Hearing Loss Autosomal Dominant 82

Mendelian MONDO:0030719 Pathograph 9 Show in embeddings browser Autosomal Dominant Nonsyndromic Hearing Loss

DFNA82 is autosomal dominant nonsyndromic hearing loss caused by heterozygous loss-of-function variants in ATP2B2, which encodes PMCA2 - the plasma-membrane calcium pump that clears Ca2+ out of hair cell stereocilia and helps hold the endolymph's own calcium concentration where it needs to be. The clinical picture is tight for a nonsyndromic deafness entity: children pass newborn hearing screening, a steeply downsloping high-frequency loss is picked up between about three and six years, it progresses rapidly, and balance is normal on formal vestibular testing. The reason this entry exists as a separate disease, rather than as a note on somebody else's, is a distinction that took fourteen years to establish and is easy to erase. For most of that time ATP2B2 was known in human hearing loss only as a *modifier*: a hypofunctional missense variant, p.Val586Met, that made CDH23-related deafness worse in three of five siblings and appeared to aggravate hearing loss from a MYO6 mutation and from noise in two unrelated people. That is a real finding and it is not this disease. DFNA82 is the monogenic entity defined by heterozygous *truncating and splice-site* ATP2B2 alleles - nonsense, frameshift and canonical splice-donor changes, two of them de novo - in people whose CDH23 was sequenced and found not to explain the phenotype. A citation about digenic ATP2B2/CDH23 modification is evidence for the modifier claim and says nothing about DFNA82. A third ATP2B2 entity has to be kept apart from both. De novo missense changes and frameshifts in the penultimate exon cause a neurodevelopmental and movement disorder with dystonia, ataxia, intellectual disability, autistic features and seizures, and in cell assays those alleles produce a mixture of loss- and gain-of-function effects on calcium handling. Same gene, different allele class, different disease. The mouse work is unusually good and it came first. Deafwaddler was the original allele, and there are now several independent lines - spontaneous, ENU-induced and null - which agree that heterozygotes have progressive, high-frequency-first hearing loss and homozygotes are profoundly deaf with vestibular dysfunction. That heterozygous mouse phenotype is the closest animal counterpart of a human dominant disease this repository curates for the ear, and the human authors used it as their prior. It also carries the clearest warning about reading mechanism off sequence: the Oblivion allele sits in a transmembrane domain, where mutations were expected to prevent the pump reaching the membrane, and the protein turned out to be trafficked correctly and simply to pump badly.

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1
Mappings
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Inheritance
4
Pathophys.
3
Phenotypes
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Hypotheses
2
Gaps
9
Pathograph
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Genes
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Medical Actions
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Models
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References
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Deep Research
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Mappings

MONDO
MONDO:0030719 hearing loss, autosomal dominant 82
skos:exactMatch MONDO
👪

Inheritance

1
Autosomal dominant HP:0000006
Heterozygous loss-of-function ATP2B2 alleles. Three segregated through families with a dominant hearing loss pattern; two arose de novo in isolated index cases, which is what rules out an inherited second locus as the explanation in those two families and is the strongest single argument that one damaged ATP2B2 copy is sufficient.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:30535804 SUPPORT Human Clinical
"Three variants c.397+1G>A (p.?), c.1998C>A (p.Cys666*), and c.2329C>T (p.Arg777*), were identified in families with an autosomal dominant inheritance pattern of hearing impairment."
The three inherited alleles and the pedigree pattern they segregate with.
PMID:30535804 SUPPORT Human Clinical
"Two variants, c.1963G>T (p.Glu655*) and c.955delG (p.Ala319fs), occurred de novo."
The two de novo alleles. A de novo truncating variant in an affected child of unaffected parents is the observation that makes single-copy loss sufficient rather than merely associated.
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Mechanistic Hypotheses

2
Monogenic haploinsufficiency for PMCA2 in outer hair cells
monogenic_pmca2_haploinsufficiency CANONICAL
Evidence balance 3 support
One truncating or splice-disrupting ATP2B2 allele leaves too little functional PMCA2 to clear calcium from the stereocilia of outer hair cells, and hearing fails from the high frequencies down. This is the model the disease entity is defined by. It is supported in humans by two de novo truncating alleles and by segregation of three more, with CDH23 sequenced and excluded in the index cases; and in mice by several independent heterozygous lines, each showing progressive high-frequency-first loss.
Pathograph links
ATP2B2 Heterozygous Loss of Function -> Impaired Calcium Extrusion from Stereocilia DIRECT
Show evidence (3 references)
PMID:30535804 SUPPORT Human Clinical
"Although a digenic inheritance pattern of hearing impairment has been reported for heterozygous missense variants of ATP2B2 and CDH23, our findings indicate a monogenic cause of hearing impairment in cases with loss-of-function variants of ATP2B2."
The authors' explicit separation of the monogenic entity from the digenic mechanism, stated as the conclusion of the study that established DFNA82.
PMID:30535804 SUPPORT Computational
"A causal association with disease is further strengthened by a pLI score of 1.00 reported for ATP2B2."
The constraint argument for dosage sensitivity: a pLI of 1.00 means the gene is extremely intolerant of losing one functional copy, which is what a haploinsufficiency model requires. Graded COMPUTATIONAL because pLI is a population-genetic prediction rather than a measurement in these patients.
PMID:23826306 SUPPORT INDIRECT Model Organism
"Mice homozygous for these mutations display profound hearing loss. Heterozygotes display mild to moderate, progressive hearing loss."
Independent ENU alleles reproducing the dose relationship the model predicts. Indirect with respect to the human disease: these are mouse missense alleles, not the truncating human ones.
ATP2B2 as a modifier of hearing loss caused by other genes
cdh23_modifier_interaction ALTERNATIVE
Evidence balance 4 support 1 no evidence
A separate and genuine role for ATP2B2 that this entry deliberately does not curate as DFNA82. A hypofunctional missense variant, p.Val586Met, was associated with worse hearing in three of five siblings homozygous for a CDH23 mutation, and with increased loss in two unrelated people whose deafness came from a MYO6 mutation and from noise. The mouse counterpart is well characterised: extracellular calcium is needed for the rigidity of cadherin 23 in the tip link, and Atp2b2 and Cdh23 alleles interact in a dose- and frequency-dependent way. It is recorded here as ALTERNATIVE not because it is doubtful - it is well supported - but because it is a claim about a different genotype. The modifier evidence is missense and hypofunctional, the DFNA82 evidence is truncating and de novo, and treating a citation about one as evidence for the other is the specific error this entry is written to prevent. One thing the founding study is careful about and this entry should be too: rare CDH23 variants co-occurred with the ATP2B2 allele in all five index cases. The authors argue each of them down - intronic and predicted not to affect splicing, synonymous, benign or common in population data, failing to co-segregate - and conclude monogenic causation. But they also state that a modifying effect of those CDH23 variants cannot be excluded. Monogenic causation and a superimposed modifier are not mutually exclusive claims, and this entry asserts the first without denying the second.
Pathograph links
Reduced Endolymph Calcium -> Outer Hair Cell Dysfunction and Degeneration INDIRECT KNOWN INTERMEDIATES Intermediates: Loss of extracellular calcium needed for cadherin 23 rigidity in the stereocilia tip link
Show evidence (5 references)
PMID:15829536 SUPPORT Human Clinical
"Genetic evaluation revealed that a homozygous mutation in CDH23 (which encodes cadherin 23) caused the hearing loss in all five siblings and that a heterozygous, hypofunctional variant (V586M) in plasma-membrane calcium pump PMCA2, which is encoded by ATP2B2, was associated with increased loss..."
The founding modifier observation. Note what causes the deafness in these siblings: CDH23, in all five. The ATP2B2 variant changes severity, and the sentence says so.
PMID:23792079 SUPPORT Model Organism
"However, extracellular Ca2+ ions surrounding the stereocilia are also required for rigidity of cadherin 23, a component of the stereocilia tip-link encoded by the Cdh23 gene."
The biochemical reason the two genes interact at all, which is what makes the modifier effect mechanistic rather than statistical.
PMID:30535804 NO_EVIDENCE Human Clinical
"Up to now ATP2B2 has only been reported as a modifier, or in a digenic mechanism with CDH23 for hearing impairment in humans."
Graded NO_EVIDENCE with respect to DFNA82: the sentence describes the state of the literature before this study and bears on the modifier claim, not on whether heterozygous ATP2B2 loss of function causes hearing loss on its own.
+ 2 more references
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Discussions and Knowledge Gaps

2
ATP2B2 carries three human phenotypes - a monogenic dominant deafness, a severity modifier for deafness caused by other genes, and a neurodevelopmental movement disorder. Does allele class fully determine which one a person gets?
KNOWLEDGE GAP atp2b2_allele_class_determines_disease
Attached to
genetic#ATP2B2 mechanistic_hypotheses#monogenic_pmca2_haploinsufficiency mechanistic_hypotheses#cdh23_modifier_interaction
The current mapping is clean enough to write down and not clean enough to rely on. Truncating and splice-site heterozygotes get DFNA82. The hypofunctional missense p.Val586Met acts as a modifier. De novo missense changes, and frameshifts in the penultimate exon, cause the neurodevelopmental disorder. Three allele classes, three phenotypes. Two things spoil the tidiness. The neurodevelopmental series includes frameshift alleles - in the penultimate exon, where escape from nonsense-mediated decay would leave a truncated protein behind rather than removing it - so "frameshift" alone does not predict the phenotype, and position within the gene is doing work that nobody has characterised. And some of those individuals have hearing loss as well as the movement and cognitive features, so the phenotypes are not disjoint. Meanwhile the cell assays on the neurodevelopmental alleles found both loss- and gain-of-function effects on calcium handling, which is a different molecular behaviour from the simple dosage reduction DFNA82 is assumed to involve - and that assumption has never been tested, because no DFNA82 allele has been assayed for pump function at all. The question matters for reporting rather than for biology alone. A laboratory finding a novel heterozygous ATP2B2 variant in a child with isolated hearing loss has to decide which of three literatures applies, and the deciding features - truncating versus missense, de novo versus inherited, position relative to the last exon - are currently a pattern observed across two small series rather than a rule anyone has validated.
Proposed experiments
Calcium-handling assay across all reported ATP2B2 disease alleles
exp_dfna82_pump_function_by_allele_class
Express each reported human ATP2B2 allele - the five DFNA82 truncating and splice alleles, the p.Val586Met modifier, and the neurodevelopmental missense and penultimate-exon frameshift alleles - in a common cell background, and measure protein level, plasma-membrane targeting, basal and stimulated calcium export, and resting cytosolic calcium, with wild-type and empty vector controls. Include a transcript-level assay of nonsense-mediated decay for every truncating allele, since whether a truncated protein persists is the variable that distinguishes the two frameshift classes.
Would support
mechanistic_hypotheses#monogenic_pmca2_haploinsufficiency
Would refute
mechanistic_hypotheses#monogenic_pmca2_haploinsufficiency
Supporting outcome
  • DFNA82 alleles produce no detectable protein and no export activity while the neurodevelopmental alleles produce mistargeted or mixed-function protein, which would make simple dosage the DFNA82 mechanism and give laboratories a functional criterion to sort a novel variant by.
Refuting outcome
  • One or more DFNA82 alleles escape nonsense-mediated decay and produce a protein with altered rather than absent activity, which would mean DFNA82 is not haploinsufficiency either, would place it on the same spectrum as the neurodevelopmental alleles, and would make allele-specific silencing rather than gene addition the rational therapy.
Show evidence (3 references)
PMID:37675773 SUPPORT Human Clinical
"The alleles comprised 5 missense substitutions that affected evolutionarily conserved sites and 2 frameshift variants in the penultimate exon."
The allele composition of the neurodevelopmental series, including the two frameshifts whose position is what stops "truncating means DFNA82" from being a rule.
PMID:37675773 SUPPORT In Vitro
"In cell-based studies, all variants caused significant alterations in cytosolic calcium handling with both loss- and gain-of-function effects."
The molecular contrast with the dosage model assumed for DFNA82, and the reason the two cannot be treated as the same lesion at different severities.
PMID:30535804 SUPPORT Human Clinical
"Whole exome sequencing in hearing impaired index cases of Dutch and Polish origins revealed five novel heterozygous (predicted to be) loss-of-function variants of ATP2B2."
The DFNA82 allele class, with the authors' hedge - predicted to be - that is exactly the untested assumption this gap names.
Allele-specific CRISPR editing restores hearing in Oblivion mice, whose mutation makes a defective pump. Four of five human DFNA82 alleles already truncate PMCA2. What would editing accomplish in a patient?
HUMAN MODEL MISMATCH atp2b2_editing_strategy_mismatch
Attached to
animal_models#Atp2b2 Oblivion mouse treated with CRISPR-Cas9 ribonucleoprotein pathophysiology#ATP2B2 Heterozygous Loss of Function
The Oblivion rescue is a real technical achievement and it is aimed at the wrong lesion for this disease. Allele-specific disruption works when the mutant allele is actively harmful - a dominant-negative or gain-of-function protein whose removal helps. Oblivion fits: the pump is trafficked normally and pumps badly, so a mutant PMCA2 is sitting in the membrane doing a poor job, and cutting it out is a coherent intervention. DFNA82 alleles are nonsense, frameshift and splice-donor changes. If they behave as the authors predict, the mutant allele contributes nothing and there is nothing to disable. Editing it would move the patient from one functional copy to one functional copy. The intervention that follows from haploinsufficiency is the opposite one - supply a working copy - and that has not been attempted for ATP2B2 in any system. So the model and the disease agree on the phenotype and disagree on the therapeutic logic, which is a more specific mismatch than the usual species caveat and one that could send a translational programme in the wrong direction. Resolving it needs the functional assay proposed in the allele-class gap above, plus a mouse carrying a human truncating allele rather than Oblivion. A smaller mismatch sits alongside. The study's digenic arm is a mouse engineered to carry two dominant deafness mutations, Tmc1 Beethoven and Atp2b2 Oblivion. That is a demonstration that two alleles can be edited at once; it is not a model of the ATP2B2-CDH23 modifier interaction seen in patients, where the ATP2B2 contribution is a hypofunctional missense variant modifying a recessive CDH23 deafness. The word digenic covers both situations and they are not the same thing.
Show evidence (4 references)
PMID:37582836 SUPPORT Model Organism
"Large deletions encompassing the Obl locus and indels were identified as the result of editing."
What the intervention does: it destroys the mutant allele. That is only useful if the mutant allele is doing harm.
PMID:18974863 SUPPORT In Vitro
"However, analyses of hair cells in cultured utricular maculae of Obl/Obl mice and of the mutant Obl pump in model cells showed that the protein was correctly targeted to the plasma membrane."
Why the Oblivion allele is a sensible editing target: a defective pump is present in the membrane. Human truncating alleles are not expected to leave one there.
PMID:30535804 SUPPORT Human Clinical
"Three variants c.397+1G>A (p.?), c.1998C>A (p.Cys666*), and c.2329C>T (p.Arg777*), were identified in families with an autosomal dominant inheritance pattern of hearing impairment."
The human allele class - two nonsense changes and a canonical splice-donor variant - which is what leaves no defective protein for an editing strategy to remove.
+ 1 more reference
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Pathophysiology

4
ATP2B2 Heterozygous Loss of Function
A single truncating or splice-disrupting ATP2B2 allele. The five reported human alleles are two nonsense changes, a frameshift, a further nonsense change and a canonical splice-donor variant; two arose de novo. This allele class is the definition of the entity and separates it from both of the other ATP2B2 phenotypes - the p.Val586Met hypofunctional missense modifier of CDH23-related deafness, and the de novo missense and penultimate-exon frameshift alleles that cause a neurodevelopmental and movement disorder.
Monogenic haploinsufficiency for PMCA2 in outer hair cells
ATP2B2 hgnc:815 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ATP2B2 (hgnc:815). hgnc:815 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Impaired Calcium Extrusion from Stereocilia Monogenic haploinsufficiency for PMCA2 in outer hair cells
Show evidence (2 references)
PMID:30535804 SUPPORT Human Clinical
"Whole exome sequencing in hearing impaired index cases of Dutch and Polish origins revealed five novel heterozygous (predicted to be) loss-of-function variants of ATP2B2."
The allele class that defines DFNA82, and the authors' own hedge - predicted to be - about loss of function not having been measured for each variant.
PMID:30535804 SUPPORT Human Clinical
"Two variants, c.1963G>T (p.Glu655*) and c.955delG (p.Ala319fs), occurred de novo."
The two de novo alleles, which are what make this a monogenic claim rather than an association in families where a second variant might be segregating unseen.
Impaired Calcium Extrusion from Stereocilia
PMCA2 is the pump that gets calcium out of a hair cell stereocilium. It sits in the stereocilia membrane of inner and outer hair cells and in the basolateral wall, it is the primary route for clearing the calcium that enters through the transduction channel, and it also supplies calcium to the endolymph on the other side of the membrane - so one pump maintains both the low intracellular concentration and part of the extracellular one. Losing it therefore has two consequences pointing in opposite directions across the same membrane, and the mouse data show both: intracellular dysregulation inside the bundle, and measurably reduced endolymph calcium. Human DFNA82 alleles are heterozygous, so what is lost is roughly half the pump rather than all of it. No measurement of PMCA2 activity or of endolymph composition has been made in a patient, and none can be; this node's mechanism is mouse throughout.
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.
calcium ion export across plasma membrane GO:1990034 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased calcium ion export across plasma membrane (GO:1990034). GO:1990034 is a biological process from the Gene Ontology. ↓ DECREASED
P-type calcium transporter activity GO:0005388 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased P-type calcium transporter activity (GO:0005388). GO:0005388 is a molecular function from the Gene Ontology. ↓ DECREASED
Animal models
Deafwaddler mouse Mouse recapitulates Where the mechanism was established. PMCA2 protein was localised to stereocilia and shown to be absent in the mutant, which is the observation the whole calcium-clearance model is built on and which no human material can provide.
Downstream
Reduced Endolymph Calcium
Outer Hair Cell Dysfunction and Degeneration
Show evidence (5 references)
PMID:30535804 SUPPORT Human Clinical
"ATP2B2 encodes the PMCA2 Ca2+ pump that plays an important role in maintaining ion homeostasis in hair cells among others by extrusion of Ca2+ from the stereocilia to the endolymph."
The pump's job, stated by the paper that defined the human disease.
PMID:23792079 SUPPORT Model Organism
"The plasma membrane Ca2+ ATPase 2 (PMCA2), encoded by the Atp2b2 gene, is the primary mechanism for clearance of Ca2+ from auditory stereocilia, keeping intracellular levels low, and also contributes to maintaining adequate levels of extracellular Ca2+ in the endolymph."
The dual role on the two sides of the stereocilia membrane, which is why this node has two downstream edges rather than one.
PMID:23792079 SUPPORT Model Organism
"Loss of auditory function in PMCA2 mutants can be attributed to dysregulation of intracellular Ca2+ inside the stereocilia bundles."
The intracellular arm, attributed by the authors as the primary auditory lesion.
+ 2 more references
Reduced Endolymph Calcium
The extracellular consequence, measured directly in deafwaddler mice with an aspirating microelectrode and a calcium-sensitive dye: endolymph calcium is significantly lower than in controls. This matters beyond ionic housekeeping because extracellular calcium is required for the rigidity of cadherin 23 in the stereocilia tip link, which is the mechanistic bridge to the ATP2B2-CDH23 interaction and the reason a pump defect and an adhesion-molecule defect converge on the same structure. Whether this arm contributes to human DFNA82 is not known. Endolymph cannot be sampled in a patient, and the measurement was made in homozygous mutants, not heterozygotes.
ATP2B2 as a modifier of hearing loss caused by other genes
calcium ion transport GO:0006816 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased calcium ion transport (GO:0006816). GO:0006816 is a biological process from the Gene Ontology. ↓ DECREASED
endolymph UBERON:0001852 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in endolymph (UBERON:0001852). UBERON:0001852 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Outer Hair Cell Dysfunction and Degeneration ATP2B2 as a modifier of hearing loss caused by other genes
Show evidence (2 references)
PMID:15357414 SUPPORT Model Organism
"Second, using an aspirating microelectrode and calcium-sensitive fluorescent dye, we found that dfw2J mice endolymph calcium concentrations are significantly lower than those of control mice."
The direct measurement, in the only preparation where it can be made.
PMID:23792079 SUPPORT Model Organism
"However, extracellular Ca2+ ions surrounding the stereocilia are also required for rigidity of cadherin 23, a component of the stereocilia tip-link encoded by the Cdh23 gene."
Why lowered endolymph calcium is a mechanical problem for the bundle and not only a chemical one.
Outer Hair Cell Dysfunction and Degeneration
Hair cells fail and are then lost, and the pattern is spatial: degeneration runs from the cochlear base towards the apex, which is the anatomical counterpart of a hearing loss that starts at high frequencies. In the Oblivion heterozygote, loss of auditory function precedes and is followed by that base-to-apex progression of hair cell degeneration; in the homozygote, basal-turn hair cells are completely degenerate while apical ones look normal. ATP2B2 is described as an outer hair cell gene in the gene-editing literature, and the rescue experiment in the Oblivion mouse is scored on outer hair cell survival and function, which is the strongest reason to name that cell type on this node.
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.
sensory perception of sound GO:0007605 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased sensory perception of sound (GO:0007605). GO:0007605 is a biological process from the Gene Ontology. ↓ DECREASED
cochlea UBERON:0001844 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cochlea (UBERON:0001844). UBERON:0001844 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Oblivion mouse Mouse recapitulates A heterozygous mouse with progressive, high-frequency-first hearing loss and a base-to-apex gradient of hair cell degeneration - the same dose, the same direction and the same spatial pattern as the human disease. That combination is rare among deafness models, most of which are recessive nulls standing in for dominant human conditions.
Atp2b2 Oblivion mouse treated with CRISPR-Cas9 ribonucleoprotein Mouse rescues The forward test: disable the mutant allele and the cells survive and work. That is a stronger argument for outer hair cell PMCA2 dysfunction being the operative lesion than the correlation between the allele and the phenotype.
Downstream
Rapidly Progressive High-Frequency Hearing Impairment
Show evidence (3 references)
PMID:18974863 SUPPORT Model Organism
"Obl/+ mutants showed increasing hearing impairment from post-natal day (P)20 to P90, and loss of auditory function was followed by a corresponding base to apex progression of hair cell degeneration."
The heterozygous time course and the spatial gradient of the cell loss, which is what a high-frequency-first audiogram looks like histologically.
PMID:18974863 SUPPORT Model Organism
"sensory hair cells were completely degenerate in the basal turn of the cochlea, although hair cells appeared normal in the apex"
The base-apex asymmetry at its extreme, in the homozygote.
PMID:37582836 SUPPORT Model Organism
"In vivo genome editing promotes outer hair cell survival and restores their function, leading to hearing recovery."
The cell type the rescue is scored on, which is the operational reason outer hair cells are named on this node rather than hair cells generally.
⬡

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 82 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

3
Rapidly Progressive High-Frequency Hearing Impairment Auditory HP:0005101 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive high-frequency sensorineural hearing impairment, annotated with High-frequency hearing impairment (HP:0005101), qualified as course progressive. HP:0005101 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:30535804 SUPPORT Human Clinical
"After normal newborn hearing screening, a rapidly progressive high-frequency hearing impairment was diagnosed at the age of about 3-6 years."
The whole clinical shape in one sentence: passed screening, high-frequency, rapidly progressive, preschool diagnosis.
PMID:30535804 SUPPORT Human Clinical
"There was no evidence for retrocochlear pathology or structural inner ear abnormalities."
The negative findings that place the lesion in the cochlea rather than the nerve or the bony labyrinth.
Tinnitus OCCASIONAL Auditory HP:0000360 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tinnitus (HP:0000360). HP:0000360 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30535804 SUPPORT Human Clinical
"Subjects III.3 and IV.2 of family W18-0139 reported complaints of tinnitus."
The two subjects and the count behind the band. Both are in one family, which is why the band is recorded rather than a rate.
Normal Vestibular Function EXCLUDED Vestibular HP:0001751 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is absent Normal vestibular function, annotated with Abnormal vestibular function (HP:0001751). HP:0001751 is a phenotype from the Human Phenotype Ontology.
∅ ABSENT
Show evidence (4 references)
PMID:30535804 SUPPORT Human Clinical
"vestibular testing of at least one affected subject per family (except for family W17-4352) revealed only minor vestibular abnormalities"
The results-section finding, which is weaker than the abstract's "did not yield abnormalities" and is the wording this record follows.
PMID:30535804 SUPPORT Human Clinical
"Two subjects reported vestibular complaints"
Two subjects did have complaints. Both had an identifiable non-genetic cause - benign paroxysmal positional vertigo, and perilymph leakage after cholesteatoma surgery - which is why they do not overturn the EXCLUDED call but do have to be stated.
PMID:30535804 NO_EVIDENCE Human Clinical
"Saccular function could not be meas- ured in subjects III.1 of family W18-0138 (bilaterally), III.1 (left ear) of W18-0111, and IV.2 of W18-0139 (left ear), whereas utricular function was not measurable in III.1 of family W18-0138."
Graded NO_EVIDENCE: for these ears the measurement was not obtained, so the sentence neither supports nor refutes vestibular sparing. Recorded so the completeness of the negative is visible.
+ 1 more reference
🧬

Genetic Associations

1
ATP2B2
Gene: ATP2B2 hgnc:815 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ATP2B2 (hgnc:815). hgnc:815 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (4 references)
PMID:30535804 SUPPORT Human Clinical
"Although a digenic inheritance pattern of hearing impairment has been reported for heterozygous missense variants of ATP2B2 and CDH23, our findings indicate a monogenic cause of hearing impairment in cases with loss-of-function variants of ATP2B2."
The allele-class distinction between DFNA82 and the digenic mechanism, in the words of the study that drew it.
PMID:37675773 SUPPORT Human Clinical
"Unlike described patients with hearing loss, the individuals displayed a spectrum of neurological abnormalities, ranging from ataxia with dystonic features to complex neurodevelopmental manifestations with intellectual disability, autism, and seizures."
The third ATP2B2 phenotype, and the authors' own contrast with the hearing loss patients. This is the entity a reader must not merge into DFNA82.
PMID:37675773 SUPPORT In Vitro
"In cell-based studies, all variants caused significant alterations in cytosolic calcium handling with both loss- and gain-of-function effects."
The molecular difference between the neurodevelopmental alleles and the DFNA82 ones: mixed loss and gain of function, not simple loss.
+ 1 more reference
💊

Medical Actions

1
Genetic Counselling with Serial Audiometry from Infancy
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. Ontology label: Genetic Counseling NCIT:C15240
Platform: Other
Counselling for a dominant condition with a 50 percent transmission risk, and scheduled audiometry starting well before school age. The surveillance recommendation is forced by the natural history rather than being generic: newborn screening is passed, diagnosis currently happens at three to six years, and the loss is rapidly progressive once it begins, so a child known to carry a familial ATP2B2 truncating allele needs testing on a schedule rather than on parental concern. Two of the five index cases arose de novo, which means unaffected parents do not exclude the diagnosis in a child.
Show evidence (2 references)
PMID:30535804 SUPPORT Human Clinical
"After normal newborn hearing screening, a rapidly progressive high-frequency hearing impairment was diagnosed at the age of about 3-6 years."
The interval between a normal screen and diagnosis, which is the window scheduled audiometry exists to shorten.
PMID:30535804 SUPPORT Human Clinical
"Two variants, c.1963G>T (p.Glu655*) and c.955delG (p.Ala319fs), occurred de novo."
Why an unremarkable family history does not lower the prior: two of five alleles were new events.
🔬

Diagnosis

1
ATP2B2 on dominant hearing loss panels, read together with CDH23
DFNA82 is reached by exome sequencing or a dominant hearing loss panel containing ATP2B2. The clinical shape that should prompt it is specific: a passed newborn screen, a steeply downsloping high-frequency loss diagnosed in the preschool years, rapid progression, and normal balance. Interpretation has a step most genes do not need. Because ATP2B2 also acts as a severity modifier, finding a variant is not the end of the analysis: the founding study sequenced CDH23 in every index case and evaluated all rare variants in it before concluding the ATP2B2 allele was the monogenic cause. A heterozygous ATP2B2 missense variant found alongside CDH23 variants is a different situation from a heterozygous ATP2B2 truncating variant found alone, and the report should say which one it is.
Show evidence (2 references)
PMID:30535804 SUPPORT Human Clinical
"Although a digenic inheritance pattern of hearing impairment has been reported for heterozygous missense variants of ATP2B2 and CDH23, our findings indicate a monogenic cause of hearing impairment in cases with loss-of-function variants of ATP2B2."
Why the interpretation step exists: the same gene supports two different genetic claims and the allele class decides which one applies.
PMID:30535804 SUPPORT Human Clinical
"After normal newborn hearing screening, a rapidly progressive high-frequency hearing impairment was diagnosed at the age of about 3-6 years."
The clinical trigger for testing.
📈

Progression

2
Presymptomatic
Age: birth to about 3 years
Hearing is good enough at birth to pass newborn screening. A passed screen therefore does not exclude DFNA82, which is the practical consequence of this phase and the reason it is curated rather than left implicit.
Show evidence (1 reference)
PMID:30535804 SUPPORT Human Clinical
"After normal newborn hearing screening, a rapidly progressive high-frequency hearing impairment was diagnosed at the age of about 3-6 years."
The normal screen and the interval before diagnosis.
Rapid progression
Age: about 3 to 6 years onwards
Diagnosis falls in the preschool and early school years and the loss then progresses, steeply downsloping across the audiogram, reaching profound in the worst-affected subjects. The rate has been measured: an age-related typical audiogram over ages 10 to 70 gives an average annual threshold deterioration of 0.5 dB/year at low frequencies, 1.1 dB/year at middle frequencies and 0.7 dB/year at high frequencies. Note what that does and does not say. The deterioration is fastest in the *middle* frequencies, not the high ones, even though the loss starts high-frequency-weighted and the audiogram is downsloping. Onset configuration and rate of decline are different quantities here, and this entry should not be read as claiming the high frequencies also decline fastest. Audiograms below age 10 were excluded from the calculation as unreliable, so the rate describes the established disease rather than its first years.
Show evidence (2 references)
PMID:30535804 SUPPORT Human Clinical
"The average annual threshold deterioration (ATD) for the ages 10–70 was 0.5 dB/year for the low frequencies (250–500Hz), 1.1 db/y for middle frequencies (1–2 kHz) and 0.7 dB/year for the high frequencies (4–8 kHz)."
The measured rate of decline, per frequency band. This is the number the entry previously said had not been published; it is in the full text of the paper this PR caches, and the middle-frequency figure is the fastest of the three.
PMID:30535804 SUPPORT INDIRECT Model Organism
"mice heterozygous for loss-of-function defects display a rapidly progressive high-frequency hearing impairment"
The mouse course the human one was compared against. Graded MODEL_ORGANISM because the sentence reports mouse data, and INDIRECT because it is prior work summarised in a human paper's abstract rather than a measurement of these patients.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
DFNA82 was defined on five index cases of Dutch and Polish origin with their families. No prevalence or incidence estimate has been published, so no rate_per_100000 is recorded and ULTRA_RARE is a qualitative band rather than a converted figure.
Show evidence (1 reference)
PMID:30535804 SUPPORT Human Clinical
"Whole exome sequencing in hearing impaired index cases of Dutch and Polish origins revealed five novel heterozygous (predicted to be) loss-of-function variants of ATP2B2."
The size and origin of the founding series, which is the whole basis for the band.
🐁

Animal Models

3
Deafwaddler mouse
The founding model and the reason ATP2B2 was ever a candidate deafness gene. Deafwaddler is a spontaneous recessive mutant that is deaf and unbalanced; the original allele is a glycine-to-serine substitution at a conserved position and the second, dfw2J, is a two base pair deletion predicting a truncated protein, with no detectable protein in the cochlea. PMCA2 localises to stereocilia and the basolateral wall of hair cells in wild-type mice and is absent in dfw2J. A later study on the same allele measured endolymph calcium directly and found it significantly reduced.
Species
Mouse
Genotype
Atp2b2 dfw (G to S substitution) and dfw2J (2 bp deletion, frameshift), homozygous
Genes
ATP2B2 hgnc:815 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns ATP2B2 (hgnc:815). hgnc:815 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:9697703
Pathograph links
Impaired Calcium Extrusion from Stereocilia recapitulates fidelity: moderate Where the mechanism was established. PMCA2 protein was localised to stereocilia and shown to be absent in the mutant, which is the observation the whole calcium-clearance model is built on and which no human material can provide.
Limitations: Homozygous, and the human disease is heterozygous - so this line models complete pump loss rather than half of it, and it carries a vestibular phenotype the patients do not have. The dfw allele is a missense change and dfw2J a frameshift, neither of which is one of the five human alleles.
Readouts
PMCA2 immunolocalisation in hair cells
Direction: ABOLISHED
Interpretation: The pump is present in wild-type stereocilia and undetectable in the mutant, which establishes both where it works and that the allele removes it.
Show evidence (1 reference)
PMID:9697703 SUPPORT Model Organism
"In the cochlea, the protein Atp2b2 is localized to stereocilia and the basolateral wall of hair cells in wild-type mice, but is not detected in dfw2J mice."
The immunolocalisation measurement behind this readout.
Endolymph calcium concentration
Direction: DECREASED
Interpretation: Endolymph calcium falls when the pump is gone, confirming that PMCA2 supplies it rather than only clearing calcium from the cell.
Show evidence (1 reference)
PMID:15357414 SUPPORT Model Organism
"Second, using an aspirating microelectrode and calcium-sensitive fluorescent dye, we found that dfw2J mice endolymph calcium concentrations are significantly lower than those of control mice."
The direct electrochemical measurement behind this readout.
Show evidence (1 reference)
PMID:9697703 SUPPORT Model Organism
"This indicates that mutation of Atp2b2 may cause deafness and imbalance by affecting sensory transduction in stereocilia as well as neurotransmitter release from the basolateral membrane."
The mechanism the founding study proposed, including the basolateral arm that the human entry does not curate because no human evidence bears on it.
Oblivion mouse
The best model of the human dominant phenotype, because the informative animal here is the heterozygote. Obl/+ mice show increasing hearing impairment from postnatal day 20 to 90, with hair cell degeneration progressing from cochlear base to apex behind the functional loss. Obl/Obl mice are small, severely vestibular by two weeks and deaf from birth. The allele also carries a lesson about inferring mechanism from position. It sits in a transmembrane domain, where such mutations were generally believed to prevent the pump reaching the plasma membrane; the protein was in fact correctly targeted and had simply lost much of its non-stimulated calcium-exporting ability.
Species
Mouse
Genotype
Atp2b2 Obl, ENU-induced p.Ser877Phe in transmembrane domain 6, heterozygous and homozygous
Genes
ATP2B2 hgnc:815 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns ATP2B2 (hgnc:815). hgnc:815 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:18974863
Pathograph links
Outer Hair Cell Dysfunction and Degeneration recapitulates fidelity: high A heterozygous mouse with progressive, high-frequency-first hearing loss and a base-to-apex gradient of hair cell degeneration - the same dose, the same direction and the same spatial pattern as the human disease. That combination is rare among deafness models, most of which are recessive nulls standing in for dominant human conditions.
Limitations: A missense allele that produces a badly working pump, against human alleles that truncate the protein or destroy a splice site; whether a hypomorphic pump and a missing one fail the same way has not been tested. Homozygotes have a severe vestibular phenotype absent from patients, so the model must be read at the heterozygous dose only. The human course runs over years and the mouse over about ten weeks.
Readouts
Auditory threshold in heterozygotes from P20 to P90
Direction: INCREASED
Interpretation: Thresholds rise progressively across the period - hearing worsens, so the threshold value goes up.
Show evidence (1 reference)
PMID:18974863 SUPPORT Model Organism
"Obl/+ mutants showed increasing hearing impairment from post-natal day (P)20 to P90, and loss of auditory function was followed by a corresponding base to apex progression of hair cell degeneration."
The functional time course and the histological gradient that follows it.
Non-stimulated calcium export by the mutant pump
Direction: DECREASED
Interpretation: The pump reaches the membrane but exports less calcium, so the lesion is catalytic rather than a trafficking failure.
Show evidence (1 reference)
PMID:18974863 SUPPORT In Vitro
"Biochemical and biophysical characterisation showed that the pump had lost a significant portion of its non-stimulated Ca(2+) exporting ability."
The biochemical measurement behind this readout. Graded IN_VITRO because it was made on the pump in model cells, not in the mouse.
Show evidence (2 references)
PMID:18974863 SUPPORT Model Organism
"We have characterised a new ENU-induced mouse mutant, Oblivion (allele symbol Obl), showing semi-dominant inheritance of hearing impairment."
Semi-dominant inheritance, which is what makes this line usable as a model of a human dominant disease rather than only of complete pump loss.
+ 1 more reference
Atp2b2 Oblivion mouse treated with CRISPR-Cas9 ribonucleoprotein
Allele-specific gene editing in a dominant deafness model. Liposome-mediated in vivo delivery of Cas9 ribonucleoprotein specifically edits the Oblivion allele, producing large deletions across the locus and indels; outer hair cell survival and function improve and hearing recovers. The same study extends the approach to a double-dominant mouse carrying both the Tmc1 Beethoven and the Atp2b2 Oblivion mutations, where targeting both yields partial recovery.
Species
Mouse
Genotype
Atp2b2 Obl/+ treated with liposome-delivered Cas9 ribonucleoprotein targeting the Obl allele
Genes
ATP2B2 hgnc:815 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns ATP2B2 (hgnc:815). hgnc:815 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:37582836
Pathograph links
Outer Hair Cell Dysfunction and Degeneration rescues fidelity: moderate The forward test: disable the mutant allele and the cells survive and work. That is a stronger argument for outer hair cell PMCA2 dysfunction being the operative lesion than the correlation between the allele and the phenotype.
Limitations: The strategy is allele-specific disruption, which suits a mouse missense allele that makes a bad pump. Four of the five human DFNA82 alleles already truncate the protein and the fifth destroys a splice donor, so there is nothing dominant left to cut out - destroying a null allele achieves nothing, and if the human disease is haploinsufficiency the correct strategy is the opposite one, adding a functional copy. Nothing in this study addresses that, and no human ATP2B2 allele has been edited. The digenic arm is a mouse carrying two engineered dominant mutations, not a model of ATP2B2-CDH23 modification in patients.
Readouts
Outer hair cell survival and function after editing
Direction: RESTORED
Interpretation: Cells that would have degenerated survive and function, and hearing recovers, tying the auditory outcome to the outer hair cell population.
Show evidence (1 reference)
PMID:37582836 SUPPORT Model Organism
"In vivo genome editing promotes outer hair cell survival and restores their function, leading to hearing recovery."
The rescue measurement behind this readout.
Show evidence (1 reference)
PMID:37582836 SUPPORT Model Organism
"Using a mouse model Atp2b2Obl/+, with a dominant hearing loss mutation (Oblivion), we show that liposome-mediated in vivo delivery of CRISPR-Cas9 ribonucleoprotein complexes leads to specific editing of the Obl allele."
The intervention and the genotype it was applied to, which is the heterozygous dose relevant to a human dominant disease.
{ }

Source YAML

click to show 
name: Hearing Loss Autosomal Dominant 82
category: Mendelian
creation_date: "2026-09-01T00:00:00Z"
synonyms:
- DFNA82
- deafness, autosomal dominant 82
- ATP2B2-related autosomal dominant nonsyndromic hearing loss
- PMCA2-related hearing loss
description: >-
  DFNA82 is autosomal dominant nonsyndromic hearing loss caused by heterozygous
  loss-of-function variants in ATP2B2, which encodes PMCA2 - the plasma-membrane calcium
  pump that clears Ca2+ out of hair cell stereocilia and helps hold the endolymph's own
  calcium concentration where it needs to be. The clinical picture is tight for a
  nonsyndromic deafness entity: children pass newborn hearing screening, a steeply
  downsloping high-frequency loss is picked up between about three and six years, it
  progresses rapidly, and balance is normal on formal vestibular testing.

  The reason this entry exists as a separate disease, rather than as a note on somebody
  else's, is a distinction that took fourteen years to establish and is easy to erase. For
  most of that time ATP2B2 was known in human hearing loss only as a *modifier*: a
  hypofunctional missense variant, p.Val586Met, that made CDH23-related deafness worse in
  three of five siblings and appeared to aggravate hearing loss from a MYO6 mutation and
  from noise in two unrelated people. That is a real finding and it is not this disease.
  DFNA82 is the monogenic entity defined by heterozygous *truncating and splice-site*
  ATP2B2 alleles - nonsense, frameshift and canonical splice-donor changes, two of them de
  novo - in people whose CDH23 was sequenced and found not to explain the phenotype. A
  citation about digenic ATP2B2/CDH23 modification is evidence for the modifier claim and
  says nothing about DFNA82.

  A third ATP2B2 entity has to be kept apart from both. De novo missense changes and
  frameshifts in the penultimate exon cause a neurodevelopmental and movement disorder with
  dystonia, ataxia, intellectual disability, autistic features and seizures, and in cell
  assays those alleles produce a mixture of loss- and gain-of-function effects on calcium
  handling. Same gene, different allele class, different disease.

  The mouse work is unusually good and it came first. Deafwaddler was the original allele,
  and there are now several independent lines - spontaneous, ENU-induced and null - which
  agree that heterozygotes have progressive, high-frequency-first hearing loss and
  homozygotes are profoundly deaf with vestibular dysfunction. That heterozygous mouse
  phenotype is the closest animal counterpart of a human dominant disease this repository
  curates for the ear, and the human authors used it as their prior. It also carries the
  clearest warning about reading mechanism off sequence: the Oblivion allele sits in a
  transmembrane domain, where mutations were expected to prevent the pump reaching the
  membrane, and the protein turned out to be trafficked correctly and simply to pump badly.
disease_term:
  preferred_term: hearing loss, autosomal dominant 82
  term:
    id: MONDO:0030719
    label: hearing loss, autosomal dominant 82
parents:
- Autosomal Dominant Nonsyndromic Hearing Loss
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0030719
      label: hearing loss, autosomal dominant 82
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
references:
- reference: PMID:30535804
  title: "De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment."
- reference: PMID:15829536
  title: "Modification of human hearing loss by plasma-membrane calcium pump PMCA2."
- reference: PMID:9697703
  title: "Mutations in a plasma membrane Ca2+-ATPase gene cause deafness in deafwaddler mice."
- reference: PMID:18974863
  title: "The novel mouse mutation Oblivion inactivates the PMCA2 pump and causes progressive hearing loss."
- reference: PMID:15357414
  title: "Low endolymph calcium concentrations in deafwaddler2J mice suggest that PMCA2 contributes to endolymph calcium maintenance."
- reference: PMID:23792079
  title: "A new Atp2b2 deafwaddler allele, dfw(i5), interacts strongly with Cdh23 and other auditory modifiers."
- reference: PMID:23826306
  title: "Two ENU-induced alleles of Atp2b2 cause deafness in mice."
- reference: PMID:37582836
  title: "Treatment of monogenic and digenic dominant genetic hearing loss by CRISPR-Cas9 ribonucleoprotein delivery in vivo."
- reference: PMID:37675773
  title: "ATP2B2 de novo variants as a cause of variable neurodevelopmental disorders that feature dystonia, ataxia, intellectual disability, behavioral symptoms, and seizures."
inheritance:
- name: Autosomal dominant
  description: >-
    Heterozygous loss-of-function ATP2B2 alleles. Three segregated through families with a
    dominant hearing loss pattern; two arose de novo in isolated index cases, which is what
    rules out an inherited second locus as the explanation in those two families and is the
    strongest single argument that one damaged ATP2B2 copy is sufficient.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:30535804
    reference_title: "De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three variants c.397+1G>A (p.?), c.1998C>A (p.Cys666*), and c.2329C>T (p.Arg777*), were identified in families with an autosomal dominant inheritance pattern of hearing impairment."
    explanation: The three inherited alleles and the pedigree pattern they segregate with.
  - reference: PMID:30535804
    reference_title: "De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two variants, c.1963G>T (p.Glu655*) and c.955delG (p.Ala319fs), occurred de novo."
    explanation: >-
      The two de novo alleles. A de novo truncating variant in an affected child of
      unaffected parents is the observation that makes single-copy loss sufficient rather
      than merely associated.
mechanistic_hypotheses:
- hypothesis_group_id: monogenic_pmca2_haploinsufficiency
  hypothesis_label: Monogenic haploinsufficiency for PMCA2 in outer hair cells
  status: CANONICAL
  description: >-
    One truncating or splice-disrupting ATP2B2 allele leaves too little functional PMCA2 to
    clear calcium from the stereocilia of outer hair cells, and hearing fails from the high
    frequencies down. This is the model the disease entity is defined by. It is supported
    in humans by two de novo truncating alleles and by segregation of three more, with
    CDH23 sequenced and excluded in the index cases; and in mice by several independent
    heterozygous lines, each showing progressive high-frequency-first loss.
  evidence:
  - reference: PMID:30535804
    reference_title: "De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although a digenic inheritance pattern of hearing impairment has been reported for heterozygous missense variants of ATP2B2 and CDH23, our findings indicate a monogenic cause of hearing impairment in cases with loss-of-function variants of ATP2B2."
    explanation: >-
      The authors' explicit separation of the monogenic entity from the digenic mechanism,
      stated as the conclusion of the study that established DFNA82.
  - reference: PMID:30535804
    reference_title: "De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "A causal association with disease is further \nstrengthened by a pLI score of 1.00 reported for ATP2B2."
    explanation: >-
      The constraint argument for dosage sensitivity: a pLI of 1.00 means the gene is
      extremely intolerant of losing one functional copy, which is what a haploinsufficiency
      model requires. Graded COMPUTATIONAL because pLI is a population-genetic prediction
      rather than a measurement in these patients.
  - reference: PMID:23826306
    reference_title: "Two ENU-induced alleles of Atp2b2 cause deafness in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "Mice homozygous for these mutations display profound hearing loss. Heterozygotes display mild to moderate, progressive hearing loss."
    explanation: >-
      Independent ENU alleles reproducing the dose relationship the model predicts.
      Indirect with respect to the human disease: these are mouse missense alleles, not the
      truncating human ones.
- hypothesis_group_id: cdh23_modifier_interaction
  hypothesis_label: ATP2B2 as a modifier of hearing loss caused by other genes
  status: ALTERNATIVE
  description: >-
    A separate and genuine role for ATP2B2 that this entry deliberately does not curate as
    DFNA82. A hypofunctional missense variant, p.Val586Met, was associated with worse
    hearing in three of five siblings homozygous for a CDH23 mutation, and with increased
    loss in two unrelated people whose deafness came from a MYO6 mutation and from noise.
    The mouse counterpart is well characterised: extracellular calcium is needed for the
    rigidity of cadherin 23 in the tip link, and Atp2b2 and Cdh23 alleles interact in a
    dose- and frequency-dependent way.

    It is recorded here as ALTERNATIVE not because it is doubtful - it is well supported -
    but because it is a claim about a different genotype. The modifier evidence is missense
    and hypofunctional, the DFNA82 evidence is truncating and de novo, and treating a
    citation about one as evidence for the other is the specific error this entry is
    written to prevent.

    One thing the founding study is careful about and this entry should be too: rare CDH23
    variants co-occurred with the ATP2B2 allele in all five index cases. The authors argue
    each of them down - intronic and predicted not to affect splicing, synonymous, benign or
    common in population data, failing to co-segregate - and conclude monogenic causation.
    But they also state that a modifying effect of those CDH23 variants cannot be excluded.
    Monogenic causation and a superimposed modifier are not mutually exclusive claims, and
    this entry asserts the first without denying the second.
  evidence:
  - reference: PMID:15829536
    reference_title: "Modification of human hearing loss by plasma-membrane calcium pump PMCA2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic evaluation revealed that a homozygous mutation in CDH23 (which encodes cadherin 23) caused the hearing loss in all five siblings and that a heterozygous, hypofunctional variant (V586M) in plasma-membrane calcium pump PMCA2, which is encoded by ATP2B2, was associated with increased loss in the three severely affected siblings."
    explanation: >-
      The founding modifier observation. Note what causes the deafness in these siblings:
      CDH23, in all five. The ATP2B2 variant changes severity, and the sentence says so.
  - reference: PMID:23792079
    reference_title: "A new Atp2b2 deafwaddler allele, dfw(i5), interacts strongly with Cdh23 and other auditory modifiers."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "However, extracellular Ca2+ ions surrounding the stereocilia are also required for rigidity of cadherin 23, a component of the stereocilia tip-link encoded by the Cdh23 gene."
    explanation: >-
      The biochemical reason the two genes interact at all, which is what makes the modifier
      effect mechanistic rather than statistical.
  - reference: PMID:30535804
    reference_title: "De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment."
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    snippet: "Up to now ATP2B2 has only been reported as a modifier, or in a digenic mechanism with CDH23 for hearing impairment in humans."
    explanation: >-
      Graded NO_EVIDENCE with respect to DFNA82: the sentence describes the state of the
      literature before this study and bears on the modifier claim, not on whether
      heterozygous ATP2B2 loss of function causes hearing loss on its own.
  - reference: PMID:30535804
    reference_title: "De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although rare CDH23 variants co-\noccurred with ATP2B2 variants in all five index cases, our \nfindings indicate that mono-allelic loss-of-function variants \nof ATP2B2 are the underlying cause of HI."
    explanation: >-
      Both halves of the finding, and the second half is the one that is easy to drop: rare
      CDH23 variants were present alongside the ATP2B2 allele in every one of the five index
      cases. The authors argue them down individually and conclude monogenic causation, which
      is the claim this entry curates.
  - reference: PMID:30535804
    reference_title: "De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We cannot exclude a modifying effect of the CDH23  \nvariants on HI in the affected subjects in our study, as has \nbeen reported for mouse mutants of Atp2b2"
    explanation: >-
      The authors' own residual hedge, and the reason the modifier mechanism is kept as a
      named ALTERNATIVE hypothesis rather than dismissed. Monogenic causation and a
      superimposed CDH23 modifying effect are not mutually exclusive, and the study rules out
      the first reading of those variants without ruling out the second.
pathophysiology:
- name: ATP2B2 Heterozygous Loss of Function
  description: >-
    A single truncating or splice-disrupting ATP2B2 allele. The five reported human alleles
    are two nonsense changes, a frameshift, a further nonsense change and a canonical
    splice-donor variant; two arose de novo. This allele class is the definition of the
    entity and separates it from both of the other ATP2B2 phenotypes - the p.Val586Met
    hypofunctional missense modifier of CDH23-related deafness, and the de novo missense and
    penultimate-exon frameshift alleles that cause a neurodevelopmental and movement
    disorder.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: ATP2B2
    term:
      id: hgnc:815
      label: ATP2B2
  downstream:
  - target: Impaired Calcium Extrusion from Stereocilia
    causal_link_type: DIRECT
    hypothesis_groups:
    - monogenic_pmca2_haploinsufficiency
  evidence:
  - reference: PMID:30535804
    reference_title: "De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole exome sequencing in hearing impaired index cases of Dutch and Polish origins revealed five novel heterozygous (predicted to be) loss-of-function variants of ATP2B2."
    explanation: >-
      The allele class that defines DFNA82, and the authors' own hedge - predicted to be -
      about loss of function not having been measured for each variant.
  - reference: PMID:30535804
    reference_title: "De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two variants, c.1963G>T (p.Glu655*) and c.955delG (p.Ala319fs), occurred de novo."
    explanation: >-
      The two de novo alleles, which are what make this a monogenic claim rather than an
      association in families where a second variant might be segregating unseen.
- name: Impaired Calcium Extrusion from Stereocilia
  description: >-
    PMCA2 is the pump that gets calcium out of a hair cell stereocilium. It sits in the
    stereocilia membrane of inner and outer hair cells and in the basolateral wall, it is
    the primary route for clearing the calcium that enters through the transduction channel,
    and it also supplies calcium to the endolymph on the other side of the membrane - so one
    pump maintains both the low intracellular concentration and part of the extracellular
    one. Losing it therefore has two consequences pointing in opposite directions across the
    same membrane, and the mouse data show both: intracellular dysregulation inside the
    bundle, and measurably reduced endolymph calcium.

    Human DFNA82 alleles are heterozygous, so what is lost is roughly half the pump rather
    than all of it. No measurement of PMCA2 activity or of endolymph composition has been
    made in a patient, and none can be; this node's mechanism is mouse throughout.
  biological_scale: CELLULAR
  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
  molecular_functions:
  - preferred_term: P-type calcium transporter activity
    term:
      id: GO:0005388
      label: P-type calcium transporter activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: calcium ion export across plasma membrane
    term:
      id: GO:1990034
      label: calcium ion export across plasma membrane
    modifier: DECREASED
  downstream:
  - target: Reduced Endolymph Calcium
    causal_link_type: DIRECT
  - target: Outer Hair Cell Dysfunction and Degeneration
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:30535804
    reference_title: "De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ATP2B2 encodes the PMCA2 Ca2+ pump that plays an important role in maintaining ion homeostasis in hair cells among others by extrusion of Ca2+ from the stereocilia to the endolymph."
    explanation: The pump's job, stated by the paper that defined the human disease.
  - reference: PMID:23792079
    reference_title: "A new Atp2b2 deafwaddler allele, dfw(i5), interacts strongly with Cdh23 and other auditory modifiers."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The plasma membrane Ca2+ ATPase 2 (PMCA2), encoded by the Atp2b2 gene, is the primary mechanism for clearance of Ca2+ from auditory stereocilia, keeping intracellular levels low, and also contributes to maintaining adequate levels of extracellular Ca2+ in the endolymph."
    explanation: >-
      The dual role on the two sides of the stereocilia membrane, which is why this node has
      two downstream edges rather than one.
  - reference: PMID:23792079
    reference_title: "A new Atp2b2 deafwaddler allele, dfw(i5), interacts strongly with Cdh23 and other auditory modifiers."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Loss of auditory function in PMCA2 mutants can be attributed to dysregulation of intracellular Ca2+ inside the stereocilia bundles."
    explanation: The intracellular arm, attributed by the authors as the primary auditory lesion.
  - reference: PMID:15357414
    reference_title: "Low endolymph calcium concentrations in deafwaddler2J mice suggest that PMCA2 contributes to endolymph calcium maintenance."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "First, using immunocytochemistry, we demonstrated that PMCA2 is present in control mice inner and outer hair cell stereocilia where it could pump calcium into the endolymph and that PMCA2 is absent in dfw2J stereocilia."
    explanation: >-
      The localisation and its loss in a mutant, which is the anatomical basis for the whole
      node.
  - reference: PMID:30535804
    reference_title: "De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All five variants affected the (predicted) \northolog of the w/a isoform of PMCA2, which is the pre-"
    explanation: >-
      Isoform specificity, and the reason this is a cochlear disease rather than a systemic
      calcium-handling one: ATP2B2 is alternatively spliced, and all five DFNA82 alleles fall
      in the isoform that is the predominant calcium pump of hair cells and localises to
      stereocilia. Quoted across the PDF cache's line break, which is why it stops mid-word;
      the sentence continues to name that isoform the predominant Ca2+-ATPase in rodent hair
      cells.
- name: Reduced Endolymph Calcium
  description: >-
    The extracellular consequence, measured directly in deafwaddler mice with an aspirating
    microelectrode and a calcium-sensitive dye: endolymph calcium is significantly lower
    than in controls. This matters beyond ionic housekeeping because extracellular calcium
    is required for the rigidity of cadherin 23 in the stereocilia tip link, which is the
    mechanistic bridge to the ATP2B2-CDH23 interaction and the reason a pump defect and an
    adhesion-molecule defect converge on the same structure.

    Whether this arm contributes to human DFNA82 is not known. Endolymph cannot be sampled
    in a patient, and the measurement was made in homozygous mutants, not heterozygotes.
  biological_scale: TISSUE
  locations:
  - preferred_term: endolymph
    term:
      id: UBERON:0001852
      label: endolymph
  biological_processes:
  - preferred_term: calcium ion transport
    term:
      id: GO:0006816
      label: calcium ion transport
    modifier: DECREASED
  downstream:
  - target: Outer Hair Cell Dysfunction and Degeneration
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Loss of extracellular calcium needed for cadherin 23 rigidity in the stereocilia tip link
    hypothesis_groups:
    - cdh23_modifier_interaction
  evidence:
  - reference: PMID:15357414
    reference_title: "Low endolymph calcium concentrations in deafwaddler2J mice suggest that PMCA2 contributes to endolymph calcium maintenance."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Second, using an aspirating microelectrode and calcium-sensitive fluorescent dye, we found that dfw2J mice endolymph calcium concentrations are significantly lower than those of control mice."
    explanation: The direct measurement, in the only preparation where it can be made.
  - reference: PMID:23792079
    reference_title: "A new Atp2b2 deafwaddler allele, dfw(i5), interacts strongly with Cdh23 and other auditory modifiers."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "However, extracellular Ca2+ ions surrounding the stereocilia are also required for rigidity of cadherin 23, a component of the stereocilia tip-link encoded by the Cdh23 gene."
    explanation: >-
      Why lowered endolymph calcium is a mechanical problem for the bundle and not only a
      chemical one.
- name: Outer Hair Cell Dysfunction and Degeneration
  description: >-
    Hair cells fail and are then lost, and the pattern is spatial: degeneration runs from
    the cochlear base towards the apex, which is the anatomical counterpart of a hearing
    loss that starts at high frequencies. In the Oblivion heterozygote, loss of auditory
    function precedes and is followed by that base-to-apex progression of hair cell
    degeneration; in the homozygote, basal-turn hair cells are completely degenerate while
    apical ones look normal.

    ATP2B2 is described as an outer hair cell gene in the gene-editing literature, and the
    rescue experiment in the Oblivion mouse is scored on outer hair cell survival and
    function, which is the strongest reason to name that cell type on this node.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: cochlear outer hair cell
    term:
      id: CL:0000601
      label: cochlear outer hair cell
  locations:
  - preferred_term: cochlea
    term:
      id: UBERON:0001844
      label: cochlea
  biological_processes:
  - preferred_term: sensory perception of sound
    term:
      id: GO:0007605
      label: sensory perception of sound
    modifier: DECREASED
  downstream:
  - target: Rapidly Progressive High-Frequency Hearing Impairment
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:18974863
    reference_title: "The novel mouse mutation Oblivion inactivates the PMCA2 pump and causes progressive hearing loss."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Obl/+ mutants showed increasing hearing impairment from post-natal day (P)20 to P90, and loss of auditory function was followed by a corresponding base to apex progression of hair cell degeneration."
    explanation: >-
      The heterozygous time course and the spatial gradient of the cell loss, which is what
      a high-frequency-first audiogram looks like histologically.
  - reference: PMID:18974863
    reference_title: "The novel mouse mutation Oblivion inactivates the PMCA2 pump and causes progressive hearing loss."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "sensory hair cells were completely degenerate in the basal turn of the cochlea, although hair cells appeared normal in the apex"
    explanation: The base-apex asymmetry at its extreme, in the homozygote.
  - reference: PMID:37582836
    reference_title: "Treatment of monogenic and digenic dominant genetic hearing loss by CRISPR-Cas9 ribonucleoprotein delivery in vivo."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In vivo genome editing promotes outer hair cell survival and restores their function, leading to hearing recovery."
    explanation: >-
      The cell type the rescue is scored on, which is the operational reason outer hair
      cells are named on this node rather than hair cells generally.
phenotypes:
- name: Rapidly Progressive High-Frequency Hearing Impairment
  category: Auditory
  description: >-
    The defining phenotype, and unusually consistent. Newborn hearing screening is passed;
    a bilateral, symmetric, sensorineural loss is diagnosed at about three to six years;
    audiogram configurations are steeply downsloping; and the loss progresses rapidly.
    Severity across the reported subjects ranges from mild to profound. One subject reported
    onset at 55 years, which is the single exception in the series and had no audiometry
    before age 64. There is no evidence of retrocochlear pathology and no structural inner
    ear abnormality on imaging.
  phenotype_term:
    preferred_term: Progressive high-frequency sensorineural hearing impairment
    term:
      id: HP:0005101
      label: High-frequency hearing impairment
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:30535804
    reference_title: "De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After normal newborn hearing screening, a rapidly progressive high-frequency hearing impairment was diagnosed at the age of about 3-6 years."
    explanation: >-
      The whole clinical shape in one sentence: passed screening, high-frequency, rapidly
      progressive, preschool diagnosis.
  - reference: PMID:30535804
    reference_title: "De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There was no evidence for retrocochlear pathology or structural inner ear abnormalities."
    explanation: >-
      The negative findings that place the lesion in the cochlea rather than the nerve or
      the bony labyrinth.
- name: Tinnitus
  category: Auditory
  frequency: OCCASIONAL
  description: >-
    Two of the eleven affected subjects in the founding series reported tinnitus, both in
    the same family. That is 18 percent, which falls in the 5 to 29 percent band. It is
    curated because it is a symptom patients report and the entry would otherwise describe
    the disease purely in threshold terms, but the denominator is eleven people from five
    families and no series has looked for it systematically.
  phenotype_term:
    preferred_term: Tinnitus
    term:
      id: HP:0000360
      label: Tinnitus
  evidence:
  - reference: PMID:30535804
    reference_title: "De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subjects III.3 and IV.2 of \nfamily W18-0139 reported complaints of tinnitus."
    explanation: >-
      The two subjects and the count behind the band. Both are in one family, which is why
      the band is recorded rather than a rate.
- name: Normal Vestibular Function
  category: Vestibular
  frequency: EXCLUDED
  description: >-
    There is no vestibular syndrome in DFNA82, and the negative is an examined one - but the
    paper's abstract states it more strongly than its own results section does, and this
    record follows the results section.

    What was actually found: vestibular history from all subjects and extensive testing of
    at least one affected subject in every family but one revealed only minor vestibular
    abnormalities. Two subjects did report vestibular complaints, and in both the cause was
    identifiable and unrelated to the genotype - benign paroxysmal positional vertigo in one,
    perilymph leakage after cholesteatoma surgery in the other. Testing was incomplete in
    places: saccular function could not be measured in three ears and utricular function in
    one, and one family was not tested at all.

    Recorded here because the mouse diverges sharply - homozygous Oblivion mice have severe
    vestibular dysfunction by two weeks, and deafwaddler is named for its gait - so an entry
    that imported the animal phenotype wholesale would predict a balance disorder these
    patients do not have. The resolution is allele dose: the human alleles are heterozygous
    and the florid mouse vestibular phenotype belongs to homozygotes.

    `frequency: EXCLUDED` carries the absence, because that is what the HPOA exporter reads
    to emit a NOT-qualified row; `modifier: ABSENT` alone documents intent and is not
    consulted. Neither slot asserts a rate. EXCLUDED remains the right call - minor
    abnormalities with attributable causes are not a vestibular phenotype - but it is a
    judgement on incomplete testing rather than a clean negative, which is why the detail is
    written out here.
  phenotype_term:
    preferred_term: Normal vestibular function
    term:
      id: HP:0001751
      label: Abnormal vestibular function
    modifier: ABSENT
  evidence:
  - reference: PMID:30535804
    reference_title: "De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "vestibular testing of at least one affected subject per \nfamily (except for family W17-4352) revealed only minor \nvestibular abnormalities"
    explanation: >-
      The results-section finding, which is weaker than the abstract's "did not yield
      abnormalities" and is the wording this record follows.
  - reference: PMID:30535804
    reference_title: "De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two subjects reported vestibular complaints"
    explanation: >-
      Two subjects did have complaints. Both had an identifiable non-genetic cause - benign
      paroxysmal positional vertigo, and perilymph leakage after cholesteatoma surgery -
      which is why they do not overturn the EXCLUDED call but do have to be stated.
  - reference: PMID:30535804
    reference_title: "De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment."
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    snippet: "Saccular function could not be meas-\nured in subjects III.1 of family W18-0138 (bilaterally), III.1 \n(left ear) of W18-0111, and IV.2 of W18-0139 (left ear), \nwhereas utricular function was not measurable in III.1 of \nfamily W18-0138."
    explanation: >-
      Graded NO_EVIDENCE: for these ears the measurement was not obtained, so the sentence
      neither supports nor refutes vestibular sparing. Recorded so the completeness of the
      negative is visible.
  - reference: PMID:18974863
    reference_title: "The novel mouse mutation Oblivion inactivates the PMCA2 pump and causes progressive hearing loss."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "Obl/Obl mutants were small, showed severe vestibular dysfunction by 2 weeks of age, and were completely deaf from birth"
    explanation: >-
      The homozygous mouse phenotype this record exists to keep out of the human
      description. Indirect: it is a different species and, more importantly, a different
      allele dose from the human disease.
genetic:
- name: ATP2B2
  notes: >-
    ATP2B2 on 3p25.3 encodes PMCA2, one of four plasma-membrane calcium ATPases. In the ear
    it is the resident calcium pump of hair cell stereocilia; it is also expressed in
    cerebellar Purkinje cells and in lactating mammary epithelium, and the gene uses
    tissue-specific first exons, with cochlear hair cell expression carried by the alpha
    transcript.

    Three distinct human phenotypes are attributed to this gene and they correspond to three
    allele classes, which is the single most important thing to keep straight about it:

    Heterozygous truncating and splice-site alleles cause DFNA82, the isolated rapidly
    progressive high-frequency hearing loss this entry curates. A heterozygous hypofunctional
    missense allele, p.Val586Met, acts as a modifier that worsens hearing loss caused by
    something else - CDH23, MYO6, or noise. And de novo missense changes, plus frameshifts in
    the penultimate exon, cause a neurodevelopmental and movement disorder with dystonia,
    ataxia, intellectual disability, autistic features and seizures; in cell assays those
    alleles alter cytosolic calcium handling with both loss- and gain-of-function effects,
    which is a different molecular behaviour from simple haploinsufficiency.

    The neurodevelopmental series includes individuals with hearing loss alongside the
    movement and cognitive features, so the two are not cleanly separable by phenotype in
    every case; they are separable by allele class and by whether the presentation is
    isolated.
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: ATP2B2
    term:
      id: hgnc:815
      label: ATP2B2
  evidence:
  - reference: PMID:30535804
    reference_title: "De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although a digenic inheritance pattern of hearing impairment has been reported for heterozygous missense variants of ATP2B2 and CDH23, our findings indicate a monogenic cause of hearing impairment in cases with loss-of-function variants of ATP2B2."
    explanation: >-
      The allele-class distinction between DFNA82 and the digenic mechanism, in the words of
      the study that drew it.
  - reference: PMID:37675773
    reference_title: "ATP2B2 de novo variants as a cause of variable neurodevelopmental disorders that feature dystonia, ataxia, intellectual disability, behavioral symptoms, and seizures."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Unlike described patients with hearing loss, the individuals displayed a spectrum of neurological abnormalities, ranging from ataxia with dystonic features to complex neurodevelopmental manifestations with intellectual disability, autism, and seizures."
    explanation: >-
      The third ATP2B2 phenotype, and the authors' own contrast with the hearing loss
      patients. This is the entity a reader must not merge into DFNA82.
  - reference: PMID:37675773
    reference_title: "ATP2B2 de novo variants as a cause of variable neurodevelopmental disorders that feature dystonia, ataxia, intellectual disability, behavioral symptoms, and seizures."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In cell-based studies, all variants caused significant alterations in cytosolic calcium handling with both loss- and gain-of-function effects."
    explanation: >-
      The molecular difference between the neurodevelopmental alleles and the DFNA82 ones:
      mixed loss and gain of function, not simple loss.
  - reference: PMID:15829536
    reference_title: "Modification of human hearing loss by plasma-membrane calcium pump PMCA2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "V586M was detected in two unrelated persons with increased sensorineural hearing loss, in the other caused by a mutation in MYO6 (which encodes myosin VI) in one and by noise exposure, suggesting that this variant may modify the severity of sensorineural hearing loss caused by a variety of factors."
    explanation: >-
      The modifier allele acting on causes other than CDH23, which is what makes it a
      general severity modifier rather than a partner in one digenic pair.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    DFNA82 was defined on five index cases of Dutch and Polish origin with their families.
    No prevalence or incidence estimate has been published, so no rate_per_100000 is
    recorded and ULTRA_RARE is a qualitative band rather than a converted figure.
  evidence:
  - reference: PMID:30535804
    reference_title: "De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole exome sequencing in hearing impaired index cases of Dutch and Polish origins revealed five novel heterozygous (predicted to be) loss-of-function variants of ATP2B2."
    explanation: The size and origin of the founding series, which is the whole basis for the band.
progression:
- phase: Presymptomatic
  age_range: birth to about 3 years
  notes: >-
    Hearing is good enough at birth to pass newborn screening. A passed screen therefore
    does not exclude DFNA82, which is the practical consequence of this phase and the reason
    it is curated rather than left implicit.
  evidence:
  - reference: PMID:30535804
    reference_title: "De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After normal newborn hearing screening, a rapidly progressive high-frequency hearing impairment was diagnosed at the age of about 3-6 years."
    explanation: The normal screen and the interval before diagnosis.
- phase: Rapid progression
  age_range: about 3 to 6 years onwards
  notes: >-
    Diagnosis falls in the preschool and early school years and the loss then progresses,
    steeply downsloping across the audiogram, reaching profound in the worst-affected
    subjects. The rate has been measured: an age-related typical audiogram over ages 10 to
    70 gives an average annual threshold deterioration of 0.5 dB/year at low frequencies,
    1.1 dB/year at middle frequencies and 0.7 dB/year at high frequencies.

    Note what that does and does not say. The deterioration is fastest in the *middle*
    frequencies, not the high ones, even though the loss starts high-frequency-weighted and
    the audiogram is downsloping. Onset configuration and rate of decline are different
    quantities here, and this entry should not be read as claiming the high frequencies also
    decline fastest. Audiograms below age 10 were excluded from the calculation as
    unreliable, so the rate describes the established disease rather than its first years.
  evidence:
  - reference: PMID:30535804
    reference_title: "De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The average annual \nthreshold deterioration (ATD) for the ages 10–70 was 0.5 \ndB/year for the low frequencies (250–500Hz), 1.1 db/y for \nmiddle frequencies (1–2 kHz) and 0.7 dB/year for the high \nfrequencies (4–8 kHz)."
    explanation: >-
      The measured rate of decline, per frequency band. This is the number the entry
      previously said had not been published; it is in the full text of the paper this PR
      caches, and the middle-frequency figure is the fastest of the three.
  - reference: PMID:30535804
    reference_title: "De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "mice heterozygous for loss-of-function defects display a rapidly progressive high-frequency hearing impairment"
    explanation: >-
      The mouse course the human one was compared against. Graded MODEL_ORGANISM because the
      sentence reports mouse data, and INDIRECT because it is prior work summarised in a
      human paper's abstract rather than a measurement of these patients.
diagnosis:
- name: ATP2B2 on dominant hearing loss panels, read together with CDH23
  description: >-
    DFNA82 is reached by exome sequencing or a dominant hearing loss panel containing
    ATP2B2. The clinical shape that should prompt it is specific: a passed newborn screen, a
    steeply downsloping high-frequency loss diagnosed in the preschool years, rapid
    progression, and normal balance.

    Interpretation has a step most genes do not need. Because ATP2B2 also acts as a
    severity modifier, finding a variant is not the end of the analysis: the founding study
    sequenced CDH23 in every index case and evaluated all rare variants in it before
    concluding the ATP2B2 allele was the monogenic cause. A heterozygous ATP2B2 missense
    variant found alongside CDH23 variants is a different situation from a heterozygous
    ATP2B2 truncating variant found alone, and the report should say which one it is.
  evidence:
  - reference: PMID:30535804
    reference_title: "De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although a digenic inheritance pattern of hearing impairment has been reported for heterozygous missense variants of ATP2B2 and CDH23, our findings indicate a monogenic cause of hearing impairment in cases with loss-of-function variants of ATP2B2."
    explanation: >-
      Why the interpretation step exists: the same gene supports two different genetic
      claims and the allele class decides which one applies.
  - reference: PMID:30535804
    reference_title: "De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After normal newborn hearing screening, a rapidly progressive high-frequency hearing impairment was diagnosed at the age of about 3-6 years."
    explanation: The clinical trigger for testing.
treatments:
- name: Genetic Counselling with Serial Audiometry from Infancy
  description: >-
    Counselling for a dominant condition with a 50 percent transmission risk, and scheduled
    audiometry starting well before school age. The surveillance recommendation is forced by
    the natural history rather than being generic: newborn screening is passed, diagnosis
    currently happens at three to six years, and the loss is rapidly progressive once it
    begins, so a child known to carry a familial ATP2B2 truncating allele needs testing on a
    schedule rather than on parental concern. Two of the five index cases arose de novo,
    which means unaffected parents do not exclude the diagnosis in a child.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:30535804
    reference_title: "De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After normal newborn hearing screening, a rapidly progressive high-frequency hearing impairment was diagnosed at the age of about 3-6 years."
    explanation: >-
      The interval between a normal screen and diagnosis, which is the window scheduled
      audiometry exists to shorten.
  - reference: PMID:30535804
    reference_title: "De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two variants, c.1963G>T (p.Glu655*) and c.955delG (p.Ala319fs), occurred de novo."
    explanation: >-
      Why an unremarkable family history does not lower the prior: two of five alleles were
      new events.
  notes: >-
    No ATP2B2-specific pharmacological treatment has been reported, and no DFNA82-specific
    clinical trial was identified. Hearing amplification and cochlear implantation are
    standard in progressive severe sensorineural hearing loss but no DFNA82-specific outcome
    data exist, so neither is curated here as a treatment - a scoping decision, not a
    judgement that they are inappropriate. Allele-specific gene editing is not curated as a
    treatment either: the work is preclinical, in a mouse missense allele rather than a
    human truncating one, and is recorded under animal_models with its limitations.
animal_models:
- name: Deafwaddler mouse
  species: Mouse
  genotype: Atp2b2 dfw (G to S substitution) and dfw2J (2 bp deletion, frameshift), homozygous
  publication: PMID:9697703
  description: >-
    The founding model and the reason ATP2B2 was ever a candidate deafness gene. Deafwaddler
    is a spontaneous recessive mutant that is deaf and unbalanced; the original allele is a
    glycine-to-serine substitution at a conserved position and the second, dfw2J, is a two
    base pair deletion predicting a truncated protein, with no detectable protein in the
    cochlea. PMCA2 localises to stereocilia and the basolateral wall of hair cells in
    wild-type mice and is absent in dfw2J. A later study on the same allele measured
    endolymph calcium directly and found it significantly reduced.
  genes:
  - preferred_term: ATP2B2
    term:
      id: hgnc:815
      label: ATP2B2
  modeled_mechanisms:
  - target: Impaired Calcium Extrusion from Stereocilia
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Where the mechanism was established. PMCA2 protein was localised to stereocilia and
      shown to be absent in the mutant, which is the observation the whole calcium-clearance
      model is built on and which no human material can provide.
    limitations: >-
      Homozygous, and the human disease is heterozygous - so this line models complete pump
      loss rather than half of it, and it carries a vestibular phenotype the patients do not
      have. The dfw allele is a missense change and dfw2J a frameshift, neither of which is
      one of the five human alleles.
    readouts:
    - name: PMCA2 immunolocalisation in hair cells
      target: Impaired Calcium Extrusion from Stereocilia
      direction: ABOLISHED
      interpretation: >-
        The pump is present in wild-type stereocilia and undetectable in the mutant, which
        establishes both where it works and that the allele removes it.
      evidence:
      - reference: PMID:9697703
        reference_title: "Mutations in a plasma membrane Ca2+-ATPase gene cause deafness in deafwaddler mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "In the cochlea, the protein Atp2b2 is localized to stereocilia and the basolateral wall of hair cells in wild-type mice, but is not detected in dfw2J mice."
        explanation: The immunolocalisation measurement behind this readout.
    - name: Endolymph calcium concentration
      target: Impaired Calcium Extrusion from Stereocilia
      direction: DECREASED
      interpretation: >-
        Endolymph calcium falls when the pump is gone, confirming that PMCA2 supplies it
        rather than only clearing calcium from the cell.
      evidence:
      - reference: PMID:15357414
        reference_title: "Low endolymph calcium concentrations in deafwaddler2J mice suggest that PMCA2 contributes to endolymph calcium maintenance."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Second, using an aspirating microelectrode and calcium-sensitive fluorescent dye, we found that dfw2J mice endolymph calcium concentrations are significantly lower than those of control mice."
        explanation: The direct electrochemical measurement behind this readout.
    evidence:
    - reference: PMID:9697703
      reference_title: "Mutations in a plasma membrane Ca2+-ATPase gene cause deafness in deafwaddler mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "This indicates that mutation of Atp2b2 may cause deafness and imbalance by affecting sensory transduction in stereocilia as well as neurotransmitter release from the basolateral membrane."
      explanation: >-
        The mechanism the founding study proposed, including the basolateral arm that the
        human entry does not curate because no human evidence bears on it.
- name: Oblivion mouse
  species: Mouse
  genotype: Atp2b2 Obl, ENU-induced p.Ser877Phe in transmembrane domain 6, heterozygous and homozygous
  publication: PMID:18974863
  description: >-
    The best model of the human dominant phenotype, because the informative animal here is
    the heterozygote. Obl/+ mice show increasing hearing impairment from postnatal day 20 to
    90, with hair cell degeneration progressing from cochlear base to apex behind the
    functional loss. Obl/Obl mice are small, severely vestibular by two weeks and deaf from
    birth.

    The allele also carries a lesson about inferring mechanism from position. It sits in a
    transmembrane domain, where such mutations were generally believed to prevent the pump
    reaching the plasma membrane; the protein was in fact correctly targeted and had simply
    lost much of its non-stimulated calcium-exporting ability.
  genes:
  - preferred_term: ATP2B2
    term:
      id: hgnc:815
      label: ATP2B2
  modeled_mechanisms:
  - target: Outer Hair Cell Dysfunction and Degeneration
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      A heterozygous mouse with progressive, high-frequency-first hearing loss and a
      base-to-apex gradient of hair cell degeneration - the same dose, the same direction and
      the same spatial pattern as the human disease. That combination is rare among deafness
      models, most of which are recessive nulls standing in for dominant human conditions.
    limitations: >-
      A missense allele that produces a badly working pump, against human alleles that
      truncate the protein or destroy a splice site; whether a hypomorphic pump and a missing
      one fail the same way has not been tested. Homozygotes have a severe vestibular
      phenotype absent from patients, so the model must be read at the heterozygous dose
      only. The human course runs over years and the mouse over about ten weeks.
    readouts:
    - name: Auditory threshold in heterozygotes from P20 to P90
      target: Outer Hair Cell Dysfunction and Degeneration
      direction: INCREASED
      interpretation: >-
        Thresholds rise progressively across the period - hearing worsens, so the threshold
        value goes up.
      evidence:
      - reference: PMID:18974863
        reference_title: "The novel mouse mutation Oblivion inactivates the PMCA2 pump and causes progressive hearing loss."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Obl/+ mutants showed increasing hearing impairment from post-natal day (P)20 to P90, and loss of auditory function was followed by a corresponding base to apex progression of hair cell degeneration."
        explanation: The functional time course and the histological gradient that follows it.
    - name: Non-stimulated calcium export by the mutant pump
      target: Outer Hair Cell Dysfunction and Degeneration
      direction: DECREASED
      interpretation: >-
        The pump reaches the membrane but exports less calcium, so the lesion is catalytic
        rather than a trafficking failure.
      evidence:
      - reference: PMID:18974863
        reference_title: "The novel mouse mutation Oblivion inactivates the PMCA2 pump and causes progressive hearing loss."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Biochemical and biophysical characterisation showed that the pump had lost a significant portion of its non-stimulated Ca(2+) exporting ability."
        explanation: >-
          The biochemical measurement behind this readout. Graded IN_VITRO because it was
          made on the pump in model cells, not in the mouse.
    evidence:
    - reference: PMID:18974863
      reference_title: "The novel mouse mutation Oblivion inactivates the PMCA2 pump and causes progressive hearing loss."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We have characterised a new ENU-induced mouse mutant, Oblivion (allele symbol Obl), showing semi-dominant inheritance of hearing impairment."
      explanation: >-
        Semi-dominant inheritance, which is what makes this line usable as a model of a human
        dominant disease rather than only of complete pump loss.
    - reference: PMID:18974863
      reference_title: "The novel mouse mutation Oblivion inactivates the PMCA2 pump and causes progressive hearing loss."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "However, analyses of hair cells in cultured utricular maculae of Obl/Obl mice and of the mutant Obl pump in model cells showed that the protein was correctly targeted to the plasma membrane."
      explanation: >-
        The trafficking result that contradicted the expectation from sequence, recorded
        because it is the reason this entry does not describe the mouse allele as a
        trafficking defect.
- name: Atp2b2 Oblivion mouse treated with CRISPR-Cas9 ribonucleoprotein
  species: Mouse
  genotype: Atp2b2 Obl/+ treated with liposome-delivered Cas9 ribonucleoprotein targeting the Obl allele
  publication: PMID:37582836
  description: >-
    Allele-specific gene editing in a dominant deafness model. Liposome-mediated in vivo
    delivery of Cas9 ribonucleoprotein specifically edits the Oblivion allele, producing
    large deletions across the locus and indels; outer hair cell survival and function
    improve and hearing recovers. The same study extends the approach to a double-dominant
    mouse carrying both the Tmc1 Beethoven and the Atp2b2 Oblivion mutations, where
    targeting both yields partial recovery.
  genes:
  - preferred_term: ATP2B2
    term:
      id: hgnc:815
      label: ATP2B2
  modeled_mechanisms:
  - target: Outer Hair Cell Dysfunction and Degeneration
    relationship: RESCUES
    fidelity: MODERATE
    description: >-
      The forward test: disable the mutant allele and the cells survive and work. That is a
      stronger argument for outer hair cell PMCA2 dysfunction being the operative lesion
      than the correlation between the allele and the phenotype.
    limitations: >-
      The strategy is allele-specific disruption, which suits a mouse missense allele that
      makes a bad pump. Four of the five human DFNA82 alleles already truncate the protein
      and the fifth destroys a splice donor, so there is nothing dominant left to cut out -
      destroying a null allele achieves nothing, and if the human disease is
      haploinsufficiency the correct strategy is the opposite one, adding a functional copy.
      Nothing in this study addresses that, and no human ATP2B2 allele has been edited. The
      digenic arm is a mouse carrying two engineered dominant mutations, not a model of
      ATP2B2-CDH23 modification in patients.
    readouts:
    - name: Outer hair cell survival and function after editing
      target: Outer Hair Cell Dysfunction and Degeneration
      direction: RESTORED
      interpretation: >-
        Cells that would have degenerated survive and function, and hearing recovers, tying
        the auditory outcome to the outer hair cell population.
      evidence:
      - reference: PMID:37582836
        reference_title: "Treatment of monogenic and digenic dominant genetic hearing loss by CRISPR-Cas9 ribonucleoprotein delivery in vivo."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "In vivo genome editing promotes outer hair cell survival and restores their function, leading to hearing recovery."
        explanation: The rescue measurement behind this readout.
    evidence:
    - reference: PMID:37582836
      reference_title: "Treatment of monogenic and digenic dominant genetic hearing loss by CRISPR-Cas9 ribonucleoprotein delivery in vivo."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Using a mouse model Atp2b2Obl/+, with a dominant hearing loss mutation (Oblivion), we show that liposome-mediated in vivo delivery of CRISPR-Cas9 ribonucleoprotein complexes leads to specific editing of the Obl allele."
      explanation: >-
        The intervention and the genotype it was applied to, which is the heterozygous dose
        relevant to a human dominant disease.
discussions:
- discussion_id: atp2b2_allele_class_determines_disease
  kind: KNOWLEDGE_GAP
  prompt: >-
    ATP2B2 carries three human phenotypes - a monogenic dominant deafness, a severity
    modifier for deafness caused by other genes, and a neurodevelopmental movement disorder.
    Does allele class fully determine which one a person gets?
  attaches_to:
  - genetic#ATP2B2
  - mechanistic_hypotheses#monogenic_pmca2_haploinsufficiency
  - mechanistic_hypotheses#cdh23_modifier_interaction
  rationale: >-
    The current mapping is clean enough to write down and not clean enough to rely on.
    Truncating and splice-site heterozygotes get DFNA82. The hypofunctional missense
    p.Val586Met acts as a modifier. De novo missense changes, and frameshifts in the
    penultimate exon, cause the neurodevelopmental disorder. Three allele classes, three
    phenotypes.

    Two things spoil the tidiness. The neurodevelopmental series includes frameshift alleles
    - in the penultimate exon, where escape from nonsense-mediated decay would leave a
    truncated protein behind rather than removing it - so "frameshift" alone does not
    predict the phenotype, and position within the gene is doing work that nobody has
    characterised. And some of those individuals have hearing loss as well as the movement
    and cognitive features, so the phenotypes are not disjoint. Meanwhile the cell assays on
    the neurodevelopmental alleles found both loss- and gain-of-function effects on calcium
    handling, which is a different molecular behaviour from the simple dosage reduction
    DFNA82 is assumed to involve - and that assumption has never been tested, because no
    DFNA82 allele has been assayed for pump function at all.

    The question matters for reporting rather than for biology alone. A laboratory finding a
    novel heterozygous ATP2B2 variant in a child with isolated hearing loss has to decide
    which of three literatures applies, and the deciding features - truncating versus
    missense, de novo versus inherited, position relative to the last exon - are currently
    a pattern observed across two small series rather than a rule anyone has validated.
  evidence:
  - reference: PMID:37675773
    reference_title: "ATP2B2 de novo variants as a cause of variable neurodevelopmental disorders that feature dystonia, ataxia, intellectual disability, behavioral symptoms, and seizures."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The alleles comprised 5 missense substitutions that affected evolutionarily conserved sites and 2 frameshift variants in the penultimate exon."
    explanation: >-
      The allele composition of the neurodevelopmental series, including the two frameshifts
      whose position is what stops "truncating means DFNA82" from being a rule.
  - reference: PMID:37675773
    reference_title: "ATP2B2 de novo variants as a cause of variable neurodevelopmental disorders that feature dystonia, ataxia, intellectual disability, behavioral symptoms, and seizures."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In cell-based studies, all variants caused significant alterations in cytosolic calcium handling with both loss- and gain-of-function effects."
    explanation: >-
      The molecular contrast with the dosage model assumed for DFNA82, and the reason the
      two cannot be treated as the same lesion at different severities.
  - reference: PMID:30535804
    reference_title: "De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole exome sequencing in hearing impaired index cases of Dutch and Polish origins revealed five novel heterozygous (predicted to be) loss-of-function variants of ATP2B2."
    explanation: >-
      The DFNA82 allele class, with the authors' hedge - predicted to be - that is exactly
      the untested assumption this gap names.
  proposed_experiments:
  - experiment_id: exp_dfna82_pump_function_by_allele_class
    name: Calcium-handling assay across all reported ATP2B2 disease alleles
    description: >-
      Express each reported human ATP2B2 allele - the five DFNA82 truncating and splice
      alleles, the p.Val586Met modifier, and the neurodevelopmental missense and
      penultimate-exon frameshift alleles - in a common cell background, and measure protein
      level, plasma-membrane targeting, basal and stimulated calcium export, and resting
      cytosolic calcium, with wild-type and empty vector controls. Include a transcript-level
      assay of nonsense-mediated decay for every truncating allele, since whether a truncated
      protein persists is the variable that distinguishes the two frameshift classes.
    would_support:
    - mechanistic_hypotheses#monogenic_pmca2_haploinsufficiency
    supporting_outcome:
    - >-
      DFNA82 alleles produce no detectable protein and no export activity while the
      neurodevelopmental alleles produce mistargeted or mixed-function protein, which would
      make simple dosage the DFNA82 mechanism and give laboratories a functional criterion
      to sort a novel variant by.
    would_refute:
    - mechanistic_hypotheses#monogenic_pmca2_haploinsufficiency
    refuting_outcome:
    - >-
      One or more DFNA82 alleles escape nonsense-mediated decay and produce a protein with
      altered rather than absent activity, which would mean DFNA82 is not haploinsufficiency
      either, would place it on the same spectrum as the neurodevelopmental alleles, and
      would make allele-specific silencing rather than gene addition the rational therapy.
- discussion_id: atp2b2_editing_strategy_mismatch
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Allele-specific CRISPR editing restores hearing in Oblivion mice, whose mutation makes a
    defective pump. Four of five human DFNA82 alleles already truncate PMCA2. What would
    editing accomplish in a patient?
  attaches_to:
  - animal_models#Atp2b2 Oblivion mouse treated with CRISPR-Cas9 ribonucleoprotein
  - pathophysiology#ATP2B2 Heterozygous Loss of Function
  rationale: >-
    The Oblivion rescue is a real technical achievement and it is aimed at the wrong lesion
    for this disease. Allele-specific disruption works when the mutant allele is actively
    harmful - a dominant-negative or gain-of-function protein whose removal helps. Oblivion
    fits: the pump is trafficked normally and pumps badly, so a mutant PMCA2 is sitting in
    the membrane doing a poor job, and cutting it out is a coherent intervention.

    DFNA82 alleles are nonsense, frameshift and splice-donor changes. If they behave as the
    authors predict, the mutant allele contributes nothing and there is nothing to disable.
    Editing it would move the patient from one functional copy to one functional copy. The
    intervention that follows from haploinsufficiency is the opposite one - supply a working
    copy - and that has not been attempted for ATP2B2 in any system.

    So the model and the disease agree on the phenotype and disagree on the therapeutic
    logic, which is a more specific mismatch than the usual species caveat and one that
    could send a translational programme in the wrong direction. Resolving it needs the
    functional assay proposed in the allele-class gap above, plus a mouse carrying a human
    truncating allele rather than Oblivion.

    A smaller mismatch sits alongside. The study's digenic arm is a mouse engineered to
    carry two dominant deafness mutations, Tmc1 Beethoven and Atp2b2 Oblivion. That is a
    demonstration that two alleles can be edited at once; it is not a model of the
    ATP2B2-CDH23 modifier interaction seen in patients, where the ATP2B2 contribution is a
    hypofunctional missense variant modifying a recessive CDH23 deafness. The word digenic
    covers both situations and they are not the same thing.
  evidence:
  - reference: PMID:37582836
    reference_title: "Treatment of monogenic and digenic dominant genetic hearing loss by CRISPR-Cas9 ribonucleoprotein delivery in vivo."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Large deletions encompassing the Obl locus and indels were identified as the result of editing."
    explanation: >-
      What the intervention does: it destroys the mutant allele. That is only useful if the
      mutant allele is doing harm.
  - reference: PMID:18974863
    reference_title: "The novel mouse mutation Oblivion inactivates the PMCA2 pump and causes progressive hearing loss."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "However, analyses of hair cells in cultured utricular maculae of Obl/Obl mice and of the mutant Obl pump in model cells showed that the protein was correctly targeted to the plasma membrane."
    explanation: >-
      Why the Oblivion allele is a sensible editing target: a defective pump is present in
      the membrane. Human truncating alleles are not expected to leave one there.
  - reference: PMID:30535804
    reference_title: "De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three variants c.397+1G>A (p.?), c.1998C>A (p.Cys666*), and c.2329C>T (p.Arg777*), were identified in families with an autosomal dominant inheritance pattern of hearing impairment."
    explanation: >-
      The human allele class - two nonsense changes and a canonical splice-donor variant -
      which is what leaves no defective protein for an editing strategy to remove.
  - reference: PMID:37582836
    reference_title: "Treatment of monogenic and digenic dominant genetic hearing loss by CRISPR-Cas9 ribonucleoprotein delivery in vivo."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We further show that in a double-dominant mutant mouse model, in which the Tmc1 Beethoven mutation and the Atp2b2 Oblivion mutation cause digenic genetic hearing loss, Cas9/sgRNA delivery targeting both mutations leads to partial hearing recovery."
    explanation: >-
      The digenic arm as the study defines it: two engineered dominant mutations. Recorded
      here so it is not read as bearing on the ATP2B2-CDH23 modifier interaction, which is a
      different genetic situation entirely.
📚

References & Deep Research

References

9
PMID:30535804
De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment.
No top-level findings curated for this source.
PMID:15829536
Modification of human hearing loss by plasma-membrane calcium pump PMCA2.
No top-level findings curated for this source.
PMID:9697703
Mutations in a plasma membrane Ca2+-ATPase gene cause deafness in deafwaddler mice.
No top-level findings curated for this source.
PMID:18974863
The novel mouse mutation Oblivion inactivates the PMCA2 pump and causes progressive hearing loss.
No top-level findings curated for this source.
PMID:15357414
Low endolymph calcium concentrations in deafwaddler2J mice suggest that PMCA2 contributes to endolymph calcium maintenance.
No top-level findings curated for this source.
PMID:23792079
A new Atp2b2 deafwaddler allele, dfw(i5), interacts strongly with Cdh23 and other auditory modifiers.
No top-level findings curated for this source.
PMID:23826306
Two ENU-induced alleles of Atp2b2 cause deafness in mice.
No top-level findings curated for this source.
PMID:37582836
Treatment of monogenic and digenic dominant genetic hearing loss by CRISPR-Cas9 ribonucleoprotein delivery in vivo.
No top-level findings curated for this source.
PMID:37675773
ATP2B2 de novo variants as a cause of variable neurodevelopmental disorders that feature dystonia, ataxia, intellectual disability, behavioral symptoms, and seizures.
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.

Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 26 citations 2026-09-01T10:18:33.441161

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Hearing Loss Autosomal Dominant 82 (DFNA82, ATP2B2-related)
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Hearing Loss Autosomal Dominant 82 (DFNA82, ATP2B2-related) covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Present this section as an ordered causal chain first, then the detail below. Open with a numbered sequence of mechanistic steps running from the initiating lesion (mutation, exposure, infection) to the clinical manifestation, one step per line, each naming what it causes next. State the causal verb explicitly ("leads to", "results in") and say where a step is inferred rather than demonstrated. Where the mechanism branches, show the branch. The categories below are a checklist of what to cover within those steps, not the organizing structure — a step may draw on several of them, and a category may contribute to several steps.

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Hearing Loss, Autosomal Dominant 82 (DFNA82; ATP2B2-related)

Executive summary

DFNA82 is an exceptionally rare, usually nonsyndromic, autosomal-dominant sensorineural hearing-loss disorder caused by heterozygous loss-of-function variants in ATP2B2, which encodes plasma-membrane Ca²⁺-ATPase 2 (PMCA2). The defining human series described five unrelated Dutch or Polish families and 11 clinically evaluated affected people. Most passed newborn hearing screening, developed bilateral high-frequency hearing loss at approximately 2–6 years, and then experienced rapid progression, sometimes to severe or profound loss. PMCA2 normally exports Ca²⁺ from cochlear hair-cell stereocilia into endolymph; reduced dosage disrupts stereociliary Ca²⁺ homeostasis and is inferred from mouse models to produce outer-hair-cell dysfunction followed by basal cochlear hair-cell degeneration. Vestibular dysfunction, structural inner-ear abnormalities, and systemic manifestations were not characteristic of the original DFNA82 cohort. The evidence base remains small, and no disease-specific therapy or clinical trial was identified.

The principal primary paper is Smits et al., Human Genetics, published online 8 December 2018 and in the January 2019 issue, DOI 10.1007/s00439-018-1965-1, PMID 30535804. Its abstract states: “After normal newborn hearing screening, a rapidly progressive high-frequency hearing impairment was diagnosed at the age of about 3–6 years” and concludes that the findings “indicate a monogenic cause of hearing impairment in cases with loss-of-function variants of ATP2B2.” (smits2019denovoand pages 1-2)

Evidence category Finding Quantitative/detail Evidence type/source
Core monogenic report ATP2B2 loss-of-function variants define ATP2B2-related autosomal dominant hearing loss (DFNA82) Five heterozygous variants across five families: c.397+1G>A, c.955delG p.Ala319fs, c.1963G>T p.Glu655, c.1998C>A p.Cys666, c.2329C>T p.Arg777* (smits2019denovoand pages 1-2, smits2019denovoand pages 4-5) Human clinical genetics, WES/segregation; Smits et al. 2019 (smits2019denovoand pages 1-2, smits2019denovoand pages 4-5)
Inheritance Mixed de novo and familial autosomal dominant transmission Two variants de novo (c.955delG, c.1963G>T); three in families with autosomal dominant inheritance (smits2019denovoand pages 1-2, smits2019denovoand pages 4-5) Human pedigree/segregation (smits2019denovoand pages 1-2, smits2019denovoand pages 4-5)
Cohort size Clinically characterized affected subjects 11 clinically evaluated affected individuals; ages 6-68 years in analyzed cohort (smits2019denovoand pages 5-7, smits2019denovoand pages 4-5) Human clinical series (smits2019denovoand pages 5-7, smits2019denovoand pages 4-5)
Onset/screening Early childhood onset despite normal newborn screening All four screened subjects passed newborn screening; diagnosis typically followed at ~2-6 years, with most onset in first decade; one outlier reported onset at 55 years (smits2019denovoand pages 1-2, smits2019denovoand pages 5-7, smits2019denovoand pages 7-9) Human audiology/natural history (smits2019denovoand pages 1-2, smits2019denovoand pages 5-7, smits2019denovoand pages 7-9)
Audiometric phenotype Nonsyndromic progressive SNHL with characteristic configuration Bilateral, sensorineural, symmetric, mild-to-profound loss; audiograms typically (steeply) downsloping with high frequencies most affected (smits2019denovoand pages 5-7, smits2019denovoand pages 7-9) Human audiometry (smits2019denovoand pages 5-7, smits2019denovoand pages 7-9)
Progression Quantified annual deterioration Average annual threshold deterioration ages 10-70 years: 0.5 dB/year low frequencies, 1.1 dB/year middle, 0.7 dB/year high (smits2019denovoand pages 5-7) Cross-sectional ARTA analysis in human cohort (smits2019denovoand pages 5-7)
Imaging No structural inner-ear or retrocochlear abnormality CT/MRI in five subjects showed normal temporal bone/cochlear anatomy and no retrocochlear pathology (except unrelated operated ear findings) (smits2019denovoand pages 1-2, smits2019denovoand pages 5-7) Human radiology/clinical workup (smits2019denovoand pages 1-2, smits2019denovoand pages 5-7)
Vestibular findings Vestibular function essentially normal in heterozygotes No balance complaints overall; extensive testing showed only minor/nonspecific abnormalities, with no clear ATP2B2-related vestibular dysfunction (smits2019denovoand pages 1-2, smits2019denovoand pages 9-10) Human vestibular phenotyping (smits2019denovoand pages 1-2, smits2019denovoand pages 9-10)
Population frequency Variants are ultra-rare/absent in reference datasets None of the five variants present in gnomAD v2.02 or an in-house database of ~20,000 exomes (smits2019denovoand pages 4-5) Human population genetics/filtering (smits2019denovoand pages 4-5)
Molecular mechanism Loss of PMCA2 function is the likely disease mechanism Variants affect exons/splice sites encoding the PMCA2 w/a ortholog; 4/5 predicted to trigger nonsense-mediated decay; distribution supports haploinsufficiency (smits2019denovoand pages 1-2, smits2019denovoand pages 7-9) Human molecular interpretation supported by model-organism biology (smits2019denovoand pages 1-2, smits2019denovoand pages 7-9)
Cochlear biology PMCA2 is a stereociliary Ca2+ pump required for hair-cell ion homeostasis PMCA2 extrudes Ca2+ from stereocilia to endolymph; w/a isoform is highly abundant in OHC stereocilia and present apically in IHCs (smits2019denovoand pages 1-2, smits2019denovoand pages 9-10) Mechanistic synthesis from human report citing prior auditory biology (smits2019denovoand pages 1-2, smits2019denovoand pages 9-10)
Model support Mouse dosage effects mirror the human phenotype Heterozygous Atp2b2 loss-of-function mice show rapidly progressive early-onset high-frequency hearing loss; homozygotes typically have severe hearing and vestibular/ataxic phenotypes (smits2019denovoand pages 1-2, smits2019denovoand pages 7-9, smits2019denovoand pages 10-11) Model-organism evidence (mouse) (smits2019denovoand pages 1-2, smits2019denovoand pages 7-9, smits2019denovoand pages 10-11)
Genetic interaction context Distinguish monogenic DFNA82 from earlier modifier evidence ATP2B2 p.Val586Met is a hypofunctional PMCA2 allele reported as a modifier/digenic contributor with CDH23-related hearing loss, not the core monogenic DFNA82 mechanism established by ATP2B2 loss-of-function alleles (schultz2005modificationofhuman pages 3-4, schultz2005modificationofhuman pages 4-6, smits2019denovoand pages 1-2) Human modifier study vs later monogenic clinical-genetic study (schultz2005modificationofhuman pages 3-4, schultz2005modificationofhuman pages 4-6, smits2019denovoand pages 1-2)

Table: This table condenses the key human and supporting model evidence defining ATP2B2-related autosomal dominant hearing loss (DFNA82). It separates the core monogenic loss-of-function evidence from the earlier ATP2B2 p.Val586Met modifier/digenic report.

1. Disease information

Definition and names

Preferred name: Hearing loss, autosomal dominant 82.
Synonyms: DFNA82; ATP2B2-related autosomal-dominant nonsyndromic hearing loss; ATP2B2-related progressive sensorineural hearing impairment; PMCA2-related hearing loss.

The condition should be distinguished from: (1) ATP2B2 as a modifier/digenic contributor to CDH23-related deafness, and (2) recently emerging, generally missense-variant ATP2B2-associated neurodevelopmental/cerebellar phenotypes, which are not equivalent to classic nonsyndromic DFNA82.

Identifiers

  • Gene: ATP2B2; approved name ATPase plasma membrane Ca²⁺ transporting 2; Ensembl ENSG00000157087; chromosomal locus 3p25.3. Open Targets associates ATP2B2 with autosomal-dominant nonsyndromic hearing loss, whose umbrella MONDO identifier is MONDO:0019587. A DFNA82-specific MONDO identifier was not recoverable from the searched evidence and should not be inferred from the umbrella term. (OpenTargets Search: autosomal dominant nonsyndromic hearing loss-ATP2B2, zhang2019researchanddiscussion pages 1-2)
  • OMIM/Orphanet: A disease-specific accession was not reliably recovered by the available tools. These fields should be populated only after direct verification in OMIM/Orphanet; the ATP2B2 gene record must not be substituted for a disease record.
  • ICD-10/ICD-11 and MeSH: No DFNA82-specific code exists in the retrieved evidence. Use the appropriate generic code for bilateral sensorineural hearing loss, supplemented by the molecular diagnosis.

The source evidence is aggregated disease-level literature and family-based research, not individual EHR data. The foundational report aggregated five pedigrees evaluated through specialist genetics, audiology, vestibular, and imaging services. (smits2019denovoand pages 1-2, smits2019denovoand pages 4-5)

2. Etiology, risk, and protective factors

Primary cause

The established cause is a heterozygous germline ATP2B2 loss-of-function allele, usually nonsense, frameshift, or canonical splice-site, acting predominantly through haploinsufficiency. Four of the five original variants were predicted to truncate PMCA2; three were expected to undergo nonsense-mediated decay. ATP2B2 had a reported pLI of 1.00, supporting marked intolerance of loss-of-function variation. (smits2019denovoand pages 5-7, smits2019denovoand pages 7-9)

Genetic modifiers

CDH23 is the best-supported modifier candidate. The earlier p.Val586Met PMCA2 allele reduced pump activity to about 50% and aggravated hearing loss in people homozygous for CDH23 p.Phe1888Ser; it did not establish classic monogenic DFNA82. Mouse Atp2b2–Cdh23 interactions independently support this modifier relationship. (schultz2005modificationofhuman pages 4-6, schultz2005modificationofhuman pages 3-4)

The 2019 DFNA82 cohort did not require pathogenic CDH23 variants: rare CDH23 findings failed segregation or had benign/VUS interpretations, supporting monogenic ATP2B2 loss of function. A MYO6 variant in one family could not be completely excluded as a modifier but did not explain the shared phenotype across families. (smits2019denovoand pages 5-7, smits2019denovoand pages 7-9)

Environmental and lifestyle risks

No affected person in the defining series reported excessive noise, prolonged antibiotic exposure, meningitis, or head trauma, so these were not necessary causes. Nevertheless, avoiding noise and ototoxic agents is biologically reasonable because reduced PMCA2 reserve may increase cochlear vulnerability. In a separate case-control study of 760 Chinese textile workers—not DFNA82 patients—the ATP2B2 rs3209637 C allele was associated with noise-induced hearing loss (OR 1.67, 95% CI 1.08–2.58); among workers exposed above 95 dB, reported susceptibility was OR 1.34 (95% CI 1.07–1.68). Interactions involving ATP2B2 polymorphisms, smoking, and alcohol were also reported, but these common-variant associations cannot be directly extrapolated to rare DFNA82 alleles. (smits2019denovoand pages 4-5, zhang2019researchanddiscussion pages 1-2)

No validated genetic or environmental protective factor is known. Hearing protection reduces an avoidable superimposed insult but does not prevent inheritance or the intrinsic progression. A 2024 developmental mouse study suggested thyroid hormone regulation of cochlear Atp2b2 expression; this remains preclinical and does not establish thyroid supplementation as prevention or treatment for DFNA82. (gregersen2024localizationandquantification pages 59-63, gregersen2024localizationandquantificationa pages 59-63)

3. Phenotypes

Core phenotype

  • Bilateral sensorineural hearing impairment — symptom/sign; typically symmetric, mild through profound depending on age; suggested HPO Sensorineural hearing impairment (HP:0000407) and Bilateral sensorineural hearing impairment (HP:0008619).
  • High-frequency-predominant/downsloping loss — clinical audiometric sign; suggested HPO High-frequency hearing impairment (HP:0005101).
  • Progressive hearing impairment — temporal characteristic; suggested HPO Progressive hearing impairment (HP:0001730).
  • Childhood onset — usually recognized at 2–6 years after a normal newborn screen; suggested HPO Childhood onset (HP:0011463). One person reported onset at 55 years, indicating substantial age-dependent variability. (smits2019denovoand pages 1-2, smits2019denovoand pages 5-7)

Among 11 evaluated affected subjects, loss was generally bilateral, symmetric, sensorineural, and steeply downsloping. Severity ranged from mild to profound. Cross-sectional age-related analysis estimated annual threshold deterioration from ages 10–70 of 0.5 dB/year at 250–500 Hz, 1.1 dB/year at 1–2 kHz, and 0.7 dB/year at 4–8 kHz. Four of four screened newborns passed; the screening method may miss thresholds below approximately 35 dB HL or loss predominantly above 4 kHz. (smits2019denovoand pages 5-7, smits2019denovoand pages 7-9)

Delayed speech development and school difficulty prompted hearing assessment in several children. Suggested HPO terms are Delayed speech and language development (HP:0000750) and Learning difficulty (HP:0001328), but these are secondary functional consequences rather than invariant primary manifestations. Two subjects reported tinnitus—suggested Tinnitus (HP:0000360)—so frequency is uncertain. (smits2019denovoand pages 4-5, smits2019denovoand pages 7-9)

Findings usually absent

Vestibular complaints were not characteristic; extensive oculomotor, caloric, rotational-chair, video-head-impulse, and vestibular-evoked-myogenic-potential testing yielded no convincing ATP2B2-related vestibulopathy. CT/MRI showed no structural inner-ear or retrocochlear pathology. Thus vertigo, vestibular areflexia, and inner-ear malformation should not be asserted as core DFNA82 phenotypes. (smits2019denovoand pages 9-10, smits2019denovoand pages 5-7)

Quality of life

No DFNA82-specific EQ-5D, SF-36, PROMIS, or hearing-related quality-of-life study was found. Expected burdens include impaired speech perception, educational difficulty, communication limitations, social isolation, and dependence on hearing technology. More generally, childhood moderate-to-profound SNHL affects language and school performance, while hearing loss in adults adversely affects social connection and autonomy. (smits2019denovoand pages 7-9, petit2023deafnessfromgenetic pages 1-5)

4. Genetic and molecular information

ATP2B2/PMCA2: the five defining variants, described on NM_001001331.2 and GRCh37/hg19, were:

  1. c.397+1G>A, canonical splice-donor;
  2. c.955delG, p.(Ala319fs), de novo frameshift;
  3. c.1963G>T, p.(Glu655*), de novo nonsense;
  4. c.1998C>A, p.(Cys666*), nonsense;
  5. c.2329C>T, p.(Arg777*), nonsense.

All were absent from gnomAD v2.02 and approximately 20,000 in-house exomes. Three variants segregated in dominant families; two arose de novo with parentage confirmed. All affect exons or splice sites encoding the PMCA2 w/a ortholog expressed in hair cells. Current ClinVar classifications should be checked variant-by-variant at the time of database entry because classifications can change. (smits2019denovoand pages 1-2, smits2019denovoand pages 4-5)

These are germline, not somatic, variants. The likely functional class is reduced PMCA2 dosage through NMD or a severely truncated pump. Dominant-negative or gain-of-function effects have not been demonstrated for classic truncating DFNA82 alleles. No recurrent chromosomal rearrangement, methylation signature, repeat expansion, mitochondrial defect, or disease-specific epigenetic lesion is established. Deletions involving ATP2B2 in 3p deletion syndromes provide supporting dosage evidence but may include additional genes. (smits2019denovoand pages 7-9)

5. Environmental information

DFNA82 is a genetic disease; toxins, radiation, pollution, infection, diet, smoking, and alcohol are not demonstrated primary causes. General acquired causes of SNHL—including intense noise, aminoglycosides, platinum chemotherapy, congenital CMV and other TORCH infections—remain clinically important competing or additive causes. Noise is the strongest plausible ATP2B2 interaction, supported by human common-variant association and mouse susceptibility data. (schultz2005modificationofhuman pages 7-8, petit2023deafnessfromgenetic pages 1-5, zhang2019researchanddiscussion pages 1-2)

6. Mechanism and pathophysiology

Ordered causal chain

  1. A heterozygous ATP2B2 truncating or splice variant leads to NMD or production of a severely impaired PMCA2 molecule.
  2. Reduced functional PMCA2 dosage leads to deficient ATP-dependent Ca²⁺ extrusion from auditory hair-cell stereocilia into endolymph.
  3. Deficient extrusion leads to disturbed stereociliary cytosolic and local extracellular Ca²⁺ homeostasis, affecting mechanotransduction-channel behavior, tip-link/cadherin function, and hair-bundle physiology; several details of this step are inferred from animal and cellular work rather than directly measured in patients. (smits2019denovoand pages 9-10, smits2019denovoand pages 1-2)
  4. Ca²⁺ dysregulation leads first to outer-hair-cell dysfunction and impaired cochlear amplification, with the basal/high-frequency cochlea most vulnerable.
  5. Persistent Ca²⁺ dysregulation is inferred to cause Ca²⁺ cytotoxicity and progressive degeneration of outer hair cells, inner hair cells, and supporting cells.
  6. Basal cochlear dysfunction and degeneration result in early high-frequency SNHL, which progressively extends in severity and frequency range.
  7. Branch: with biallelic or very severe Atp2b2 deficiency in mice, the same mechanism also affects vestibular hair cells and cerebellar circuitry, producing imbalance/ataxia; this branch is not typical of heterozygous human DFNA82. (smits2019denovoand pages 9-10, smits2019denovoand pages 7-9)

PMCA2 is the predominant plasma-membrane Ca²⁺ pump in rodent hair bundles. The w/a isoform is abundant in outer-hair-cell stereocilia and less abundant at the apical surface of inner hair cells. Alternative splicing at site A regulates hair-bundle targeting. Neuroplastin/Np55 acts as an essential PMCA auxiliary partner: adult outer-hair-cell neuroplastin is required to maintain PMCA2 membrane localization, and Nptn deficiency reduces mature mechanotransduction currents. (newton2022neuroplastingeneticallyinteracts pages 1-2, smits2019denovoand pages 1-2, smits2019denovoand pages 7-9)

Suggested annotations include GO:0055085 transmembrane transport, GO:0006816 calcium ion transport, GO:1901660 calcium ion export across plasma membrane, GO:0050881 musculoskeletal movement/vestibular-related processes only for model evidence, GO:0007605 sensory perception of sound, and GO:0032420 stereocilium. Relevant cell types are cochlear outer hair cell, cochlear inner hair cell, vestibular hair cell, and supporting cell; CL accession verification is recommended before ingestion. Relevant compartments are plasma membrane (GO:0005886), stereocilium membrane, and hair bundle.

No DFNA82-specific human transcriptomic, proteomic, metabolomic, lipidomic, spatial-transcriptomic, single-cell, or CRISPR-screen signature was identified. A 2024 developmental mouse study localized Atp2b2/PMCA2 in hair-cell stereocilia and greater epithelial ridge and reported thyroid-hormone-associated expression changes, but proposed scRNA-seq and ChIP-seq remained future work. (gregersen2024localizationandquantification pages 59-63, gregersen2024localizationandquantificationa pages 59-63)

7. Anatomical structures affected

The primary organ is the inner ear, specifically the cochlea/organ of Corti. Suggested terms include UBERON:0001844 cochlea, UBERON:0002227 organ of Corti, and stereociliary hair bundles at the apical surface of inner and outer hair cells. The basal cochlear turn is functionally most affected, explaining high-frequency loss. Disease is normally bilateral and approximately symmetric. (smits2019denovoand pages 9-10, smits2019denovoand pages 5-7)

Although ATP2B2 is expressed in vestibular sensory epithelia, cerebellum, retina, and mammary tissue, reproducible secondary-organ disease was not observed in the original DFNA82 families. These expression sites should not be converted into human disease phenotypes without variant- and syndrome-specific evidence.

8. Temporal development

The usual course is insidious, chronic, lifelong, and progressive. Hearing may be normal or only subtly abnormal at birth; recognizable loss usually emerges in early childhood. High frequencies are affected first, followed by progressive involvement of speech frequencies. One late-onset case at 55 years suggests variable expressivity or genetic/environmental modification. There is no spontaneous remission. (smits2019denovoand pages 1-2, smits2019denovoand pages 5-7, smits2019denovoand pages 7-9)

The interval after newborn screening but before speech and educational consequences is the critical diagnostic and potential therapeutic window. Progressive DFNA disorders are considered attractive future gene-therapy targets because residual hair cells and a postnatal intervention window may remain, but no ATP2B2 intervention has yet demonstrated rescue in humans. (petit2023deafnessfromgenetic pages 23-26)

9. Inheritance and population

Inheritance is autosomal dominant, with both vertical transmission and de novo occurrence. Each affected heterozygote has an expected 50% transmission risk per pregnancy, assuming a conventional germline genotype. Penetrance appears high in the few reported pedigrees but is not quantifiable; it may be age-dependent. Expressivity is variable, especially for age at onset and severity. No anticipation, founder effect, sex bias, carrier frequency, or consanguinity effect is established. Germline mosaicism was not reported, although low residual recurrence risk is generally considered after an apparently de novo variant.

Disease-specific prevalence and incidence are unknown. The defining study found qualifying ATP2B2 variants while examining approximately 700 hearing-impaired index cases, including 110 referred with dominant inheritance, but this selected diagnostic cohort cannot provide population prevalence. The five families were Dutch or Polish, with no evidence that DFNA82 is restricted to these populations. (smits2019denovoand pages 4-5)

10. Diagnostics

Recommended approach

  1. Audiology: age-appropriate pure-tone audiometry including frequencies through 8 kHz, bone conduction, speech reception/recognition, tympanometry, and otoacoustic emissions. Serial testing is essential because newborn screening may be normal.
  2. Clinical assessment: otoscopy; developmental, educational, tinnitus, vestibular, noise, infection, trauma, and ototoxic-exposure history; three-generation pedigree.
  3. Molecular testing: a comprehensive hereditary-hearing-loss panel that includes ATP2B2 and copy-number analysis, or exome/genome sequencing with CNV calling. Confirm candidate variants by an orthogonal method and test parents/relatives for segregation and de novo status.
  4. Variant interpretation: prioritize rare heterozygous predicted loss-of-function variants affecting biologically relevant transcripts. Evaluate CDH23 and other hearing-loss genes, but do not require a second CDH23 allele for monogenic DFNA82.
  5. Imaging/vestibular testing: not required to prove DFNA82; use CT/MRI for atypical, asymmetric, conductive, neurologic, implant-planning, or retrocochlear concerns. Vestibular testing is indicated for imbalance, vertigo, delayed motor milestones, or atypical variants. The defining cohort’s imaging was normal and vestibular testing essentially unrevealing. (smits2019denovoand pages 1-2, smits2019denovoand pages 5-7)

WES was effective in the original discovery and broader hearing-loss cohorts; WGS may add noncoding and structural-variant detection. CMA, karyotype, FISH, mitochondrial sequencing, repeat-expansion testing, biopsy, metabolomics, and liquid biopsy are not routine for an otherwise typical ATP2B2 phenotype. A 2020 clinical series emphasized that WES can identify rare genes, dual diagnoses, and initially inapparent syndromic disease and that molecular diagnosis informs prognosis, surveillance, and counseling. (morgan2020lightsandshadows pages 12-14)

Differential diagnoses include other dominant progressive high-frequency hearing losses—such as KCNQ4/DFNA2, COCH/DFNA9, MYO6/DFNA22, ACTG1/DFNA20/26, POU4F3/DFNA15, TECTA-related disease—and acquired noise, ototoxic, infectious, autoimmune, and age-related loss. Vestibular dysfunction or neurologic disease should prompt consideration of COCH-related disease or a broader ATP2B2-associated neurologic phenotype rather than classic DFNA82.

Cascade audiologic and molecular testing is appropriate for relatives. Normal newborn screening does not exclude the disorder. Prenatal or preimplantation genetic testing becomes technically possible after a familial pathogenic variant is established.

11. Outcome and prognosis

DFNA82 is not known to shorten life expectancy or cause disease-specific mortality. Morbidity is auditory: progressive communication disability, educational and speech effects in childhood, tinnitus in some patients, and eventual need for amplification or implantation. At least one person in the defining cohort received a cochlear implant by age 24, demonstrating that severe progression can occur, but ATP2B2-specific implant response rates were not reported. (smits2019denovoand pages 4-5)

Prognostic indicators are age, serial audiometric slope, baseline speech-frequency thresholds, speech recognition, and possibly variant class or modifiers. No validated molecular prognostic biomarker exists. Recovery of lost native hearing is not expected with present care; functional rehabilitation is possible with hearing technology.

12. Treatment and current applications

There is no approved ATP2B2-targeted drug, pharmacogenomic guideline, RNA therapy, cell therapy, gene therapy, or immunotherapy. No relevant ATP2B2/DFNA82 clinical trial was identified in the ClinicalTrials.gov search.

Current care is supportive and follows pediatric/adult SNHL practice:

  • Hearing aids for aidable mild-to-severe loss; suggested NCIT concept: Hearing Aid.
  • Remote microphone/classroom systems, educational accommodations, auditory-verbal or speech-language therapy; NCIT concepts should be mapped locally to Assistive Device, Speech Therapy, and Audiologic Rehabilitation.
  • Cochlear implantation when appropriately fitted hearing aids no longer provide sufficient speech understanding; suggested NCIT concept: Cochlear Implantation. Genetic diagnosis helps set expectations, although no ATP2B2-specific response estimate is available. (morgan2020lightsandshadows pages 12-14, petit2023deafnessfromgenetic pages 1-5)
  • Tinnitus management and psychosocial/communication support when required.

The authoritative 2023 review by Petit, Bonnet, and Safieddine states that hearing aids and cochlear implants remain the corrective options for mild-to-severe and profound SNHL, respectively, while reviewing preclinical gene replacement, augmentation, and editing strategies. It also cautions that mouse cochlear physiology does not fully reproduce human low-frequency speech hearing. ATP2B2 is therefore a plausible future gene-augmentation target, but vector capacity, cell-specific delivery, dosage control, timing, and durable safety remain unresolved. (petit2023deafnessfromgenetic pages 23-26, petit2023deafnessfromgenetic pages 1-5)

13. Prevention

Primary prevention of the genotype is not possible. Reproductive options after molecular confirmation include genetic counseling, prenatal diagnosis, donor gametes, and preimplantation genetic testing. Counseling should cover the nominal 50% transmission risk, de novo cases, uncertain age-dependent penetrance, and variable severity.

Secondary prevention consists of cascade testing, audiologic surveillance of genetically at-risk children despite a passed newborn screen, prompt assessment of speech or school difficulties, and early amplification. Tertiary prevention includes hearing conservation, careful risk–benefit review of ototoxic drugs, treatment of middle-ear disease, optimized hearing technology, speech/language services, and educational accommodations. Vaccination has no DFNA82-specific preventive role, though routine vaccination helps prevent some infectious causes of acquired hearing loss.

14. Other species and natural disease

The principal comparative species is Mus musculus (NCBI Taxonomy 10090), with ortholog Atp2b2. Numerous naturally occurring or induced deafwaddler alleles produce hearing and balance phenotypes. Heterozygous loss-of-function mice develop early, rapidly progressive, high-frequency hearing loss resembling human DFNA82; homozygotes commonly have congenital severe-to-profound deafness plus vestibular/ataxic behavior. Degeneration is most severe in the cochlear base. (smits2019denovoand pages 7-9)

The phenotype is noninfectious and nontransmissible, with no zoonotic potential. No robust naturally occurring companion-animal breed disease equivalent was identified. Conservation of PMCA-dependent Ca²⁺ handling across mammalian mechanosensory hair cells makes the mouse especially informative, although timing, frequency range, and cochlear dimensions differ from humans.

15. Model organisms and experimental systems

Mouse models

Available models include spontaneous deafwaddler, null, missense, truncating, ENU-induced, and interaction strains. They are assessed with auditory brainstem response, distortion-product otoacoustic emissions, vestibular behavior, hair-cell electrophysiology, and cochlear histology. Heterozygotes reproduce the human dosage-sensitive, progressive high-frequency phenotype; homozygotes model more severe auditory, vestibular, and cerebellar consequences. (smits2019denovoand pages 10-11, xu2011identificationofa pages 8-8, smits2019denovoand pages 7-9)

The models support a sequence in which outer-hair-cell dysfunction precedes degeneration and show that relatively small changes in PMCA2 activity can markedly change hearing. Their limitations include faster disease time scales, different audible-frequency ranges, strain-specific Cdh23 alleles, and poor modeling of human speech-frequency perception. (smits2019denovoand pages 9-10, smits2019denovoand pages 7-9, petit2023deafnessfromgenetic pages 23-26)

Interaction and cellular models

Nptn knockout/conditional mouse models establish that neuroplastin maintains PMCA2 at the outer-hair-cell membrane. Nptn-null mature outer hair cells have reduced maximum mechanotransduction currents and channel-open probability; most hearing loss reflects hair-cell dysfunction rather than afferent-synapse abnormalities. The abstract states: “continued expression of NEUROPLASTIN in OHCs of adult mice is required for membrane localisation of Plasma Membrane Ca2+ ATPase 2.” (newton2022neuroplastingeneticallyinteracts pages 1-2)

Heterologous cell assays demonstrated reduced activity of the older PMCA2 p.Val586Met modifier allele, but patient-derived iPSC hair cells, cochlear organoids carrying defining DFNA82 variants, and ATP2B2-specific therapeutic rescue models were not identified. These constitute important current research gaps.

Evidence appraisal and key gaps

The gene–disease relationship is supported by five independent loss-of-function alleles, two confirmed de novo events, dominant segregation, absence from large reference datasets, a coherent dosage mechanism, and strong mouse phenocopy. Nevertheless, clinical confidence intervals are wide because the foundational phenotype rests on only five families and 11 evaluated affected people. Penetrance, prevalence, sex effects, genotype–phenotype correlations, cochlear-implant outcomes, vestibular risk across the lifespan, and the boundary between nonsyndromic DFNA82 and neurologic ATP2B2 disease remain insufficiently characterized.

The most important recent advances are broader genomic diagnosis of hearing loss, increasingly precise definition of the neuroplastin–PMCA2 complex, developmental localization studies, and rapid progress in inner-ear gene therapy generally. As of the searched 2023–2024 literature, none has yet produced an ATP2B2-specific clinical intervention. The disease entry should therefore separate established human DFNA82 facts, mouse-supported mechanistic inference, and general hearing-loss management extrapolation rather than presenting all three as equivalent evidence.

References

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