-phospholipid flippase Atp11a is required for maintenance of eye and ear structure in zebrafish.
No top-level findings curated for this source.
PMID:41007806
Unraveling the Functional Impact of Splicing Variants in Inherited Hearing Disorders Through Minigene Splicing Assays.
No top-level findings curated for this source.
PMID:42371110
Integrative genetic and functional analysis of autosomal dominant hearing loss in 108 multigenerational families.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (3)

Record notes

Literature base. A PubMed sweep run on 2026-09-04 for ATP11A crossed with hearing loss, deafness, auditory, cochlea, DFNA84 and 13q34 returns six ATP11A hearing-loss reports, all of which are cited here, plus PMID:28601886, the pre-gene clinical description of the AUNA2 family, which was added to the AUNA2 subtype as a result. "DFNA84" as a query string returns nothing indexed. A falcon deep-research report was also generated and is committed at research/Hearing_Loss_Autosomal_Dominant_84-deep-research-falcon.md. It introduced no reference the entry was missing: every indexed source in its citation list resolves to a paper already cited here - the Research Square preprint DOI:10.21203/rs.3.rs-530835/v1 is the preprint of PMID:35278131, and its remaining DOIs are PMID:36300302, PMID:37671045, PMID:40223426 and PMID:41007806. Its only other two sources are unindexed dissertations (von Loh 2021; Pater 2019) with no PMID or DOI. The manual sweep and the retrieval pass therefore agree that the citable literature base is complete, which is a stronger statement of completeness than either check alone. One preflight warning on that report is a false positive worth recording, because it will recur for every audiology entry curated from a deep-research report: preflight-dr flags "ABR" as a rival gene symbol - hgnc:81 is a real gene called ABR - but every occurrence of ABR in this report and in this entry is the auditory brainstem response. The report also suggests GO:0004012, which is obsolete and replaced by GO:0140326; it was treated as a lead and not bound, and this entry binds GO:0140346, GO:0140331, GO:0097035 and GO:0005886 instead. GeneReviews. PMID:20301607, the Genetic Hearing Loss Overview, is cached and is tagged GeneReviews in sibling hearing-loss entries, but it is deliberately not tagged here. Its cached record is abstract-only - the body is the chapter's six-point statement of scope and nothing more - and contains no occurrence of ATP11A, DFNA84 or AUNA2, so tagging it would produce a tagged-but-not-mined reference. There is no ATP11A-specific GeneReviews chapter; the entity was first described in 2022. This paragraph records the negative so it is auditable rather than looking like an omission. AUNA2 and kb/disorders/Auditory_Neuropathy.yaml. The AUNA2 subtype below is also carried as a subtype of Auditory_Neuropathy, bound to the same MONDO:0957279 term and citing the same PMID:36300302 finding. That is deliberate overlap along two different axes - this entry groups by gene and allelic mechanism, Auditory_Neuropathy groups by the audiological presentation - and neither is a duplicate of the other. If the two are ever reconciled, the gene-side pathophysiology lives here and the audiological differential lives there.

Review round 3: reconcile notes with the committed deep-research artifact · 2026-09-04T17:07:00Z · View source

Addressed the CHANGES_REQUESTED review of 2026-09-04T08:02Z on PR #10901. IMPORTANT (fixed). The notes: literature-base paragraph still said no deep-research provider report was generated, which commit c9e341228 in this same PR falsified by adding research/Hearing_Loss_Autosomal_Dominant_84-deep-research-falcon.md. Rewrote the paragraph to record both checks: the manual PubMed sweep (which surfaced PMID:28601886) and the falcon report, plus what the report contributed. Every indexed source in the report's citation list resolves to a paper already cited here - DOI:10.21203/rs.3.rs-530835/v1 is the Research Square preprint of PMID:35278131, and the remaining DOIs are PMID:36300302, PMID:37671045, PMID:40223426 and PMID:41007806. The report's only other sources are two unindexed dissertations (von Loh 2021; Pater 2019) with no PMID or DOI. The prior round's history record was left untouched; history is append-only. SUGGESTION 1 (taken). The pathophysiology node ATP11A C-Terminal and 3' Region Variants opened by asserting that all reported disease alleles disturb the C-terminal region or the 3' end, then listed c.1221+5G>C, an intron 12 allele that the prevalence note already and correctly calls VUS-grade. Reworded to 'every established disease allele' and split c.1221+5G>C out as the double exception - mid-gene position, and uncertain rather than established significance - so the node and the prevalence note now agree. SUGGESTION 2 (taken). Added GO:0007605 sensory perception of sound with modifier ABNORMAL to the conforming node Cochlear Hair Cell and Supporting Cell Dysfunction, and recorded in its conformance paragraph why the module's other process, GO:0050910, is deliberately omitted: no ATP11A study demonstrates a mechanotransduction defect. The nearest observation is a Yo-Pro-1 uptake difference in one zebrafish lateral-line neuromast that PMID:40223426's authors read as either cell loss or loss of mechanotransduction capacity without deciding between them, and which is not a cochlear hair cell. SUGGESTION 3 (taken). Recorded the preflight-dr Named Entity Confusion false positive in notes: it flags ABR as a rival gene symbol (hgnc:81 is a real gene called ABR), but every occurrence of ABR here is the auditory brainstem response. This will recur for any audiology entry curated from a DR report. Also recorded that the report's GO:0004012 suggestion is obsolete (replaced by GO:0140326) and was not bound. Not changed. The DFNA33 locus remains deliberately unresolved (PMID:37671045 reports implausible double and triple recombinations in the original haplotypes). The spiral-ganglion node is still not conformed to the module's amplification-loss node, because AUNA2 has preserved outer-hair-cell amplification and a primary neural deficit. Validation. just validate, validate-terms, count-verified-snippets (60/60), check-entity-refs, check-duplicate-keys, check-causal-targets, check-enum-values, check-qualifier-terms all pass on the file. Whole-KB check-folded-hyphens, check-title-snippets, check-snippet-length and check-snippet-grading all report no new divergences. The term validator again reserialized references_cache/PMID_36300302.md frontmatter; that drift was reverted so this PR does not touch a cache file another entry owns.

Review round 1: address CHANGES_REQUESTED on PR #10901 · 2026-09-04T06:31:32Z · View source

Addressed the eight IMPORTANT findings and three suggestions in the automated review of PR #10901. Fixed: - Replaced the truncated PMID:41007806 snippet ("the variant induced the selection of a cryptic 5") with the authors' summary sentence at cache line 102, which contains no typographic prime and names ATP11A explicitly. The previous item's justification - that the reference validator normalises the prime glyph - is not documented in conf/reference_validator_config.yaml, and the reviewer was right that a snippet stopping mid-token is not propositional. - Bound the AUNA2 subtype to MONDO:0957279, copying the binding already used in kb/disorders/Auditory_Neuropathy.yaml. - Recorded the deliberate AUNA2 overlap with Auditory_Neuropathy.yaml in a subtype review_notes and in the entry's top-level notes, rather than resolving the lump/split silently. - Added conforms_to "sensorineural_hair_cell_loss#Cochlear Sensory Epithelium Insult" on the Cochlear Hair Cell and Supporting Cell Dysfunction node, following the ADNSHL_17 precedent, and wrote into both that node and the spiral-ganglion node why the deeper module nodes are not claimed. - Rebound the Deiters cell descriptor from CL:0002490 (organ of Corti supporting cell) to CL:0000635 (Deiter's cell). - Added a top-level references: block, external_assertions for OMIM:619810, and classifications.harrisons_chapter NEUROLOGIC. - Added notes recording why the hearing-aid treatment_term is unbound and why the intrafamilial-variability phenotype uses the generic HP:0000407. Declined, with reasons written into the entry: - No deep-research artifact was added. CLAUDE.md forbids hand-writing markdown into research/, and no provider recipe was available in this environment. A manual PubMed sweep was run instead on 2026-09-04 (ATP11A crossed with hearing loss / deafness / auditory / cochlea / 13q34 / phosphatidylserine flippase, plus DFNA84 and AUNA2 as strings). It returned exactly the six ATP11A hearing-loss reports already cited, plus one genuinely missing paper: PMID:28601886, the pre-gene clinical description of the AUNA2 family. That paper was fetched and mined into the AUNA2 subtype (natural history, the 12q24/13q34 linkage that later resolved to ATP11A, and the nonsyndromic character). The sweep is recorded in the entry's top-level notes. - PMID:20301607 (Genetic Hearing Loss Overview) was not tagged GeneReviews. Its cached record is abstract-only and its body is the chapter's six-point statement of scope; it contains no occurrence of ATP11A, DFNA84 or AUNA2, so tagging it would create a tagged-but-not-mined reference - the same defect the reviewer flagged in the sibling DFNB26 review. The negative is recorded in the entry's notes so it is auditable. Validation: just validate (60/60 snippets verified), validate-terms, check-entity-refs, check-duplicate-keys, check-causal-targets, check-enum-values, check-qualifier-terms, check-folded-hyphens, check-title-snippets, check-snippet-length, check-snippet-grading all pass. references_cache/PMID_36300302.md was rewritten by the validator run and reverted, as in the previous round.

Falcon ▸
Hearing Loss, Autosomal Dominant 84 (DFNA84): Disease-Characteristics Report
Edison Scientific Literature 16 citations 2026-09-04T00:01:35.388890

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.

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:

  • NM_032189.3:c.3322_3327+2dupGTCCAGGT, extending exon 28 by 8 bp and predicting p.Asn1110ValfsTer43;
  • a 3′ cryptic-donor variant reported as chr13:113534963G>A, causing retention of 153 intronic bases in several ATP11A transcripts;
  • NM_015205.3:c.1221+5G>C, reported in 2025 as a VUS, not an established causal DFNA84 allele (pater2022autosomaldominantnonsyndromic pages 9-11, pater2021autosomaldominantnonsyndromic pages 5-7, rosso2025unravelingthefunctional pages 5-7).

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.

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.

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.