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Inheritance

1

Autosomal dominant HP:0000006

Heterozygous HOMER2 variants segregate with hearing loss across multi-generation pedigrees - five generations in the founding European family, four in the most recent Chinese one - and none of the six primary reports describes a homozygote or a compound heterozygote. Dominance here is a statement about the allele, not only about the pedigree. The heterozygous mouse null hears normally and the gene is tolerant of loss-of-function variation in population data, so a simple halving of HOMER2 dose does not produce the phenotype. The human alleles are dominant because they interfere with the wild-type protein they are co-expressed with, by one of the three routes set out in the pathophysiology nodes below.

Autosomal dominant inheritance

Show evidence (4 references)

PMID:25816005 SUPPORT Human Clinical

"Pure tone audiometric evaluation of affected members showed bilateral post-lingual progressive hearing loss that segregated as an autosomal dominant trait; bone conduction thresholds excluded conductive hearing impairment."

The segregation pattern in the founding family, together with the exclusion of a conductive component that would have pointed at a different lesion.

PMID:37173411 SUPPORT Human Clinical

"DFNA68 is a rare subtype of autosomal dominant nonsyndromic hearing impairment caused by heterozygous alterations in the HOMER2 gene."

States the mode of inheritance and the heterozygous state of the causal alleles for the entity as a whole.

PMID:40515814 SUPPORT Human Clinical

"Low pLI score (0.01) of HOMER2 suggests that alteration of HOMER2 exerts a pathogenic effect via a mechanism other than loss-of-function."

The population-genetic argument that dominance here cannot be haploinsufficiency: HOMER2 tolerates loss-of-function variation in the general population.

+ 1 more reference

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Discussions and Knowledge Gaps

3

Does HOMER2 keep hair cells working by regulating stereociliary actin through CDC42, by holding calcium-handling proteins in place, or by both?

KNOWLEDGE GAP OPEN dfna68_actin_versus_calcium_mechanism

Attached to

pathophysiology#Disrupted HOMER2-CDC42 Coupling at the Hair Bundle pathophysiology#Dysregulated Hair Cell Cytosolic Calcium Handling

The founding paper set out two hypotheses and declined to choose, and a decade later nothing has chosen for it. Both are carried in this entry as separate nodes rather than collapsed, because collapsing them would manufacture a resolution. The actin branch has the better circumstantial case. The HOMER2-CDC42 interaction is mapped to the same residue range the disease alleles fall in; CDC42 is present and active at stereociliary membranes; and removing CDC42 from mouse hair cells produces stereocilia fusion and depletion with progressive high-frequency hearing loss that looks like the human disease. What is missing is any measurement of the HOMER2-CDC42 complex in a cochlear hair cell, and any binding assay for a disease allele. The calcium branch has one real measurement and it is in the wrong tissue: deleting Homer2 from mouse parotid acinar cells raises PMCA expression and speeds calcium extrusion. The reason to care is that PMCA2 is the only calcium clearance route out of a stereocilium, so a scaffold that sets pump behaviour would matter there. But the Homer2 partner established among TRPC channels is TRPC1, while the TRPCs hair cells need are TRPC3 and TRPC6, and the PMCA2 partnership has been proposed rather than shown. The two are not mutually exclusive. A tetrameric hub holds several partners at once, and an allele that degrades hub assembly would be expected to loosen the grip on all of them. It is entirely possible that the answer is "both, and the actin arm dominates the phenotype" - but that is a hypothesis with no data behind it either.

Proposed experiments

HOMER2 partner mapping and allele-specific binding in cochlear hair cells

dfna68_homer2_cdc42_interaction_in_hair_cells

Immunoprecipitate HOMER2 from mouse cochlear sensory epithelium and identify its partners by mass spectrometry, asking specifically whether CDC42, PMCA2 and TRPC channels are among them; then measure binding of each disease allele class to whichever partners are found, in a hair-cell-derived line rather than in HEK cells.

Readouts

CDC42 recovery in HOMER2 immunoprecipitates from cochlear epithelium

pathophysiology#Disrupted HOMER2-CDC42 Coupling at the Hair Bundle

Direction: DECREASED

Interpretation: Recovery of CDC42 from wild-type cochlea, reduced for disease alleles, would move this node from provisional to established. Failure to recover CDC42 at all would undercut the better-supported of the two hypotheses and push the field to the calcium branch.

PMCA2 recovery in HOMER2 immunoprecipitates from cochlear epithelium

pathophysiology#Dysregulated Hair Cell Cytosolic Calcium Handling

Interpretation: A HOMER2-PMCA2 complex in cochlear tissue would convert the calcium hypothesis from an extrapolation out of salivary gland into a claim about the right cell.

Every HOMER2 hearing model is either a null or an overexpression assay. Does a mouse heterozygous for an actual human DFNA68 allele go deaf, and does it do so the way a patient does?

HUMAN MODEL MISMATCH OPEN dfna68_no_model_of_the_human_genotype

Attached to

animal_models#Mouse pathophysiology#HOMER2 Coiled-Coil Missense Variant

This is a mismatch of genotype, not of species, and it runs through the whole evidence base. The mammalian model is a homozygous constitutive null whose heterozygote - the genotype corresponding to a human carrier - hears normally. The zebrafish assays inject human mutant mRNA into embryos with intact endogenous homer2, at supraphysiological and transient levels, and read out otic vesicle size, neuromast dye uptake and startle behaviour. Neither system contains a single copy of a human disease allele expressed at its own level in a mammalian cochlea, which is what the disease is. Why it matters rather than being a routine caveat: the entire mechanistic classification of this disease turns on the difference between absence of HOMER2 and interference by a mutant HOMER2. The mouse tests absence. The fish tests excess. The disease is neither. The specific claims that are unverified as a result are the dominant-negative classification of the missense allele, the gain-of-function classification of the extension alleles, and the assertion that hair cells survive - which is measured at eight weeks in an animal whose disease runs its whole course in six. Filed as HUMAN_MODEL_MISMATCH rather than KNOWLEDGE_GAP because the experiments have been done, in models whose correspondence to the human genotype is the open question, rather than not done at all.

Proposed experiments

Knock-in mouse series carrying human DFNA68 alleles

dfna68_knock_in_mouse_allelic_series

Generate heterozygous knock-in mice carrying the orthologues of one allele from each class - the coiled-coil missense, a CDC42-binding-domain frameshift, and a C-terminal extension - and follow auditory brainstem response and distortion-product otoacoustic emission thresholds, hair-bundle morphology by scanning electron microscopy, and hair-cell counts, to an age well past threshold onset.

Readouts

Auditory brainstem response threshold in heterozygous knock-in mice

pathophysiology#Progressive Sensorineural Hearing Loss

Direction: INCREASED

Interpretation: Rising thresholds in a heterozygote, where the null heterozygote has none, would be the direct demonstration that these alleles act on the wild-type product, and would convert the dominant-negative and gain-of-function classifications from inference into measurement.

Hair cell counts at and beyond threshold onset

pathophysiology#Hair Cell Functional Failure Without Hair Cell Loss

Interpretation: Preserved hair cells late in a slowly progressing model would establish the entry's distinctive claim in the right genotype. Progressive hair-cell loss would instead place the disease inside the module's ordinary death pathway and change what this node asserts.

Stereocilia morphology by scanning electron microscopy

pathophysiology#Failure of Stereocilia Actin Maintenance

Direction: ALTERED

Interpretation: Fusion and depletion resembling the Cdc42 conditional knockout would connect the HOMER2 allele to the actin branch directly, which is the step the CDC42 experiment cannot supply.

Is the cardiac anomaly seen in zebrafish injected with the longest HOMER2 extension allele a signal about human carriers, or an artefact of overexpressing an aberrant protein in an embryo?

OPEN QUESTION OPEN dfna68_extension_allele_cardiac_signal

Attached to

pathophysiology#HOMER2 C-Terminal Extension Variant

DFNA68 is nonsyndromic in every reported family. Against that, the group that characterised the longest extension allele reported that it increased the frequency of cardiac anomalies and general morphological abnormalities in injected zebrafish, more than an artificial pure-truncation control did, and raised the possibility that human fetuses carrying such a variant might not survive - which would make the human families an ascertainment of the survivors. The case against taking it seriously is straightforward: the patient carrying the allele had no cardiac abnormality, the assay is supraphysiological mRNA injection into an embryo, and morphological abnormality in that system is a common non-specific outcome. The case for not dismissing it is that the effect was dose-ordered against a designed control rather than incidental, and that none of the six primary reports describes cardiac imaging in a DFNA68 family. Recorded as an open question rather than as a phenotype or a knowledge gap: none of the six primary reports describes a cardiac feature in a DFNA68 patient, and curating one on the strength of a fish would be exactly the import this entry is otherwise careful to avoid.

Proposed experiments

Echocardiography and electrocardiography in DFNA68 carriers

dfna68_cardiac_assessment_of_reported_families

Cardiac assessment of carriers in the reported families, stratified by allele class, reported whether normal or abnormal. The question is answerable with existing cohorts and no new genetics.

Readouts

Left ventricular function and rhythm in HOMER2 carriers

pathophysiology#HOMER2 C-Terminal Extension Variant

Interpretation: Normal cardiac findings across carriers, particularly extension-allele carriers, would close the question and confirm the fish result as assay-specific. Any consistent abnormality would change DFNA68 from a nonsyndromic entity into a syndromic one and would add cardiac surveillance to its management.

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Pathophysiology

9

HOMER2 Coiled-Coil Missense Variant

The founding allele, p.Arg185Pro numbered against HOMER2 isoform 1 and p.Arg196Pro against the longer isoform 2, is a single amino acid substitution inside the coiled-coil domain. Arginine is replaced by proline, which the reporting authors predict will alter the domain's conformation or its ability to multimerise and to bind partner proteins, and the residue sits in the stretch that both drives multimerisation and carries the CDC42-binding site. Its classification as dominant negative rests on a positive experiment rather than on inference from the pedigree: injecting mutant mRNA into zebrafish embryos, which retain their own wild-type homer2, reduced ear size and kinocilium number, while knocking the fish gene down did not change ear size or morphology. An allele that damages a process only when it is present, and not when the gene is simply absent, is acting on the wild-type product.

HOMER2 hgnc:17513

Genetic context HOMER2 hgnc:17513 allele_type: missense substitution in the coiled-coil domain variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: DOMINANT_NEGATIVE

DOMINANT_NEGATIVE is the authors' own conclusion and is supported by the contrast between mutant-mRNA overexpression, which produced a phenotype, and morpholino knockdown, which did not. The two published protein numberings for this variant differ because HOMER2 has two transcripts of 343 and 354 residues; both appear in the literature for the same change and neither is wrong.

scaffold protein binding GO:0097110 ↓ DECREASED

Animal models

Zebrafish HOMER2 mutant mRNA overexpression model Zebrafish recapitulates The assay that established the dominant-negative classification of the founding allele, by the contrast between mutant-mRNA injection and gene knockdown.

Downstream

Impaired HOMER2 Multimerisation A proline substitution in the coiled coil is predicted to alter the domain's conformation or its capacity to multimerise; the dominant-negative behaviour in zebrafish is what the authors read as evidence that it does.

Show evidence (4 references)

PMID:25816005 SUPPORT Human Clinical

"Only a single variant, p.Arg185Pro in HOMER2, segregated with the hearing-loss phenotype in the extended family."

The allele, and the genetic evidence that it is the cause in the founding family.

PMID:25816005 SUPPORT BACKGROUND Human Clinical

"This amino acid change alters a highly conserved residue in the coiled-coil domain of HOMER2 that is essential for protein multimerization and the HOMER2-CDC42 interaction."

Places the substitution in the domain whose two established functions are the ones this entry's downstream nodes describe. BACKGROUND because the domain's role is established elsewhere and restated here.

PMID:25816005 SUPPORT Model Organism

"These results show that HOMER2 plays an essential role in the normal development and/or maintenance of hair cells in the zebrafish inner ear and that the p.Arg185Pro mutation has a dominant-negative effect on this process."

The experimental basis for the dominant-negative classification, in the species where it was tested.

+ 1 more reference

HOMER2 Frameshift Truncation in the CDC42-Binding Domain

Two independent frameshift alleles, a single-base duplication reported in a Chinese family and a five-base deletion reported in a Spanish family, introduce premature stop codons a few residues apart inside the CDC42-binding domain. They are curated as one node because the two truncated products share an identical aberrant C-terminal tail, which is the observation the Spanish authors use to argue that the two families share a mechanism. What is measured, rather than predicted, comes from the Chinese allele expressed in cells: the mutant protein was less stable than wild type, multimerised less well, and lost the perinuclear clustering that wild-type HOMER2 shows, distributing diffusely through the cytoplasm instead.

HOMER2 hgnc:17513

Genetic context HOMER2 hgnc:17513 allele_type: frameshift variant producing a premature stop codon within the CDC42-binding domain variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: DOMINANT_NEGATIVE

The recorded value follows the measured properties of the truncated product - reduced multimerisation with a stable, mislocalised protein still present in the cell - which is the signature of interference with wild-type product rather than of its absence. It is not the only reading the literature offers: the Spanish authors state explicitly that the mechanism is either a gain of function of the aberrant C-terminal tail or a dominant negative, and do not choose between them. That unresolved alternative is recorded here rather than smoothed away, and the single-valued slot should not be read as a settled answer.

protein homooligomerization GO:0051260 ↓ DECREASED

Downstream

Impaired HOMER2 Multimerisation Truncation inside the coiled coil removes the region required for tetramer formation, and the measured consequence is a protein that multimerises less well than wild type.

Show evidence (5 references)

PMID:30047143 SUPPORT Human Clinical

"The pathogenic variant c.840_841insC in HOMER2 (NM_199330), segregating with the hearing-loss phenotype in the family, leads to a premature stop codon producing a truncated protein."

The first truncating allele, and its segregation with hearing loss.

PMID:30047143 SUPPORT In Vitro

"HOMER2MU protein tended to be distributed in a diffuse manner, whereas HOMER2WT and the reported mutant HOMER2 tended to cluster together."

The mislocalisation of the truncated product in transfected cells, measured against both wild type and the missense allele.

PMID:33809266 SUPPORT Human Clinical

"This frameshift mutation produces a premature stop codon that may lead in the absence of NMD to a shorter variant (p.Pro278Alafs*10) that truncates HOMER2 at the CDC42 binding domain (CBD) of the coiled-coil structure, a region that is essential for protein multimerization and HOMER2-CDC42 interaction."

The second truncating allele, located in the same domain, with the consequence for both domain functions stated.

+ 2 more references

HOMER2 C-Terminal Extension Variant

A third allele class leaves the reading frame running past the point where it should stop. It includes a nonstop substitution that converts the termination codon to a tryptophan codon and adds ten residues, a frameshift that alters the last ten residues and adds fifty-three more, and a seven-nucleotide deletion producing an extended incorrect C terminus. These alleles are not simply weaker truncations. Transcripts carrying the nonstop variant escape nonstop decay, so the aberrant product is made; the frameshift-extension allele lies in the last exon and so is likewise not expected to be removed by nonsense-mediated decay. Structure prediction for the longest of them puts the damage not in the coiled coil, where the residue sits, but in the distant EVH1 domain, with the predicted CDC42 interface disturbed while dimer and tetramer formation is preserved. On that reading the extension acts by adding something, which is why this node is graded as a gain of function while the other two allele classes are not.

HOMER2 hgnc:17513

Genetic context HOMER2 hgnc:17513 allele_type: nonstop or frameshift variant extending the protein beyond its normal termination codon variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION

GAIN_OF_FUNCTION is stated in those words by the group that characterised the longest extension allele, and is argued from a comparison the study built for the purpose: an artificial variant truncating the same ten C-terminal residues had a milder effect in zebrafish than the patient allele that truncates those residues and adds fifty-three more. The same paper also describes the combined change as likely dominant-negative in its discussion, so the two vocabularies are not cleanly separated in the source.

small GTPase binding GO:0031267 ↓ DECREASED

Downstream

Disrupted HOMER2-CDC42 Coupling at the Hair Bundle This allele class is modelled as reaching the CDC42 interface through a conformational change in the EVH1 domain rather than through loss of the coiled-coil binding site, so the link is drawn around the multimerisation node rather than through it. The intermediate step - the predicted structural rearrangement - is named but has not been measured.

Show evidence (6 references)

PMID:37173411 SUPPORT Human Clinical

"This novel alteration is a nonstop substitution (c.1064 A > G) that converts the translational termination codon (TAG) of the gene into a tryptophan codon (TGG) and is predicted to extend the HOMER2 protein by 10 amino acids."

The first extension allele and the change it makes to the protein's C terminus.

PMID:37173411 SUPPORT Human Clinical

"RNA analyses from the proband suggested that HOMER2 transcripts carrying the nonstop variant escaped the non-stop decay pathway."

Establishes in patient material that the extended transcript survives, which is what makes an added-function mechanism available at all.

PMID:40515814 SUPPORT Human Clinical

"we identified a novel frameshift extension variant, c.1033delC (p.Arg345Glufs*64; p.R345Efs*64), which introduces a significantly longer protein extension than previously reported extension variants, in a patient in their sixties presenting with progressive profound SNHL"

The longest extension allele reported, and the patient it was found in.

+ 3 more references

Impaired HOMER2 Multimerisation

Homer proteins work as tetramers assembled through the parallel alignment of their coiled-coil domains, and it is the tetramer, not the monomer, that acts as a hub holding several binding partners together. Both the missense and the truncating disease alleles fall in that domain, and the truncating one has been shown directly to oligomerise less than wild type. Because a mutant subunit is still made and can still enter a hub, reduced multimerisation in a heterozygote is not the same as having half as much scaffold: an assembly built from a mixture of wild-type and mutant subunits can be worse than one built from fewer wild-type subunits alone. That is the reading under which a dominant allele coexists with a mouse heterozygote that hears normally.

protein homotetramerization GO:0051289 ↓ DECREASED

stereocilium tip GO:0032426

Downstream

Disrupted HOMER2-CDC42 Coupling at the Hair Bundle The CDC42-binding domain sits inside the coiled coil, so the alleles that damage multimerisation also damage, or remove outright, the surface that binds CDC42.

Dysregulated Hair Cell Cytosolic Calcium Handling The second of the two mechanisms proposed for this disease. Homer scaffolds hold calcium-handling proteins in place, so a scaffold that assembles poorly is expected to hold them less well - but which partner matters in a hair cell has never been established, so the intermediates are unknown.

Show evidence (2 references)

PMID:16914674 SUPPORT In Vitro

"We conducted a series of biophysical experiments that provide the first evidence that Homer forms a tetramer via its coiled-coil domain, in which all subunits are aligned in parallel orientation."

The biophysical basis for treating the coiled coil as a tetramerisation domain, which is what the disease alleles disturb.

PMID:25816005 SUPPORT BACKGROUND Other

"The CC region is required for homo/hetero-multimerization to form tetrameric hubs (in which the CC domains align in a parallel fashion) and for interaction with Rho family GTPase proteins like CDC42"

States both functions of the coiled coil in one sentence, which is why a single lesion there can reach two downstream branches. Graded OTHER with quote_role BACKGROUND because it is the citing paper's summary of established structural work rather than a study result of any kind.

Disrupted HOMER2-CDC42 Coupling at the Hair Bundle

Mechanism confidence: Provisional

The first of the two proposed downstream lesions, and the better supported one. HOMER2 binds activated CDC42 through the CDC42-binding domain, and CDC42 is the Rho-family GTPase that tunes actin turnover. In hair cells CDC42 is present and active at the stereociliary membrane, so the interaction has somewhere to happen. The argument that this is the disease-relevant partnership is comparative rather than direct: deleting Cdc42 from murine hair cells produces a hearing phenotype of the same shape as the human one. None of the six primary DFNA68 reports measures binding for any disease allele, and none demonstrates a HOMER2-CDC42 complex in a cochlear hair cell; the interaction was mapped in neurons, and the cochlear evidence is colocalisation plus the CDC42 knockout.

cochlear inner hair cell CL:0000589 cochlear outer hair cell CL:0000601

small GTPase binding GO:0031267 ↓ DECREASED

stereocilium GO:0032420

Downstream

Failure of Stereocilia Actin Maintenance The intermediate is CDC42-dependent actin turnover, and it has been tested by removing CDC42 itself rather than by disturbing its coupling to HOMER2.

Show evidence (4 references)

PMID:25816005 SUPPORT Other

"One hypothesis posits that HOMER2 exerts its function by regulating actin dynamics in stereocilia through its interaction with CDC42, a highly conserved small GTPase of the RHO family that fine-tunes actin-turnover"

The hypothesis in the authors' own words. Graded OTHER because it is a proposal set out in a discussion, not a result the paper reports.

PMID:25816005 SUPPORT Model Organism

"Organ of Corti expression was particularly enriched in the tips of stereocilia of both IHCs and OHCs"

Puts the protein where the lesion is claimed to be, measured by immunolabelling in mouse cochlea.

PMID:24610943 SUPPORT INDIRECT Model Organism

"fluorescence resonance energy transfer (FRET) imaging of hair cells from transgenic mice expressing a Cdc42-FRET biosensor indicated Cdc42 presence and activation at stereociliary membranes and AJCs in cochlear hair cells"

Puts the other half of the proposed complex in the same place, and shows it is active there rather than merely present. INDIRECT because it says nothing about HOMER2.

+ 1 more reference

Dysregulated Hair Cell Cytosolic Calcium Handling

Mechanism confidence: Hypothetical

The alternative proposed lesion, and the weaker of the two. Homer proteins bind and regulate several calcium-handling proteins, and deleting Homer2 from mouse parotid acinar cells raises plasma-membrane calcium pump expression and speeds calcium extrusion, which is a measured regulatory relationship in a real tissue. The reason it is interesting for hearing is that PMCA2 is the only route by which calcium is cleared from a stereocilium, so a scaffold that sets pump behaviour would matter there disproportionately. Nothing has tested this in a hair cell. No HOMER2 calcium phenotype has been measured in the cochlea, the established Homer2 partner among the TRPC channels is TRPC1 rather than the TRPC3 and TRPC6 that hair cells need, and the PMCA2 partnership is a proposal rather than an observation. The node is carried because the founding paper put it forward as a live alternative and because discarding it would make the entry look more settled than the field is.

cochlear outer hair cell CL:0000601

regulation of cytosolic calcium ion concentration GO:0051480 ↕ DYSREGULATED

Downstream

Hair Cell Functional Failure Without Hair Cell Loss Drawn because the calcium hypothesis, if true, would produce hair-cell dysfunction rather than hair-cell death - which is the phenotype the models show. No step between the two has been demonstrated.

Show evidence (5 references)

PMID:25049230 SUPPORT INDIRECT Model Organism

"These findings reveal an important regulation of PMCA by Homer2 that has a central role on PMCA-mediated Ca(2+) signaling in parotid acinar cells."

The only direct demonstration that Homer2 sets calcium-pump behaviour in a tissue. INDIRECT because the tissue is salivary gland, not cochlea.

PMID:25816005 SUPPORT Other

"A suitable interacting partner of HOMER2 may be the PMCA2 pump (MIM 108733), which represents the only system for clearance of Ca2+ from hair cell stereocilia"

The reason the salivary-gland result is thought to transfer to a stereocilium, and the fact that makes the transfer worth proposing. Graded OTHER: it is a suggestion in a discussion, and its hedging is preserved in the quote.

PMID:25816005 SUPPORT Other

"While both proteins are potentially interacting partners for HOMER2, to date only an interaction with TRPC1 (MIM 602343) has been established"

The specific gap in the calcium hypothesis: the TRPC channels hair cells need are TRPC3 and TRPC6, and the only established Homer2 TRPC partner is TRPC1. Graded OTHER because it is the authors' account of the state of the field rather than a result.

+ 2 more references

Failure of Stereocilia Actin Maintenance

Mechanism confidence: Provisional

The hair bundle is a stable actin structure that has to be actively maintained rather than simply built once, and the maintenance is CDC42-dependent. When Cdc42 is deleted from murine hair cells the bundles form normally and then come apart after maturation: stereocilia fuse and are depleted, the circumferential actin belt at the apical junctions thins, and hearing declines progressively and first at high frequencies. That "normal, then lost" shape is what makes the node the right substitution for this disease. DFNA68 patients hear normally through infancy, acquire speech, and then deteriorate over decades. No stereocilia morphology has been reported for any HOMER2 patient or animal - the mouse null cochlea was assessed by phalloidin staining read for hair-cell death rather than for bundle structure - so the cellular lesion here is inferred from the CDC42 experiment and from where the protein sits, not observed.

cochlear inner hair cell CL:0000589 cochlear outer hair cell CL:0000601

auditory receptor cell stereocilium organization GO:0060088 ⚠ ABNORMAL actin cytoskeleton organization GO:0030036 ↕ DYSREGULATED

Downstream

Hair Cell Functional Failure Without Hair Cell Loss Stereocilia that fuse, shorten or are lost cannot deflect normally, and the bundle is the structure that opens the transduction channels.

Show evidence (3 references)

PMID:24610943 SUPPORT INDIRECT Model Organism

"Cochlear hair cell degeneration was more robust in inner hair cells than in outer hair cells, and began as stereocilia fusion and depletion, accompanied by a thinning and waving circumferential actin belt at apical junctional complexes (AJCs)."

The cellular lesion in the CDC42 model, described at the level of the actin structures. INDIRECT because the gene removed is CDC42, not HOMER2.

PMID:24610943 SUPPORT INDIRECT Model Organism

"Hair cells of Atoh1-Cre;Cdc42(flox/flox) mice developed normally but progressively degenerated after maturation, resulting in progressive hearing loss particularly at high frequencies."

The normal-development-then-progressive-loss course, which is the feature that makes this model resemble the human disease.

PMID:33809266 SUPPORT INDIRECT REVIEW SYNTHESIS Other

"targeted deletion of Cdc42 in murine hair cells causes a progressive hearing loss phenotype that is comparable to the hearing loss phenotype in the Spanish and Chinese families"

The comparison drawn explicitly against the human families, by a group that characterised one of them. REVIEW_SYNTHESIS because it is their reading of another group's mouse work.

Hair Cell Functional Failure Without Hair Cell Loss

The cellular endpoint that the animal data actually establish, and it is a functional one. In the homozygous Homer2-null mouse, thresholds rise progressively while the organ of Corti keeps its full complement of inner and outer hair cells at eight weeks, so the deafness is not a consequence of cells dying. In zebrafish injected with mutant HOMER2 mRNA, neuromast hair-cell numbers are unchanged but the cells take up far less FM1-43, which the reporting group uses as a marker for active mechanosensory hair cells - a readout of function, not of survival. This is the mechanistically distinctive claim of the entry. The module this disease conforms to has apoptotic hair-cell death as its central effector; the HOMER2 evidence says instead that the cells are there and are not working. Whether that remains true in an older human cochlea over five decades is not known: none of the six primary DFNA68 reports describes human cochlear histopathology, and the mouse count was made at eight weeks.

cochlear inner hair cell CL:0000589 cochlear outer hair cell CL:0000601

detection of mechanical stimulus involved in sensory perception of sound GO:0050910 ↓ DECREASED

Animal models

Homer2 constitutive knockout mouse Mouse partially recapitulates The model's distinctive contribution: profound deafness in the presence of an intact hair-cell population, which is what separates this disease from the hair-cell-death mechanisms the module it conforms to normally describes.

Zebrafish HOMER2 mutant mRNA overexpression model Zebrafish recapitulates The functional extension of the assay, in which disease alleles reduce FM1-43 uptake by neuromast hair cells while leaving hair-cell numbers unchanged - the fish counterpart of the mouse null's intact organ of Corti.

Downstream

Progressive Sensorineural Hearing Loss Hair cells that cannot transduce cannot drive the auditory nerve, and the deficit accumulates because the failure is a maintenance failure rather than a single event.

Show evidence (3 references)

PMID:25816005 SUPPORT Model Organism

"No differences in IHCs and OHCs were observed in any animals regardless of genotype indicating the absence of Homer2 does not impair hair cell formation and development"

The negative histological result that separates this node from hair-cell death, in the mouse null at the age when its hearing loss is profound.

PMID:40515814 SUPPORT INDIRECT Model Organism

"The data suggest that HOMER2 variants severely impaired the capacity of neuromast hair cells to uptake FM1-43, indicating disrupted hair cell function in variant larvae."

The positive functional measurement. INDIRECT because it was made in lateral-line neuromasts of a fish, which have no cochlea and no endocochlear potential.

PMID:40515814 SUPPORT INDIRECT Model Organism

"The statistical analysis from the four neuromasts revealed no significant differences in hair cell numbers between the groups"

The matching negative in the fish: function falls while cell number does not, which is the pairing this node asserts.

Progressive Sensorineural Hearing Loss

The clinical endpoint: bilateral sensorineural hearing loss that begins after speech is acquired and worsens for the rest of life. In the founding family the rate was measured by regressing threshold on age and came to 1.2 to 1.6 dB per year at every frequency, which is the one quantitative statement of pace the disease has. The mouse null reaches the same endpoint far faster - early onset, starting high and rapidly involving everything - which is what a complete absence of the protein does rather than what a heterozygous interfering allele does.

sensory perception of sound GO:0007605 ↓ DECREASED

Animal models

Homer2 constitutive knockout mouse Mouse partially recapitulates Reproduces the audiometric shape of the human disease - progressive, starting at high frequencies, eventually involving all of them - on a radically compressed timescale.

Downstream

Progressive Sensorineural Hearing Impairment

Postlingual Onset

Bilateral Involvement

High-Frequency-Onset Down-Sloping Hearing Loss

Low-Frequency Hearing Loss at Presentation Drawn as an alternative presentation of the same lesion rather than as a separate one: the reporting authors read the differing audiometric configurations as stages of one disease.

Show evidence (3 references)

PMID:25816005 SUPPORT Human Clinical

"Hearing impairment had a typical onset in the first decade of life in the high frequencies, with significant subsequent progression of hearing loss over all frequencies."

The onset, the starting frequency region, and the direction of change in the founding family.

PMID:25816005 SUPPORT Human Clinical

"The resulting annual threshold deterioration (ATD) was 1.2 to 1.6 dB per year"

The measured rate, derived from linear regression of threshold on age.

PMID:25816005 SUPPORT Model Organism

"Its complete absence in mice leads to early onset progressive hearing loss starting at the high frequencies and rapidly involving all frequencies."

The mouse endpoint, cited to show that the same audiometric shape emerges from total loss of the protein, at a very different pace.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

8

Ear 6

Progressive Sensorineural Hearing Impairment OBLIGATE HP:0000408

Course: PROGRESSIVE

Show evidence (2 references)

PMID:41351289 SUPPORT Human Clinical

"The family exhibited autosomal dominant, progressive, post-lingual, nonsyndromic sensorineural hearing loss, similar to that observed in previously reported DFNA68 families."

The phenotype in the most recently reported family, stated as matching the earlier ones - which is the sentence that licenses treating this as one disease description.

PMID:33809266 SUPPORT Human Clinical

"age-matched patients in both families display quite similar hearing loss phenotypes consisting of early-onset, moderate-to-profound progressive hearing loss"

The severity range reached, in the two families carrying truncating alleles.

Postlingual Onset OBLIGATE Postlingual sensorineural hearing impairment HP:0008596

Recorded as OBLIGATE rather than FREQUENT because postlingual onset is part of how every reporting group characterises the entity, including the one whose patient presented in her sixties, and none of the six primary reports describes a prelingual or congenital case. The claim is about the entity as reported, not a per-carrier count; no denominator of carriers has been published.

Show evidence (2 references)

PMID:41351289 SUPPORT Human Clinical

"Affected individuals with variants in HOMER2 exhibit bilateral post‐lingual progressive hearing loss that typically begins in the high frequencies during the first or second decade of life."

The onset timing generalised across the reported families by the most recent group to review them.

PMID:41351289 SUPPORT Human Clinical

"The ages at onset of the affected individuals ranged from 17 to 24 years."

A later onset window than the first-decade one reported elsewhere, quoted to show the spread rather than to replace it.

Bilateral Involvement OBLIGATE Bilateral sensorineural hearing impairment HP:0008619

Show evidence (1 reference)

PMID:25816005 SUPPORT Human Clinical

"Pure tone audiometric evaluation of affected members showed bilateral post-lingual progressive hearing loss that segregated as an autosomal dominant trait; bone conduction thresholds excluded conductive hearing impairment."

Bilaterality and the exclusion of a conductive component, in the family that was most fully audiometrically characterised.

High-Frequency-Onset Down-Sloping Hearing Loss VERY_FREQUENT High-frequency sensorineural hearing impairment HP:0001757

VERY_FREQUENT rather than OBLIGATE because one reported proband presented with the opposite configuration, curated as its own phenotype below. No published series gives a per-patient count of audiometric shape, so the band reflects the reported families rather than a measured proportion.

Show evidence (2 references)

PMID:33809266 SUPPORT Human Clinical

"Individuals II:2 (8 years old) and II:3 (15 years old) exhibited moderate hearing loss with greater impact on the high frequencies (downsloping profile). Their mother (patient I:2, 39 years old) showed a more severe phenotype, displaying profound hearing loss at frequencies higher than 2000 Hz."

The audiometric configuration and its worsening with age, within a single family so that genotype is held constant.

PMID:40515814 SUPPORT Human Clinical

"Preoperative pure tone audiograms show profound down-sloping sensorineural hearing loss with 8% speech discrimination score bilaterally."

The same configuration at the severe end of the range, with a speech-discrimination figure that shows what it costs functionally.

Low-Frequency Hearing Loss at Presentation VERY_RARE Low-frequency sensorineural hearing impairment HP:0008573

VERY_RARE reflects that this is a single reported proband against a literature in which every other described family starts at the high frequencies. It is not a measured frequency; no denominator exists.

Show evidence (2 references)

PMID:41351289 SUPPORT Human Clinical

"Unlike the initially high-frequency hearing loss observed in the previously reported families, the young proband in our study (IV:4, 18 years old) exhibited typical low-frequency hearing loss."

The observation itself, stated against the background it departs from.

PMID:41351289 SUPPORT Human Clinical

"The older patients (43 years old) displayed flatter audiograms, indicating hearing loss across all frequencies. Accordingly, the different forms of auditory configuration may present different stages of the disease."

The authors' own reading of the discrepancy, which is what justifies curating this as a presentation of the same disease rather than as a contradiction.

Tinnitus OCCASIONAL HP:0000360

Show evidence (2 references)

PMID:33809266 SUPPORT Human Clinical

"The presence of tinnitus or cranial tinnitus, however, has only been displayed by some affected members of the Chinese family and this phenotype was not present in any of the other two families."

Both halves of the frequency claim in one sentence: present in some members of one family, absent in two others.

PMID:41351289 SUPPORT Human Clinical

"Most affected individuals in this family complain of tinnitus but do not experience vertigo, and their intelligence and speech functions are normal."

A second family in which tinnitus is common, which is why the band is OCCASIONAL across the disease rather than VERY_RARE.

Other 2

Absence of Vestibular Dysfunction

Show evidence (2 references)

PMID:41351289 REFUTE Human Clinical

"Symptoms of vertigo, balance disorders, and vestibular system involvement were not reported."

A statement made across the reported families, not only about the one this paper describes.

PMID:41351289 REFUTE Human Clinical

"Tandem gait and Romberg tests did not reveal any symptoms of vestibular dysfunction in all family members."

The tested negative, in one family, which is stronger than the reported absence above because it names the examination that was performed.

Absence of Syndromic Features

Show evidence (1 reference)

PMID:25816005 REFUTE Human Clinical

"Clinical examination was negative for any findings consistent with syndromic hearing loss and also ruled out autoimmune phenotypes."

The examination that established the nonsyndromic label in the family the disease was defined in.

🧬

Genetic Associations

1

HOMER2

Gene: HOMER2 hgnc:17513 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (5 references)

PMID:25816005 SUPPORT Human Clinical

"These data provide compelling evidence that HOMER2 is required for normal hearing and that its sequence alteration in humans leads to ADNSHL through a dominant-negative mode of action."

The gene-disease relationship as first established, together with its proposed mode of action.

PMID:30047143 SUPPORT Human Clinical

"This is the second family reported globally with hearing loss caused by a variant in HOMER2."

The independent replication of the gene-disease relationship in an unrelated family, which is what moved it past a single-pedigree claim.

PMID:33809266 SUPPORT BACKGROUND Human Clinical

"The HOMER2 gene maps to chromosome 15q24.3"

The locus. BACKGROUND because it restates the gene's map position from an earlier source rather than reporting a mapping result of this study.

+ 2 more references

🗃️

External Assertions

1

OMIM deafness, autosomal dominant 68 record

OMIM disease record OMIM:616707

The OMIM phenotype record under which DFNA68 was designated, and the identifier the clinical literature uses for the disorder. Recorded here rather than under mappings because the DiseaseMappings class carries only ICD-10-CM, ICD-11, MONDO and NCIT slots.

Show evidence (1 reference)

PMID:41351289 SUPPORT Human Clinical

"Deafness, autosomal dominant 68 (DFNA68, OMIM #616707) is a rare subtype of ADNSHL caused by heterozygous variants in the HOMER2"

The OMIM number, the DFNA designation and the causal gene in one sentence.

💊

Medical Actions

3

Hearing Amplification

Platform: Device

Hearing aids are the first-line intervention while thresholds remain within the range amplification can address. None of the six primary DFNA68 reports names a disease-modifying therapy or a trial, and no HOMER2-directed agent appears among them. What is specific to this disorder is the commitment rather than the modality: the loss is progressive at a measurable rate, so the useful clinical act is repeated audiological review that catches deterioration and re-fits, not a single fitting decision.

Target Phenotypes: Progressive sensorineural hearing impairment HP:0000408

Show evidence (1 reference)

PMID:37371710 SUPPORT Other

"A long audiological follow-up is of paramount importance to identify hearing threshold deteriorations early and ensure prompt treatment with hearing aids or cochlear implants."

Cited at the group level deliberately. This is a narrative review of autosomal dominant nonsyndromic hearing loss as a class, not of DFNA68, so it supports the management approach for the class rather than an outcome in this disorder. Graded OTHER because a narrative review reports no study of its own.

Cochlear Implantation

Action: cochlear device implantation Ontology label: Surgical Procedure NCIT:C15329

Platform: Device

Implantation once amplification no longer delivers useful speech understanding. This disorder, unusually for one described in so few families, has a published outcome: a patient in her sixties with profound down-sloping loss and 8 percent bilateral speech discrimination was implanted, and speech recognition improved significantly at three and six months across syllable and sentence conditions. The mechanism supports the intervention in principle as well. The lesion is in the hair cell, upstream of the spiral ganglion neurons an implant stimulates, and the animal data show hair-cell dysfunction without hair-cell death, so there is no reason to expect the neural substrate an implant depends on to be compromised. That reasoning is the entry's, not a published claim; the outcome datapoint is published.

Mechanism Target:

BYPASSES Hair Cell Functional Failure Without Hair Cell Loss — An implant does not repair the hair cell; it stimulates the spiral ganglion directly, bypassing the transduction step that has failed. BYPASSES rather than RESTORES because nothing about the hair-cell lesion changes.

Target Phenotypes: Progressive sensorineural hearing impairment HP:0000408

Show evidence (2 references)

PMID:40515814 SUPPORT Human Clinical

"Post-Cochlear Implantation speech outcome speech recognition improves significantly at 3- and 6-months post-implantation across various syllable and sentence conditions."

The only published implantation outcome in a genetically confirmed DFNA68 patient. One patient, no control, and the follow-up is six months.

PMID:40515814 SUPPORT Human Clinical

"HOMER2 is a causative gene in elderly patients, particularly those in their 60 s or 70 s, who develop profound SNHL and require CI"

The authors' statement of when in the disease course implantation becomes the relevant intervention.

Genetic Counselling and Cascade Testing

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

Counselling for a dominant condition with a 50 percent transmission risk. Two things are specific to DFNA68 and worth saying to a family. The first is that a normal audiogram in a young carrier does not mean much: onset is postlingual and in one reported family did not begin until the late teens or twenties, so an unaffected-looking child may simply not have reached onset. The second is that the finding predicts a trajectory rather than a state - a known rate of decline is the main thing a molecular diagnosis adds here, because there is no treatment it selects.

Show evidence (2 references)

PMID:41351289 SUPPORT Human Clinical

"The ages at onset of the affected individuals ranged from 17 to 24 years."

The late-onset window that makes a normal childhood audiogram uninformative about carrier status in some families.

PMID:41351289 SUPPORT Human Clinical

"contribute to the development of genetic counseling for inherited deafness"

The authors' own framing of what the molecular diagnosis is for in this disorder. Quoted from their conclusion, where counselling is named as the clinical use of the finding.

🔬

Diagnosis

2

Comprehensive hearing-loss gene panel or exome sequencing

DFNA68 is reached by sequencing, not by any distinguishing clinical sign. Every reported family was found the same way - a targeted deafness gene panel or whole exome sequencing in a pedigree with dominant, postlingual, progressive sensorineural hearing loss, followed by Sanger segregation across the family. There is no biochemical marker and no audiometric pattern specific enough to point at HOMER2 rather than at any of the fifty-odd genes associated with autosomal dominant nonsyndromic hearing loss, and the one temporal bone CT reported in a DFNA68 proband was normal. The practical point the reporting groups make is about panel content rather than about technique: HOMER2 is a low-prevalence deafness gene, so whether it is found depends on whether it is on the panel that was ordered.

Show evidence (4 references)

PMID:33809266 SUPPORT Human Clinical

"Our study also highlights the importance of using NGS-based diagnostic methods to identify mutations in low-prevalence deafness genes like HOMER2"

The diagnostic argument in the authors' own words, and the reason a gene this rare needs a broad panel to be found at all.

PMID:41351289 SUPPORT Human Clinical

"Whole exome sequencing analysis was conducted to detect the disease-causing variant. Co-segregation analysis was performed using Sanger sequencing."

The two-step route - discovery by sequencing, confirmation by segregation - as applied in practice.

PMID:33809266 SUPPORT BACKGROUND Human Clinical

"Sixty-seven of these loci and 50 of these genes are associated with autosomal dominant NSSNHL"

The size of the differential a panel has to cover, which is why the diagnosis is made by broad sequencing rather than by a targeted test. BACKGROUND because it restates a field count from a gene-count resource.

+ 1 more reference

Pure tone audiometry with serial follow-up

Pure tone audiometry establishes the sensorineural character, the configuration and, over repeated visits, the rate. Bone conduction thresholds are what exclude a conductive component. Serial audiometry matters more here than in a static hearing loss: the audiogram's shape changes as the disease advances, so a single audiogram describes a stage rather than the disorder, and the rate of deterioration is only obtainable by regressing thresholds on age across visits.

Show evidence (2 references)

PMID:25816005 SUPPORT Human Clinical

"Linear regression analyses of threshold on age were used to evaluate progression of hearing impairment at individual frequencies."

The method by which the one quantitative natural-history figure for this disease was obtained.

PMID:41351289 SUPPORT Human Clinical

"The older patients (43 years old) displayed flatter audiograms, indicating hearing loss across all frequencies. Accordingly, the different forms of auditory configuration may present different stages of the disease."

Why one audiogram is not enough: configuration is stage-dependent in this disorder, on the reporting group's own reading.

📈

Progression

4

Presymptomatic

Hearing is normal through infancy and early childhood and speech is acquired normally, so the disorder is invisible to newborn hearing screening. In the founding family a two-year-old carrier had not had a formal auditory brainstem response performed, which is the practical shape of this phase: carriers are identified genetically before they are identified audiometrically.

Show evidence (1 reference)

PMID:41351289 SUPPORT Human Clinical

"Prelingual hearing loss is present before speech develops and usually begins before 3 years of age, whereas post‐lingual hearing loss occurs after the development of normal speech"

The definition the reporting group applied when classifying this disorder as postlingual, which is what establishes that a presymptomatic window exists.

High-frequency onset

Age: first to second decade in most reported families

Loss begins at the high frequencies, giving a down-sloping audiogram while speech frequencies are still relatively spared. Reported onset ages span the first decade in the European and Spanish families and the late teens to early twenties in the most recent Chinese one.

Show evidence (1 reference)

PMID:33809266 SUPPORT Human Clinical

"Affected individuals show progressive hearing loss affecting mainly the high frequencies (downsloping profile) with a typical onset in the first decade of life"

The onset window and audiometric shape, generalised across three families.

Progressive decline

Thresholds deteriorate at a measured 1.2 to 1.6 dB per year across all frequencies in the founding family, and the lower frequencies are progressively drawn in so that the audiogram flattens. This is the one phase of the disease with a quantitative description.

Show evidence (1 reference)

PMID:41351289 SUPPORT Human Clinical

"The degree of hearing loss ranges from mild to severe hearing loss and the annual threshold deterioration is between 1.2 and 1.6 dB HL per year across all frequencies"

The rate and the severity range, restated across the reported families by the most recent group.

Severe-to-profound loss

The endpoint reached by older affected individuals, with profound loss and very poor speech discrimination. The one patient for whom a functional figure is published had 8 percent speech discrimination bilaterally and proceeded to cochlear implantation in her sixties. How typical that timing is cannot be said from one patient.

Show evidence (1 reference)

PMID:40515814 SUPPORT Human Clinical

"SB1190-1923 began to experience more severe progressive SNHL in the high-frequency range starting in their 50 s."

The late-severity trajectory in the one patient followed to implantation, quoted because it is the only longitudinal account of the disease's end stage.

📊

Prevalence

1

Worldwide

Cases In Literature Ultra Rare

No prevalence estimate exists and none of the reporting groups offers one; each describes the disorder qualitatively as rare or extremely rare. What can be counted is families: the founding European pedigree in 2015, then Chinese, Spanish, Sicilian and Italian families, then an isolated patient and a further Chinese family, with the two most recent reports describing their alleles as the seventh and the sixth HOMER2 variant on record. Fewer than ten unrelated families is therefore the honest statement of the literature's size. prevalence_class is the qualitative ULTRA_RARE tier and no rate_per_100000 is given, because no numerator and no denominator have been published and a band beside this note would be an invention. The tier is compatible with measure_type CASES_IN_LITERATURE, which is what is actually being reported. The two published counts disagree by one. They were written months apart and enumerate the variant list differently, and neither group reconciles its count with the other's. Both are quoted below rather than reconciled here.

Show evidence (3 references)

PMID:33809266 SUPPORT Human Clinical

"Hearing loss caused by HOMER2 mutations is an extremely rare disorder."

The qualitative rarity statement from a group that reported one of the families.

PMID:41351289 SUPPORT Human Clinical

"To date, only five heterozygous variants in the HOMER2 gene have been reported worldwide in five isolated families of European, Chinese, Sicilian, Italian and Spanish origins"

A count of families and their origins, which is the closest thing to a denominator the literature provides.

PMID:40515814 SUPPORT Human Clinical

"Our review found that this frameshift extension variant is only the seventh HOMER2 variant documented in patients with SNHL."

The other published count, quoted alongside the first because the two do not agree and neither should be presented as settled.

⚖️

Clinical Burden

Moderate

DFNA68 is not life-threatening and involves no organ system other than the ear, but it is lifelong, progressive and ends in severe or profound deafness in an adult who acquired speech normally and then lost access to it. The functional cost is documented at the severe end: one patient reached 8 percent bilateral speech discrimination and required cochlear implantation. Management is amplification, then implantation, then ongoing audiological follow-up; none of the six primary reports names a disease-modifying option. MODERATE rather than HIGH because the burden is confined to one sensory modality, is substantially correctable by devices whose benefit in this disease has been demonstrated, and carries no reported mortality or systemic morbidity. MODERATE rather than LOW because the deficit is progressive and permanent, and the endpoint is profound deafness.

Show evidence (2 references)

PMID:40515814 SUPPORT Human Clinical

"Ten years after the onset of significant SNHL, SB1190-1923 had developed profound deafness with a speech discrimination score of only 8%"

The functional severity reached, and the interval over which it was reached, in the one patient with a published longitudinal course.

PMID:33809266 SUPPORT Human Clinical

"age-matched patients in both families display quite similar hearing loss phenotypes consisting of early-onset, moderate-to-profound progressive hearing loss"

The severity range across two independent families, which is what the band is set against.

🐁

Animal Models

2

Homer2 constitutive knockout mouse

The only mammalian model of the gene's role in hearing among the nine PubMed records swept for this entry, and the one that supplied both the strongest and the most awkward result. Homozygous nulls have progressively rising auditory brainstem response thresholds from two weeks of age and are profoundly deaf by eight weeks, with the loss starting at high frequencies and spreading. At that point the organ of Corti still has its full complement of inner and outer hair cells. The awkward result is the heterozygote. It hears normally, which means the mouse models absence of the protein while every human allele is something other than absence. The model therefore supports the claim that HOMER2 is required for hearing, and does not model the human genotype.

Species

Mouse

Genotype

Homer2 targeted deletion, homozygous and heterozygous

Genes

HOMER2 hgnc:17513

Publication

PMID:25816005

Pathograph links

Hair Cell Functional Failure Without Hair Cell Loss partially recapitulates fidelity: moderate observes: cellular The model's distinctive contribution: profound deafness in the presence of an intact hair-cell population, which is what separates this disease from the hair-cell-death mechanisms the module it conforms to normally describes.

Limitations: The genotype is a homozygous null and the human disease is heterozygous for non-null alleles; the heterozygous mouse, the genotype that corresponds to a human carrier, has no phenotype at all. The hair-cell count was made at eight weeks in an animal with a very compressed disease course, so it does not exclude hair-cell loss over the decades a human cochlea is exposed to the lesion. No knock-in mouse carrying a human DFNA68 allele appears among the nine PubMed records returned by the search recorded in the entry notes.

Readouts

Inner and outer hair cell counts in whole-mount organ of Corti

Direction: UNCHANGED

Interpretation: An unchanged hair-cell population alongside profound threshold elevation is what makes the lesion functional rather than degenerative in this model.

Show evidence (1 reference)

PMID:25816005 SUPPORT Model Organism

"No differences in IHCs and OHCs were observed in any animals regardless of genotype indicating the absence of Homer2 does not impair hair cell formation and development"

The measurement itself, reported as a negative across all genotypes.

Show evidence (1 reference)

PMID:25816005 SUPPORT Model Organism

"mouse mutants homozygous for the targeted deletion of Homer2 present with early-onset rapidly progressive hearing loss"

Establishes that this model is informative for the hearing phenotype at all, which is the precondition for reading its hair-cell result.

Progressive Sensorineural Hearing Loss partially recapitulates fidelity: moderate observes: organism Reproduces the audiometric shape of the human disease - progressive, starting at high frequencies, eventually involving all of them - on a radically compressed timescale.

Limitations: Onset is at two weeks and the endpoint at eight, against decades in humans, so the model cannot speak to the human rate, to the stage-dependent change in audiometric configuration, or to anything about late adult disease. The genotype mismatch above applies here too.

Readouts

Auditory brainstem response threshold

Direction: INCREASED

Interpretation: Rising thresholds over successive ages are the measurement that makes the model's phenotype progressive rather than static.

Show evidence (1 reference)

PMID:25816005 SUPPORT Model Organism

"Its complete absence in mice leads to early onset progressive hearing loss starting at the high frequencies and rapidly involving all frequencies."

The authors' summary of the threshold data, naming both onset and direction of spread.

Show evidence (1 reference)

PMID:25816005 SUPPORT Model Organism

"we measured auditory brainstem responses (ABR), an electrophysiological hearing test that reflects the activity of afferent auditory neurons downstream of IHCs"

Names the assay and what it reports on, which is what licenses reading the mouse result as a hearing phenotype rather than a behavioural one.

Zebrafish HOMER2 mutant mRNA overexpression model

The workhorse assay of this field, used by three separate groups. Human HOMER2 mRNA - wild type or mutant - is injected into wild-type embryos, so the fish's own homer2 is intact and any phenotype is an effect of the mutant product on a normal background. That design is what makes it a dominant-negative assay rather than a loss-of-function one, and the founding study made the point explicitly by showing that morpholino knockdown of the fish gene did not change ear size while mutant mRNA did. Later groups extended it from morphology to function: FM1-43 uptake in neuromast hair cells and startle-reflex testing, both reduced by disease alleles.

Species

Zebrafish

Genotype

wild-type embryos injected with in vitro transcribed mutant human HOMER2 mRNA

Publication

PMID:25816005

Pathograph links

HOMER2 Coiled-Coil Missense Variant recapitulates fidelity: moderate observes: organism The assay that established the dominant-negative classification of the founding allele, by the contrast between mutant-mRNA injection and gene knockdown.

Limitations: Zebrafish homer2 is 67 percent identical to the human protein, the injected message is supraphysiological and transient, and the readout is otic vesicle size and kinocilium number in an embryo rather than hearing in a mature cochlea. A fish has no cochlea, no endocochlear potential and no outer-hair-cell amplifier, so the assay reports that the allele is harmful to hair cells, not how it causes human deafness.

Readouts

Otic vesicle size in injected larvae

Direction: DECREASED

Interpretation: Smaller ears after mutant but not wild-type mRNA injection is the positive result the dominant-negative reading rests on.

Show evidence (1 reference)

PMID:25816005 SUPPORT Model Organism

"injection of in vitro synthesized mRNA encoding HOMER2 P185-mutant RNA (P185RNA) resulted in significantly smaller ear size in larvae as compared to injections with WT HOMER2"

The measurement, with its wild-type-mRNA control stated in the same sentence.

Show evidence (1 reference)

PMID:25816005 SUPPORT Model Organism

"Although knockdown of homer2 altered neither ear size nor morphology (p>0.5)"

The knockdown control. It is what makes the model informative about a dominant-negative mechanism specifically rather than about the gene being needed.

Hair Cell Functional Failure Without Hair Cell Loss recapitulates fidelity: moderate observes: cellular The functional extension of the assay, in which disease alleles reduce FM1-43 uptake by neuromast hair cells while leaving hair-cell numbers unchanged - the fish counterpart of the mouse null's intact organ of Corti.

Limitations: Neuromasts are lateral-line organs, not cochlear, and FM1-43 uptake is a proxy for open mechanotransduction channels rather than a direct measurement of transduction current. The injected alleles are extension variants, so the result is not established for the missense or truncating classes.

Readouts

FM1-43 uptake by neuromast hair cells

Direction: DECREASED

Interpretation: Reduced dye entry indicates fewer open transduction channels, so the hair cells are present but not transducing.

Show evidence (1 reference)

PMID:40515814 SUPPORT Model Organism

"in the HOMER2 variant groups, FM1-43 uptake was markedly reduced"

The measurement itself, against injected wild-type and fluorescent-protein controls.

Startle reflex latency and distance

Direction: ALTERED

Interpretation: A behavioural readout of hearing in the fish, which is what converts a dye-uptake result into a claim about auditory function.

Show evidence (1 reference)

PMID:40515814 SUPPORT Model Organism

"In the startle reflex test, both variants reduced distance and increased latency, providing strong evidence for hearing loss and the pathogenicity of the p.R345Efs*64 variant."

The behavioural result and the inference the authors draw from it.

Show evidence (1 reference)

PMID:37173411 SUPPORT Model Organism

"in vivo studies using a zebrafish animal model and behavioral tests clearly established the deleterious impact of this novel HOMER2 alteration on hearing function"

An independent group reaching the same conclusion with the same system, which is what makes the assay a reproducible tool rather than a single study's result.

{ }

Source YAML

click to show

name: Autosomal Dominant Nonsyndromic Hearing Loss 68
category: Mendelian
creation_date: "2026-09-18T00:00:00Z"
synonyms:
- DFNA68
- deafness, autosomal dominant 68
- deafness, autosomal dominant type 68
- autosomal dominant nonsyndromic deafness 68
- HOMER2 autosomal dominant nonsyndromic deafness
description: >-
  DFNA68 is bilateral, postlingual, progressive nonsyndromic sensorineural hearing loss
  caused by heterozygous variants in HOMER2, which encodes a scaffolding protein of the
  Homer family. Hearing is normal at birth and through early childhood; loss typically
  declares itself in the first or second decade at the high frequencies, with a
  down-sloping audiogram that flattens as the lower frequencies are drawn in, and
  deteriorates by roughly 1.2 to 1.6 dB per year until it is severe or profound.

  The mechanistic interest of the entity is that it is a scaffold disease rather than a
  transducer disease. HOMER2 does not itself carry current, move the hair bundle, or
  recycle potassium. Its long isoform is built from an N-terminal EVH1 domain that binds
  proline-rich motifs and a C-terminal coiled-coil domain that does two things: it makes
  Homer proteins multimerise into tetrameric hubs, and it carries the binding site for
  CDC42, the Rho-family GTPase that tunes actin turnover. In the mouse cochlea the
  protein is enriched at the tips of the stereocilia of both inner and outer hair cells,
  which is the observation that connects a general signalling scaffold to hearing.

  Two candidate downstream lesions are on the table and neither has been settled. The
  first is actin: HOMER2 couples to CDC42, and deleting Cdc42 from murine hair cells
  produces stereocilia fusion and depletion with a progressive high-frequency hearing
  loss that resembles the human picture. The second is calcium: Homer proteins regulate
  TRPC channels and the plasma-membrane calcium pump, and PMCA2 is the only route by
  which calcium leaves a stereocilium. The paper that founded the disease named both
  hypotheses and left them open, and nothing since has closed them.

  What the allele series shows is that this is not a haploinsufficiency disease. Mice
  heterozygous for a Homer2 null hear normally and only the homozygous null is deaf;
  HOMER2 is tolerant of loss-of-function variation in population data. The human alleles
  instead cluster into three classes that each interfere with the wild-type protein: a
  coiled-coil missense change shown to act as a dominant negative in zebrafish; frameshift
  variants that truncate the protein inside the CDC42-binding domain and reduce its
  stability and its ability to multimerise; and variants that extend the protein past its
  normal stop codon, for which a gain-of-function effect of the aberrant C-terminal tail
  has been argued directly.

  The entity is very rare. Fewer than ten unrelated families have been reported worldwide
  since the gene was identified, and the whole clinical description rests on them.
disease_term:
  preferred_term: autosomal dominant nonsyndromic hearing loss 68
  term:
    id: MONDO:0014740
    label: autosomal dominant nonsyndromic hearing loss 68
parents:
- Autosomal Dominant Nonsyndromic Hearing Loss
references:
- reference: PMID:25816005
  title: "HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice."
- reference: PMID:30047143
  title: "Whole exome sequencing identified a second pathogenic variant in HOMER2 for autosomal dominant non-syndromic deafness."
- reference: PMID:33809266
  title: "A Novel Truncating Mutation in HOMER2 Causes Nonsyndromic Progressive DFNA68 Hearing Loss in a Spanish Family."
- reference: PMID:37173411
  title: "Identification and in vivo functional investigation of a HOMER2 nonstop variant causing hearing loss."
- reference: PMID:40515814
  title: "Impact of HOMER2 frameshift extension variant on auditory function and development."
- reference: PMID:41351289
  title: "A Novel Frameshift Variant c.1023_1029del (p.Asp342ArgfsTer54) Leading to Extended Incorrect Protein C Termini in HOMER2 Causing Autosomal Dominant Nonsyndromic Hearing Loss."
- reference: PMID:24610943
  title: "Maintenance of stereocilia and apical junctional complexes by Cdc42 in cochlear hair cells."
- reference: PMID:25049230
  title: "Homer2 protein regulates plasma membrane Ca²⁺-ATPase-mediated Ca²⁺ signaling in mouse parotid gland acinar cells."
- reference: PMID:19309525
  title: "Interaction of Cupidin/Homer2 with two actin cytoskeletal regulators, Cdc42 small GTPase and Drebrin, in dendritic spines."
- reference: PMID:16914674
  title: "Tetrameric hub structure of postsynaptic scaffolding protein homer."
- reference: PMID:37371710
  title: "Autosomal Dominant Non-Syndromic Hearing Loss (DFNA): A Comprehensive Narrative Review."
- reference: PMID:20301607
  title: Genetic Hearing Loss Overview.
  tags:
  - GeneReviews
inheritance:
- name: Autosomal dominant
  description: >-
    Heterozygous HOMER2 variants segregate with hearing loss across multi-generation
    pedigrees - five generations in the founding European family, four in the most recent
    Chinese one - and none of the six primary reports describes a homozygote or a compound
    heterozygote.

    Dominance here is a statement about the allele, not only about the pedigree. The
    heterozygous mouse null hears normally and the gene is tolerant of loss-of-function
    variation in population data, so a simple halving of HOMER2 dose does not produce the
    phenotype. The human alleles are dominant because they interfere with the wild-type
    protein they are co-expressed with, by one of the three routes set out in the
    pathophysiology nodes below.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:25816005
    reference_title: "HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pure tone audiometric evaluation of affected members showed bilateral post-lingual progressive hearing loss that segregated as an autosomal dominant trait; bone conduction thresholds excluded conductive hearing impairment."
    explanation: >-
      The segregation pattern in the founding family, together with the exclusion of a
      conductive component that would have pointed at a different lesion.
  - reference: PMID:37173411
    reference_title: "Identification and in vivo functional investigation of a HOMER2 nonstop variant causing hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DFNA68 is a rare subtype of autosomal dominant nonsyndromic hearing impairment caused by heterozygous alterations in the HOMER2 gene."
    explanation: >-
      States the mode of inheritance and the heterozygous state of the causal alleles for
      the entity as a whole.
  - reference: PMID:40515814
    reference_title: "Impact of HOMER2 frameshift extension variant on auditory function and development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Low pLI score (0.01) of HOMER2 suggests that alteration of HOMER2 exerts a pathogenic effect via a mechanism other than loss-of-function."
    explanation: >-
      The population-genetic argument that dominance here cannot be haploinsufficiency:
      HOMER2 tolerates loss-of-function variation in the general population.
  - reference: PMID:33809266
    reference_title: "A Novel Truncating Mutation in HOMER2 Causes Nonsyndromic Progressive DFNA68 Hearing Loss in a Spanish Family."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: "mice heterozygous for the targeted deletion of exon 3 in Homer2 (Homer−/+) displayed normal hearing levels"
    explanation: >-
      The experimental counterpart of the same argument: the genotype corresponding to a
      human carrier, but of a null allele, has no phenotype. INDIRECT because it is a
      mouse, and BACKGROUND because this paper restates the founding study's result.
pathophysiology:
- name: HOMER2 Coiled-Coil Missense Variant
  biological_scale: MOLECULAR
  description: >-
    The founding allele, p.Arg185Pro numbered against HOMER2 isoform 1 and p.Arg196Pro
    against the longer isoform 2, is a single amino acid substitution inside the
    coiled-coil domain. Arginine is replaced by proline, which the reporting authors predict
    will alter the domain's conformation or its ability to multimerise and to bind partner
    proteins, and the residue sits in the stretch that both drives multimerisation and
    carries the CDC42-binding site.

    Its classification as dominant negative rests on a positive experiment rather than on
    inference from the pedigree: injecting mutant mRNA into zebrafish embryos, which
    retain their own wild-type homer2, reduced ear size and kinocilium number, while
    knocking the fish gene down did not change ear size or morphology. An allele that
    damages a process only when it is present, and not when the gene is simply absent, is
    acting on the wild-type product.
  genes:
  - preferred_term: HOMER2
    term:
      id: hgnc:17513
      label: HOMER2
  genetic_context:
    genes:
    - preferred_term: HOMER2
      term:
        id: hgnc:17513
        label: HOMER2
    allele_type: missense substitution in the coiled-coil domain
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: DOMINANT_NEGATIVE
    notes: >-
      DOMINANT_NEGATIVE is the authors' own conclusion and is supported by the contrast
      between mutant-mRNA overexpression, which produced a phenotype, and morpholino
      knockdown, which did not. The two published protein numberings for this variant
      differ because HOMER2 has two transcripts of 343 and 354 residues; both appear in
      the literature for the same change and neither is wrong.
  molecular_functions:
  - preferred_term: scaffold protein binding
    modifier: DECREASED
    term:
      id: GO:0097110
      label: scaffold protein binding
  evidence:
  - reference: PMID:25816005
    reference_title: "HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Only a single variant, p.Arg185Pro in HOMER2, segregated with the hearing-loss phenotype in the extended family."
    explanation: The allele, and the genetic evidence that it is the cause in the founding family.
  - reference: PMID:25816005
    reference_title: "HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "This amino acid change alters a highly conserved residue in the coiled-coil domain of HOMER2 that is essential for protein multimerization and the HOMER2-CDC42 interaction."
    explanation: >-
      Places the substitution in the domain whose two established functions are the ones
      this entry's downstream nodes describe. BACKGROUND because the domain's role is
      established elsewhere and restated here.
  - reference: PMID:25816005
    reference_title: "HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These results show that HOMER2 plays an essential role in the normal development and/or maintenance of hair cells in the zebrafish inner ear and that the p.Arg185Pro mutation has a dominant-negative effect on this process."
    explanation: >-
      The experimental basis for the dominant-negative classification, in the species
      where it was tested.
  - reference: PMID:25816005
    reference_title: "HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: COMPUTATIONAL
    snippet: "Proline, in contrast, is non-polar and is predicted to alter the conformational structure of the CC domain or affect its ability to multimerize and/or interact with partner proteins."
    explanation: >-
      The structural prediction behind the choice of allele, and the source of this node's
      statement about what the substitution is expected to do. COMPUTATIONAL and INDIRECT
      because it is a prediction from the residue's chemistry, not a measurement.
  downstream:
  - target: Impaired HOMER2 Multimerisation
    causal_link_type: DIRECT
    description: >-
      A proline substitution in the coiled coil is predicted to alter the domain's
      conformation or its capacity to multimerise; the dominant-negative behaviour in
      zebrafish is what the authors read as evidence that it does.
    evidence:
    - reference: PMID:25816005
      reference_title: "HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "these data strongly suggest that the p.Arg185Pro mutation in HOMER2 exerts its effect through a dominant-negative mechanism on wild-type protein by either inhibiting multimerization or competing for other partner proteins"
      explanation: >-
        INDIRECT because the authors name two alternative routes to the same
        dominant-negative outcome and do not distinguish them experimentally.
- name: HOMER2 Frameshift Truncation in the CDC42-Binding Domain
  biological_scale: MOLECULAR
  description: >-
    Two independent frameshift alleles, a single-base duplication reported in a Chinese
    family and a five-base deletion reported in a Spanish family, introduce premature stop
    codons a few residues apart inside the CDC42-binding domain. They are curated as one
    node because the two truncated products share an identical aberrant C-terminal tail,
    which is the observation the Spanish authors use to argue that the two families share
    a mechanism.

    What is measured, rather than predicted, comes from the Chinese allele expressed in
    cells: the mutant protein was less stable than wild type, multimerised less well, and
    lost the perinuclear clustering that wild-type HOMER2 shows, distributing diffusely
    through the cytoplasm instead.
  genes:
  - preferred_term: HOMER2
    term:
      id: hgnc:17513
      label: HOMER2
  genetic_context:
    genes:
    - preferred_term: HOMER2
      term:
        id: hgnc:17513
        label: HOMER2
    allele_type: frameshift variant producing a premature stop codon within the CDC42-binding domain
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: DOMINANT_NEGATIVE
    notes: >-
      The recorded value follows the measured properties of the truncated product -
      reduced multimerisation with a stable, mislocalised protein still present in the
      cell - which is the signature of interference with wild-type product rather than of
      its absence. It is not the only reading the literature offers: the Spanish authors
      state explicitly that the mechanism is either a gain of function of the aberrant
      C-terminal tail or a dominant negative, and do not choose between them. That
      unresolved alternative is recorded here rather than smoothed away, and the
      single-valued slot should not be read as a settled answer.
  biological_processes:
  - preferred_term: protein homooligomerization
    modifier: DECREASED
    term:
      id: GO:0051260
      label: protein homooligomerization
  evidence:
  - reference: PMID:30047143
    reference_title: "Whole exome sequencing identified a second pathogenic variant in HOMER2 for autosomal dominant non-syndromic deafness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The pathogenic variant c.840_841insC in HOMER2 (NM_199330), segregating with the hearing-loss phenotype in the family, leads to a premature stop codon producing a truncated protein."
    explanation: The first truncating allele, and its segregation with hearing loss.
  - reference: PMID:30047143
    reference_title: "Whole exome sequencing identified a second pathogenic variant in HOMER2 for autosomal dominant non-syndromic deafness."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "HOMER2MU protein tended to be distributed in a diffuse manner, whereas HOMER2WT and the reported mutant HOMER2 tended to cluster together."
    explanation: >-
      The mislocalisation of the truncated product in transfected cells, measured against
      both wild type and the missense allele.
  - reference: PMID:33809266
    reference_title: "A Novel Truncating Mutation in HOMER2 Causes Nonsyndromic Progressive DFNA68 Hearing Loss in a Spanish Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This frameshift mutation produces a premature stop codon that may lead in the absence of NMD to a shorter variant (p.Pro278Alafs*10) that truncates HOMER2 at the CDC42 binding domain (CBD) of the coiled-coil structure, a region that is essential for protein multimerization and HOMER2-CDC42 interaction."
    explanation: >-
      The second truncating allele, located in the same domain, with the consequence for
      both domain functions stated.
  - reference: PMID:33809266
    reference_title: "A Novel Truncating Mutation in HOMER2 Causes Nonsyndromic Progressive DFNA68 Hearing Loss in a Spanish Family."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Functional assessment of the Chinese mutant revealed decreased protein stability, reduced ability to multimerize, and altered distribution pattern in transfected cells when compared with wild-type HOMER2."
    explanation: >-
      The three measured properties of the truncated product, summarised by an independent
      group.
  - reference: PMID:33809266
    reference_title: "A Novel Truncating Mutation in HOMER2 Causes Nonsyndromic Progressive DFNA68 Hearing Loss in a Spanish Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It may indicate that a moderate or even low extent NMD might be associated with HOMER2 frameshift mutations thus suggesting that the pathophysiology of the DFNA68 hearing loss in the Spanish and Chinese families would not be mediated by haploinsufficiency, but by a gain-of-function of the Ct aberrant tail or by a dominant-negative mechanism as it has been postulated for the p.Arg196Pro missense mutation"
    explanation: >-
      The authors' own statement of the mechanism and of the alternative they leave open,
      quoted because the genetic_context slot can carry only one of the two.
  downstream:
  - target: Impaired HOMER2 Multimerisation
    causal_link_type: DIRECT
    description: >-
      Truncation inside the coiled coil removes the region required for tetramer
      formation, and the measured consequence is a protein that multimerises less well
      than wild type.
    evidence:
    - reference: PMID:30047143
      reference_title: "Whole exome sequencing identified a second pathogenic variant in HOMER2 for autosomal dominant non-syndromic deafness."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "HOMER2 homo-/hetero-multimerization might be the first step in exerting its normal function."
      explanation: >-
        The authors' reading of why a multimerisation defect is the operative consequence
        of this allele class.
- name: HOMER2 C-Terminal Extension Variant
  biological_scale: MOLECULAR
  description: >-
    A third allele class leaves the reading frame running past the point where it should
    stop. It includes a nonstop substitution that converts the termination codon to a
    tryptophan codon and adds ten residues, a frameshift that alters the last ten residues
    and adds fifty-three more, and a seven-nucleotide deletion producing an extended
    incorrect C terminus.

    These alleles are not simply weaker truncations. Transcripts carrying the nonstop
    variant escape nonstop decay, so the aberrant product is made; the frameshift-extension
    allele lies in the last exon and so is likewise not expected to be removed by
    nonsense-mediated decay. Structure prediction for the longest of them puts the damage
    not in the coiled coil, where the residue sits, but in the distant EVH1 domain, with
    the predicted CDC42 interface disturbed while dimer and tetramer formation is
    preserved. On that reading the extension acts by adding something, which is why this
    node is graded as a gain of function while the other two allele classes are not.
  genes:
  - preferred_term: HOMER2
    term:
      id: hgnc:17513
      label: HOMER2
  genetic_context:
    genes:
    - preferred_term: HOMER2
      term:
        id: hgnc:17513
        label: HOMER2
    allele_type: nonstop or frameshift variant extending the protein beyond its normal termination codon
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: GAIN_OF_FUNCTION
    notes: >-
      GAIN_OF_FUNCTION is stated in those words by the group that characterised the
      longest extension allele, and is argued from a comparison the study built for the
      purpose: an artificial variant truncating the same ten C-terminal residues had a
      milder effect in zebrafish than the patient allele that truncates those residues and
      adds fifty-three more. The same paper also describes the combined change as likely
      dominant-negative in its discussion, so the two vocabularies are not cleanly
      separated in the source.
  molecular_functions:
  - preferred_term: small GTPase binding
    modifier: DECREASED
    term:
      id: GO:0031267
      label: small GTPase binding
  evidence:
  - reference: PMID:37173411
    reference_title: "Identification and in vivo functional investigation of a HOMER2 nonstop variant causing hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This novel alteration is a nonstop substitution (c.1064 A > G) that converts the translational termination codon (TAG) of the gene into a tryptophan codon (TGG) and is predicted to extend the HOMER2 protein by 10 amino acids."
    explanation: The first extension allele and the change it makes to the protein's C terminus.
  - reference: PMID:37173411
    reference_title: "Identification and in vivo functional investigation of a HOMER2 nonstop variant causing hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RNA analyses from the proband suggested that HOMER2 transcripts carrying the nonstop variant escaped the non-stop decay pathway."
    explanation: >-
      Establishes in patient material that the extended transcript survives, which is what
      makes an added-function mechanism available at all.
  - reference: PMID:40515814
    reference_title: "Impact of HOMER2 frameshift extension variant on auditory function and development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified a novel frameshift extension variant, c.1033delC (p.Arg345Glufs*64; p.R345Efs*64), which introduces a significantly longer protein extension than previously reported extension variants, in a patient in their sixties presenting with progressive profound SNHL"
    explanation: The longest extension allele reported, and the patient it was found in.
  - reference: PMID:40515814
    reference_title: "Impact of HOMER2 frameshift extension variant on auditory function and development."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "AlphaFold2 predicts that the p.R345Efs*64 variant causes significant structural changes in the HOMER2 EVH1 domain, disrupting interactions with Cdc42 and contributing to SNHL."
    explanation: >-
      The structural prediction that routes this allele class to the same CDC42 lesion as
      the others, by a different part of the protein. Graded COMPUTATIONAL because it is a
      structure prediction, not a binding measurement.
  - reference: PMID:40515814
    reference_title: "Impact of HOMER2 frameshift extension variant on auditory function and development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our findings reveal a solid pathogenic gain-of-function effect related to the long extension to the C-terminal of HOMER2, and a possible link to cardiac anomalies."
    explanation: >-
      The gain-of-function claim itself, drawn by the authors from their zebrafish
      comparison between the patient allele and an artificial pure-truncation control.
  - reference: PMID:41351289
    reference_title: "A Novel Frameshift Variant c.1023_1029del (p.Asp342ArgfsTer54) Leading to Extended Incorrect Protein C Termini in HOMER2 Causing Autosomal Dominant Nonsyndromic Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A novel frameshift variant, c.1023_1029del (p.Asp342ArgfsTer54), in HOMER2 was identified, which co-segregated with the hearing loss phenotype in the family. The variant deletes 7 nucleotides, leading to an extended incorrect protein C terminus."
    explanation: A third extension allele, segregating in a four-generation family.
  downstream:
  - target: Disrupted HOMER2-CDC42 Coupling at the Hair Bundle
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      This allele class is modelled as reaching the CDC42 interface through a
      conformational change in the EVH1 domain rather than through loss of the
      coiled-coil binding site, so the link is drawn around the multimerisation node
      rather than through it. The intermediate step - the predicted structural
      rearrangement - is named but has not been measured.
    evidence:
    - reference: PMID:40515814
      reference_title: "Impact of HOMER2 frameshift extension variant on auditory function and development."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: COMPUTATIONAL
      snippet: "the p.R345Efs*64 variant is expected to cause more severe structural changes, affecting both the CC and EVH1 domains and their interaction with Cdc42, leading to a greater impact on hearing than the p.R345* variant"
      explanation: >-
        INDIRECT because the CDC42 consequence is a prediction from a modelled structure;
        no binding assay has been reported for any HOMER2 disease allele.
- name: Impaired HOMER2 Multimerisation
  biological_scale: MOLECULAR
  description: >-
    Homer proteins work as tetramers assembled through the parallel alignment of their
    coiled-coil domains, and it is the tetramer, not the monomer, that acts as a hub
    holding several binding partners together. Both the missense and the truncating
    disease alleles fall in that domain, and the truncating one has been shown directly to
    oligomerise less than wild type.

    Because a mutant subunit is still made and can still enter a hub, reduced
    multimerisation in a heterozygote is not the same as having half as much scaffold: an
    assembly built from a mixture of wild-type and mutant subunits can be worse than one
    built from fewer wild-type subunits alone. That is the reading under which a dominant
    allele coexists with a mouse heterozygote that hears normally.
  biological_processes:
  - preferred_term: protein homotetramerization
    modifier: DECREASED
    term:
      id: GO:0051289
      label: protein homotetramerization
  cellular_components:
  - preferred_term: stereocilium tip
    term:
      id: GO:0032426
      label: stereocilium tip
  evidence:
  - reference: PMID:16914674
    reference_title: "Tetrameric hub structure of postsynaptic scaffolding protein homer."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We conducted a series of biophysical experiments that provide the first evidence that Homer forms a tetramer via its coiled-coil domain, in which all subunits are aligned in parallel orientation."
    explanation: >-
      The biophysical basis for treating the coiled coil as a tetramerisation domain,
      which is what the disease alleles disturb.
  - reference: PMID:25816005
    reference_title: "HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "The CC region is required for homo/hetero-multimerization to form tetrameric hubs (in which the CC domains align in a parallel fashion) and for interaction with Rho family GTPase proteins like CDC42"
    explanation: >-
      States both functions of the coiled coil in one sentence, which is why a single
      lesion there can reach two downstream branches. Graded OTHER with quote_role
      BACKGROUND because it is the citing paper's summary of established structural work
      rather than a study result of any kind.
  downstream:
  - target: Disrupted HOMER2-CDC42 Coupling at the Hair Bundle
    causal_link_type: DIRECT
    description: >-
      The CDC42-binding domain sits inside the coiled coil, so the alleles that damage
      multimerisation also damage, or remove outright, the surface that binds CDC42.
    evidence:
    - reference: PMID:19309525
      reference_title: "Interaction of Cupidin/Homer2 with two actin cytoskeletal regulators, Cdc42 small GTPase and Drebrin, in dendritic spines."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "Cupidin/Homer2 interacted with activated Cdc42 small GTPase via the Cdc42-binding domain that resides around amino acid residues 191-283, within the C-terminal coiled-coil domain."
      explanation: >-
        Localises the CDC42 interaction to the same residue range the disease alleles fall
        in. INDIRECT because it was mapped in neurons, not hair cells.
  - target: Dysregulated Hair Cell Cytosolic Calcium Handling
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The second of the two mechanisms proposed for this disease. Homer scaffolds hold
      calcium-handling proteins in place, so a scaffold that assembles poorly is expected
      to hold them less well - but which partner matters in a hair cell has never been
      established, so the intermediates are unknown.
    evidence:
    - reference: PMID:25816005
      reference_title: "HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      quote_role: BACKGROUND
      snippet: "A second hypothesis focuses on the role of HOMER2 in cytoplasmic Ca2+ control. Several studies have shown that HOMER2 regulates a number of Ca2+ handling proteins including TRPC and PMCA channels."
      explanation: >-
        The proposal itself, quoted as the hypothesis it is. Graded OTHER because the
        sentence is the authors' framing of other groups' work rather than a result.
- name: Disrupted HOMER2-CDC42 Coupling at the Hair Bundle
  biological_scale: MOLECULAR
  description: >-
    The first of the two proposed downstream lesions, and the better supported one.
    HOMER2 binds activated CDC42 through the CDC42-binding domain, and CDC42 is the
    Rho-family GTPase that tunes actin turnover. In hair cells CDC42 is present and active
    at the stereociliary membrane, so the interaction has somewhere to happen.

    The argument that this is the disease-relevant partnership is comparative rather than
    direct: deleting Cdc42 from murine hair cells produces a hearing phenotype of the same
    shape as the human one. None of the six primary DFNA68 reports measures binding for any
    disease allele, and none demonstrates a HOMER2-CDC42 complex in a cochlear hair cell;
    the interaction was mapped in neurons, and the cochlear evidence is colocalisation plus
    the CDC42 knockout.
  mechanism_confidence: PROVISIONAL
  molecular_functions:
  - preferred_term: small GTPase binding
    modifier: DECREASED
    term:
      id: GO:0031267
      label: small GTPase binding
  cellular_components:
  - preferred_term: stereocilium
    term:
      id: GO:0032420
      label: stereocilium
  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
  evidence:
  - reference: PMID:25816005
    reference_title: "HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "One hypothesis posits that HOMER2 exerts its function by regulating actin dynamics in stereocilia through its interaction with CDC42, a highly conserved small GTPase of the RHO family that fine-tunes actin-turnover"
    explanation: >-
      The hypothesis in the authors' own words. Graded OTHER because it is a proposal set
      out in a discussion, not a result the paper reports.
  - reference: PMID:25816005
    reference_title: "HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Organ of Corti expression was particularly enriched in the tips of stereocilia of both IHCs and OHCs"
    explanation: >-
      Puts the protein where the lesion is claimed to be, measured by immunolabelling in
      mouse cochlea.
  - reference: PMID:24610943
    reference_title: "Maintenance of stereocilia and apical junctional complexes by Cdc42 in cochlear hair cells."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "fluorescence resonance energy transfer (FRET) imaging of hair cells from transgenic mice expressing a Cdc42-FRET biosensor indicated Cdc42 presence and activation at stereociliary membranes and AJCs in cochlear hair cells"
    explanation: >-
      Puts the other half of the proposed complex in the same place, and shows it is active
      there rather than merely present. INDIRECT because it says nothing about HOMER2.
  - reference: PMID:33809266
    reference_title: "A Novel Truncating Mutation in HOMER2 Causes Nonsyndromic Progressive DFNA68 Hearing Loss in a Spanish Family."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "It has also been postulated that HOMER2 could play an important role in maintaining stereocilia through its interaction with CDC42"
    explanation: >-
      An independent group restating the same proposal. Recorded as REVIEW_SYNTHESIS
      because it is this paper's summary of the hypothesis rather than its own test of it,
      and it is cited here to show the proposal is shared rather than to add support.
  downstream:
  - target: Failure of Stereocilia Actin Maintenance
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The intermediate is CDC42-dependent actin turnover, and it has been tested by
      removing CDC42 itself rather than by disturbing its coupling to HOMER2.
    evidence:
    - reference: PMID:24610943
      reference_title: "Maintenance of stereocilia and apical junctional complexes by Cdc42 in cochlear hair cells."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Thus, Cdc42 influenced the maintenance of stable actin structures through elaborate tuning of actin turnover, and maintained function and viability of cochlear hair cells."
      explanation: >-
        Establishes the intermediate step in the cell type this entry is about. INDIRECT
        because the experiment removed CDC42, not HOMER2, and so tests the downstream half
        of the proposed chain only.
- name: Dysregulated Hair Cell Cytosolic Calcium Handling
  biological_scale: MOLECULAR
  description: >-
    The alternative proposed lesion, and the weaker of the two. Homer proteins bind and
    regulate several calcium-handling proteins, and deleting Homer2 from mouse parotid
    acinar cells raises plasma-membrane calcium pump expression and speeds calcium
    extrusion, which is a measured regulatory relationship in a real tissue. The reason it
    is interesting for hearing is that PMCA2 is the only route by which calcium is cleared
    from a stereocilium, so a scaffold that sets pump behaviour would matter there
    disproportionately.

    Nothing has tested this in a hair cell. No HOMER2 calcium phenotype has been measured
    in the cochlea, the established Homer2 partner among the TRPC channels is TRPC1 rather
    than the TRPC3 and TRPC6 that hair cells need, and the PMCA2 partnership is a proposal
    rather than an observation. The node is carried because the founding paper put it
    forward as a live alternative and because discarding it would make the entry look more
    settled than the field is.
  mechanism_confidence: HYPOTHETICAL
  biological_processes:
  - preferred_term: regulation of cytosolic calcium ion concentration
    modifier: DYSREGULATED
    term:
      id: GO:0051480
      label: regulation of cytosolic calcium ion concentration
  cell_types:
  - preferred_term: cochlear outer hair cell
    term:
      id: CL:0000601
      label: cochlear outer hair cell
  evidence:
  - reference: PMID:25049230
    reference_title: "Homer2 protein regulates plasma membrane Ca²⁺-ATPase-mediated Ca²⁺ signaling in mouse parotid gland acinar cells."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "These findings reveal an important regulation of PMCA by Homer2 that has a central role on PMCA-mediated Ca(2+) signaling in parotid acinar cells."
    explanation: >-
      The only direct demonstration that Homer2 sets calcium-pump behaviour in a tissue.
      INDIRECT because the tissue is salivary gland, not cochlea.
  - reference: PMID:25816005
    reference_title: "HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A suitable interacting partner of HOMER2 may be the PMCA2 pump (MIM 108733), which represents the only system for clearance of Ca2+ from hair cell stereocilia"
    explanation: >-
      The reason the salivary-gland result is thought to transfer to a stereocilium, and
      the fact that makes the transfer worth proposing. Graded OTHER: it is a suggestion
      in a discussion, and its hedging is preserved in the quote.
  - reference: PMID:25816005
    reference_title: "HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "While both proteins are potentially interacting partners for HOMER2, to date only an interaction with TRPC1 (MIM 602343) has been established"
    explanation: >-
      The specific gap in the calcium hypothesis: the TRPC channels hair cells need are
      TRPC3 and TRPC6, and the only established Homer2 TRPC partner is TRPC1. Graded OTHER
      because it is the authors' account of the state of the field rather than a result.
  - reference: PMID:25816005
    reference_title: "HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "Two TRPCs—TRPC3 (MIM 602345) and TRPC6 (MIM 603652)—are expressed in both sensory neurons and cochlear hair cells and are required for normal function."
    explanation: >-
      Names which TRPC channels hair cells actually use, which is what makes the TRPC1-only
      partnership above a gap rather than a detail. BACKGROUND because it restates another
      group's mouse work.
  - reference: PMID:25816005
    reference_title: "HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice."
    supports: NO_EVIDENCE
    evidence_source: OTHER
    snippet: "While both of these hypotheses are attractive, further functional studies are needed to identify the partner proteins of HOMER2 in inner ear and investigate the effect of the p.Arg185Pro mutation on these interactions."
    explanation: >-
      Recorded as NO_EVIDENCE deliberately: the founding paper states that neither
      hypothesis has been tested, so this sentence bears on the claim by withholding
      support from it rather than by supporting or contradicting it.
  downstream:
  - target: Hair Cell Functional Failure Without Hair Cell Loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Drawn because the calcium hypothesis, if true, would produce hair-cell dysfunction
      rather than hair-cell death - which is the phenotype the models show. No step
      between the two has been demonstrated.
- name: Failure of Stereocilia Actin Maintenance
  biological_scale: CELLULAR
  conforms_to: "sensorineural_hair_cell_loss#Cochlear Sensory Epithelium Insult"
  description: >-
    The hair bundle is a stable actin structure that has to be actively maintained rather
    than simply built once, and the maintenance is CDC42-dependent. When Cdc42 is deleted
    from murine hair cells the bundles form normally and then come apart after maturation:
    stereocilia fuse and are depleted, the circumferential actin belt at the apical
    junctions thins, and hearing declines progressively and first at high frequencies.

    That "normal, then lost" shape is what makes the node the right substitution for this
    disease. DFNA68 patients hear normally through infancy, acquire speech, and then
    deteriorate over decades. No stereocilia morphology has been reported for any HOMER2
    patient or animal - the mouse null cochlea was assessed by phalloidin staining read for
    hair-cell death rather than for bundle structure - so the cellular lesion here is
    inferred from the CDC42 experiment and from where the protein sits, not observed.
  mechanism_confidence: PROVISIONAL
  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
  biological_processes:
  - preferred_term: auditory receptor cell stereocilium organization
    modifier: ABNORMAL
    term:
      id: GO:0060088
      label: auditory receptor cell stereocilium organization
  - preferred_term: actin cytoskeleton organization
    modifier: DYSREGULATED
    term:
      id: GO:0030036
      label: actin cytoskeleton organization
  notes: >-
    Conformance is asserted at the module's sensory-epithelium-insult node and not at
    "Hair Cell Mechanotransduction Failure and Death". The module's middle nodes run
    through ionic disruption, oxidative stress and apoptotic hair-cell death, and
    hair-cell death is specifically what the HOMER2 models do not show: the homozygous
    null mouse is deaf with a normal complement of inner and outer hair cells, and the
    zebrafish allele models lose hair-cell function with unchanged hair-cell counts.
    Substituting the module's chain here would assert a mechanism this disease has been
    shown not to have.
  evidence:
  - reference: PMID:24610943
    reference_title: "Maintenance of stereocilia and apical junctional complexes by Cdc42 in cochlear hair cells."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Cochlear hair cell degeneration was more robust in inner hair cells than in outer hair cells, and began as stereocilia fusion and depletion, accompanied by a thinning and waving circumferential actin belt at apical junctional complexes (AJCs)."
    explanation: >-
      The cellular lesion in the CDC42 model, described at the level of the actin
      structures. INDIRECT because the gene removed is CDC42, not HOMER2.
  - reference: PMID:24610943
    reference_title: "Maintenance of stereocilia and apical junctional complexes by Cdc42 in cochlear hair cells."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Hair cells of Atoh1-Cre;Cdc42(flox/flox) mice developed normally but progressively degenerated after maturation, resulting in progressive hearing loss particularly at high frequencies."
    explanation: >-
      The normal-development-then-progressive-loss course, which is the feature that makes
      this model resemble the human disease.
  - reference: PMID:33809266
    reference_title: "A Novel Truncating Mutation in HOMER2 Causes Nonsyndromic Progressive DFNA68 Hearing Loss in a Spanish Family."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "targeted deletion of Cdc42 in murine hair cells causes a progressive hearing loss phenotype that is comparable to the hearing loss phenotype in the Spanish and Chinese families"
    explanation: >-
      The comparison drawn explicitly against the human families, by a group that
      characterised one of them. REVIEW_SYNTHESIS because it is their reading of another
      group's mouse work.
  downstream:
  - target: Hair Cell Functional Failure Without Hair Cell Loss
    causal_link_type: DIRECT
    description: >-
      Stereocilia that fuse, shorten or are lost cannot deflect normally, and the bundle is
      the structure that opens the transduction channels.
- name: Hair Cell Functional Failure Without Hair Cell Loss
  biological_scale: CELLULAR
  description: >-
    The cellular endpoint that the animal data actually establish, and it is a functional
    one. In the homozygous Homer2-null mouse, thresholds rise progressively while the
    organ of Corti keeps its full complement of inner and outer hair cells at eight weeks,
    so the deafness is not a consequence of cells dying. In zebrafish injected with mutant
    HOMER2 mRNA, neuromast hair-cell numbers are unchanged but the cells take up far less
    FM1-43, which the reporting group uses as a marker for active mechanosensory hair
    cells - a readout of function, not of survival.

    This is the mechanistically distinctive claim of the entry. The module this disease
    conforms to has apoptotic hair-cell death as its central effector; the HOMER2 evidence
    says instead that the cells are there and are not working. Whether that remains true in
    an older human cochlea over five decades is not known: none of the six primary DFNA68
    reports describes human cochlear histopathology, and the mouse count was made at eight
    weeks.
  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
  biological_processes:
  - preferred_term: detection of mechanical stimulus involved in sensory perception of sound
    modifier: DECREASED
    term:
      id: GO:0050910
      label: detection of mechanical stimulus involved in sensory perception of sound
  evidence:
  - reference: PMID:25816005
    reference_title: "HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "No differences in IHCs and OHCs were observed in any animals regardless of genotype indicating the absence of Homer2 does not impair hair cell formation and development"
    explanation: >-
      The negative histological result that separates this node from hair-cell death, in
      the mouse null at the age when its hearing loss is profound.
  - reference: PMID:40515814
    reference_title: "Impact of HOMER2 frameshift extension variant on auditory function and development."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "The data suggest that HOMER2 variants severely impaired the capacity of neuromast hair cells to uptake FM1-43, indicating disrupted hair cell function in variant larvae."
    explanation: >-
      The positive functional measurement. INDIRECT because it was made in lateral-line
      neuromasts of a fish, which have no cochlea and no endocochlear potential.
  - reference: PMID:40515814
    reference_title: "Impact of HOMER2 frameshift extension variant on auditory function and development."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "The statistical analysis from the four neuromasts revealed no significant differences in hair cell numbers between the groups"
    explanation: >-
      The matching negative in the fish: function falls while cell number does not, which
      is the pairing this node asserts.
  downstream:
  - target: Progressive Sensorineural Hearing Loss
    causal_link_type: DIRECT
    description: >-
      Hair cells that cannot transduce cannot drive the auditory nerve, and the deficit
      accumulates because the failure is a maintenance failure rather than a single event.
- name: Progressive Sensorineural Hearing Loss
  biological_scale: ORGANISM
  conforms_to: "sensorineural_hair_cell_loss#Progressive Sensorineural Hearing Loss"
  description: >-
    The clinical endpoint: bilateral sensorineural hearing loss that begins after speech
    is acquired and worsens for the rest of life. In the founding family the rate was
    measured by regressing threshold on age and came to 1.2 to 1.6 dB per year at every
    frequency, which is the one quantitative statement of pace the disease has.

    The mouse null reaches the same endpoint far faster - early onset, starting high and
    rapidly involving everything - which is what a complete absence of the protein does
    rather than what a heterozygous interfering allele does.
  biological_processes:
  - preferred_term: sensory perception of sound
    modifier: DECREASED
    term:
      id: GO:0007605
      label: sensory perception of sound
  evidence:
  - reference: PMID:25816005
    reference_title: "HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hearing impairment had a typical onset in the first decade of life in the high frequencies, with significant subsequent progression of hearing loss over all frequencies."
    explanation: The onset, the starting frequency region, and the direction of change in the founding family.
  - reference: PMID:25816005
    reference_title: "HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The resulting annual threshold deterioration (ATD) was 1.2 to 1.6 dB per year"
    explanation: The measured rate, derived from linear regression of threshold on age.
  - reference: PMID:25816005
    reference_title: "HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Its complete absence in mice leads to early onset progressive hearing loss starting at the high frequencies and rapidly involving all frequencies."
    explanation: >-
      The mouse endpoint, cited to show that the same audiometric shape emerges from total
      loss of the protein, at a very different pace.
  downstream:
  - target: Progressive Sensorineural Hearing Impairment
    causal_link_type: DIRECT
  - target: Postlingual Onset
    causal_link_type: DIRECT
  - target: Bilateral Involvement
    causal_link_type: DIRECT
  - target: High-Frequency-Onset Down-Sloping Hearing Loss
    causal_link_type: DIRECT
  - target: Low-Frequency Hearing Loss at Presentation
    causal_link_type: DIRECT
    description: >-
      Drawn as an alternative presentation of the same lesion rather than as a separate
      one: the reporting authors read the differing audiometric configurations as stages
      of one disease.
phenotypes:
- name: Progressive Sensorineural Hearing Impairment
  category: Auditory
  description: >-
    The defining feature and, across every reported family, the only one. The loss is
    sensorineural - bone conduction thresholds in the founding family excluded a
    conductive component - and it deteriorates for decades rather than being static,
    reaching severe or profound levels.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Progressive sensorineural hearing impairment
    term:
      id: HP:0000408
      label: Progressive sensorineural hearing impairment
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:41351289
    reference_title: "A Novel Frameshift Variant c.1023_1029del (p.Asp342ArgfsTer54) Leading to Extended Incorrect Protein C Termini in HOMER2 Causing Autosomal Dominant Nonsyndromic Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The family exhibited autosomal dominant, progressive, post-lingual, nonsyndromic sensorineural hearing loss, similar to that observed in previously reported DFNA68 families."
    explanation: >-
      The phenotype in the most recently reported family, stated as matching the earlier
      ones - which is the sentence that licenses treating this as one disease description.
  - reference: PMID:33809266
    reference_title: "A Novel Truncating Mutation in HOMER2 Causes Nonsyndromic Progressive DFNA68 Hearing Loss in a Spanish Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "age-matched patients in both families display quite similar hearing loss phenotypes consisting of early-onset, moderate-to-profound progressive hearing loss"
    explanation: The severity range reached, in the two families carrying truncating alleles.
- name: Postlingual Onset
  category: Auditory
  description: >-
    Hearing is normal through infancy, speech is acquired normally, and the loss declares
    itself afterwards - usually in the first or second decade, but not until her fifties in
    one reported patient. The practical consequence is that a carrier passes newborn
    hearing screening, so the disease is not found by the programme designed to find
    congenital deafness.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Postlingual sensorineural hearing impairment
    term:
      id: HP:0008596
      label: Postlingual sensorineural hearing impairment
  notes: >-
    Recorded as OBLIGATE rather than FREQUENT because postlingual onset is part of how
    every reporting group characterises the entity, including the one whose patient
    presented in her sixties, and none of the six primary reports describes a prelingual or
    congenital case. The claim is about the entity as reported, not a per-carrier count; no
    denominator of carriers has been published.
  evidence:
  - reference: PMID:41351289
    reference_title: "A Novel Frameshift Variant c.1023_1029del (p.Asp342ArgfsTer54) Leading to Extended Incorrect Protein C Termini in HOMER2 Causing Autosomal Dominant Nonsyndromic Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected individuals with variants in HOMER2 exhibit bilateral post‐lingual progressive hearing loss that typically begins in the high frequencies during the first or second decade of life."
    explanation: >-
      The onset timing generalised across the reported families by the most recent group
      to review them.
  - reference: PMID:41351289
    reference_title: "A Novel Frameshift Variant c.1023_1029del (p.Asp342ArgfsTer54) Leading to Extended Incorrect Protein C Termini in HOMER2 Causing Autosomal Dominant Nonsyndromic Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The ages at onset of the affected individuals ranged from 17 to 24 years."
    explanation: >-
      A later onset window than the first-decade one reported elsewhere, quoted to show the
      spread rather than to replace it.
- name: Bilateral Involvement
  category: Auditory
  description: >-
    Both ears are affected. This is stated for the founding family, whose binaural symmetry
    was verified before thresholds were averaged, and none of the six primary reports
    describes a unilateral case.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Bilateral sensorineural hearing impairment
    term:
      id: HP:0008619
      label: Bilateral sensorineural hearing impairment
  evidence:
  - reference: PMID:25816005
    reference_title: "HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pure tone audiometric evaluation of affected members showed bilateral post-lingual progressive hearing loss that segregated as an autosomal dominant trait; bone conduction thresholds excluded conductive hearing impairment."
    explanation: >-
      Bilaterality and the exclusion of a conductive component, in the family that was
      most fully audiometrically characterised.
- name: High-Frequency-Onset Down-Sloping Hearing Loss
  category: Auditory
  description: >-
    The characteristic audiogram. Thresholds are worst at the high frequencies first,
    giving a down-sloping curve, and the lower frequencies are drawn in as the disease
    advances until the audiogram flattens. In the Spanish family this is visible as a
    cross-sectional gradient within one pedigree: the two children had moderate loss
    weighted to the high frequencies, their mother had profound loss above 2000 Hz.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: High-frequency sensorineural hearing impairment
    term:
      id: HP:0001757
      label: High-frequency sensorineural hearing impairment
  notes: >-
    VERY_FREQUENT rather than OBLIGATE because one reported proband presented with the
    opposite configuration, curated as its own phenotype below. No published series gives
    a per-patient count of audiometric shape, so the band reflects the reported families
    rather than a measured proportion.
  evidence:
  - reference: PMID:33809266
    reference_title: "A Novel Truncating Mutation in HOMER2 Causes Nonsyndromic Progressive DFNA68 Hearing Loss in a Spanish Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals II:2 (8 years old) and II:3 (15 years old) exhibited moderate hearing loss with greater impact on the high frequencies (downsloping profile). Their mother (patient I:2, 39 years old) showed a more severe phenotype, displaying profound hearing loss at frequencies higher than 2000 Hz."
    explanation: >-
      The audiometric configuration and its worsening with age, within a single family so
      that genotype is held constant.
  - reference: PMID:40515814
    reference_title: "Impact of HOMER2 frameshift extension variant on auditory function and development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Preoperative pure tone audiograms show profound down-sloping sensorineural hearing loss with 8% speech discrimination score bilaterally."
    explanation: >-
      The same configuration at the severe end of the range, with a speech-discrimination
      figure that shows what it costs functionally.
- name: Low-Frequency Hearing Loss at Presentation
  category: Auditory
  description: >-
    One reported proband, aged eighteen with onset at seventeen, presented with the
    inverse of the usual pattern: moderate loss confined to the low frequencies, an
    ascending audiogram. Older affected members of the same family had flat audiograms
    with loss across all frequencies.

    The reporting authors read this as a stage effect rather than as a different disease,
    and the entry follows them. It matters diagnostically: an ascending audiogram in a
    young adult would not usually prompt a DFNA68 hypothesis, and this family shows that
    it should not exclude one.
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Low-frequency sensorineural hearing impairment
    term:
      id: HP:0008573
      label: Low-frequency sensorineural hearing impairment
  notes: >-
    VERY_RARE reflects that this is a single reported proband against a literature in
    which every other described family starts at the high frequencies. It is not a measured
    frequency; no denominator exists.
  evidence:
  - reference: PMID:41351289
    reference_title: "A Novel Frameshift Variant c.1023_1029del (p.Asp342ArgfsTer54) Leading to Extended Incorrect Protein C Termini in HOMER2 Causing Autosomal Dominant Nonsyndromic Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Unlike the initially high-frequency hearing loss observed in the previously reported families, the young proband in our study (IV:4, 18 years old) exhibited typical low-frequency hearing loss."
    explanation: The observation itself, stated against the background it departs from.
  - reference: PMID:41351289
    reference_title: "A Novel Frameshift Variant c.1023_1029del (p.Asp342ArgfsTer54) Leading to Extended Incorrect Protein C Termini in HOMER2 Causing Autosomal Dominant Nonsyndromic Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The older patients (43 years old) displayed flatter audiograms, indicating hearing loss across all frequencies. Accordingly, the different forms of auditory configuration may present different stages of the disease."
    explanation: >-
      The authors' own reading of the discrepancy, which is what justifies curating this as
      a presentation of the same disease rather than as a contradiction.
- name: Tinnitus
  category: Auditory
  description: >-
    Reported in some affected members of two families and explicitly absent in two others.
    It is curated because it is the only symptom besides hearing loss that any of the six
    primary reports records, and because a family in which tinnitus is prominent looks different to a
    clinician from one in which it is not.

    Deliberately not wired into the pathograph. Tinnitus accompanying cochlear hearing
    loss is unsurprising, but none of the six primary reports proposes a mechanism for it,
    and the entry's hair-cell nodes were not built to explain it. Drawing an edge from
    "Hair Cell Functional Failure Without Hair Cell Loss" would assert a causal claim
    that nothing cited here makes. The disconnection is the honest state of the evidence,
    not an oversight.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Tinnitus
    term:
      id: HP:0000360
      label: Tinnitus
  evidence:
  - reference: PMID:33809266
    reference_title: "A Novel Truncating Mutation in HOMER2 Causes Nonsyndromic Progressive DFNA68 Hearing Loss in a Spanish Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The presence of tinnitus or cranial tinnitus, however, has only been displayed by some affected members of the Chinese family and this phenotype was not present in any of the other two families."
    explanation: >-
      Both halves of the frequency claim in one sentence: present in some members of one
      family, absent in two others.
  - reference: PMID:41351289
    reference_title: "A Novel Frameshift Variant c.1023_1029del (p.Asp342ArgfsTer54) Leading to Extended Incorrect Protein C Termini in HOMER2 Causing Autosomal Dominant Nonsyndromic Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most affected individuals in this family complain of tinnitus but do not experience vertigo, and their intelligence and speech functions are normal."
    explanation: >-
      A second family in which tinnitus is common, which is why the band is OCCASIONAL
      across the disease rather than VERY_RARE.
- name: Absence of Vestibular Dysfunction
  category: Vestibular
  diagnostic: true
  description: >-
    No vertigo, imbalance or vestibular involvement has been reported in any DFNA68
    family, and in the most recently reported family it was actively looked for: tandem
    gait and Romberg testing were performed in all family members and were normal. That is
    a substantive negative rather than an omission - it is the result of a test, not the
    silence of a report - and it is one of the things that separates a DFNA68 presentation
    from the vestibulocochlear differential a clinician would otherwise be working
    through.

    Curated as a REFUTED phenotype with no phenotype_term and no frequency, following the
    pattern used for "Absence of Retinitis Pigmentosa" in
    Autosomal_Dominant_Nonsyndromic_Hearing_Loss_11. The schema has no negation slot and
    FrequencyEnum has no EXCLUDED value, so binding a vestibular HP term with a frequency
    here would export as the assertion that DFNA68 patients have vestibular dysfunction,
    which is the opposite of the finding.
  evidence:
  - reference: PMID:41351289
    reference_title: "A Novel Frameshift Variant c.1023_1029del (p.Asp342ArgfsTer54) Leading to Extended Incorrect Protein C Termini in HOMER2 Causing Autosomal Dominant Nonsyndromic Hearing Loss."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Symptoms of vertigo, balance disorders, and vestibular system involvement were not reported."
    explanation: >-
      A statement made across the reported families, not only about the one this paper
      describes.
  - reference: PMID:41351289
    reference_title: "A Novel Frameshift Variant c.1023_1029del (p.Asp342ArgfsTer54) Leading to Extended Incorrect Protein C Termini in HOMER2 Causing Autosomal Dominant Nonsyndromic Hearing Loss."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Tandem gait and Romberg tests did not reveal any symptoms of vestibular dysfunction in all family members."
    explanation: >-
      The tested negative, in one family, which is stronger than the reported absence above
      because it names the examination that was performed.
- name: Absence of Syndromic Features
  category: Constitutional
  diagnostic: true
  description: >-
    DFNA68 is nonsyndromic, and that is a finding rather than a default. The founding
    family was examined for syndromic features and for autoimmune causes and had neither;
    a later family had normal intelligence and speech. The one caveat worth carrying is
    that a zebrafish study of the longest extension allele found an increase in cardiac
    anomalies and raised the possibility of a broader effect in humans, while noting that
    its own patient had no cardiac abnormality. That is curated as an open question below
    rather than as a phenotype.

    Curated as a REFUTED phenotype, with no phenotype_term and no frequency, for the same
    reason as the vestibular entry above.
  evidence:
  - reference: PMID:25816005
    reference_title: "HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical examination was negative for any findings consistent with syndromic hearing loss and also ruled out autoimmune phenotypes."
    explanation: >-
      The examination that established the nonsyndromic label in the family the disease
      was defined in.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No prevalence estimate exists and none of the reporting groups offers one; each
    describes the disorder qualitatively as rare or extremely rare. What can be counted is
    families: the founding European pedigree in 2015, then Chinese, Spanish, Sicilian and
    Italian families, then an isolated patient and a further Chinese family, with the two
    most recent reports describing their alleles as the seventh and the sixth HOMER2 variant
    on record. Fewer than ten unrelated families is therefore the honest statement of the
    literature's size.

    prevalence_class is the qualitative ULTRA_RARE tier and no rate_per_100000 is given,
    because no numerator and no denominator have been published and a band beside this
    note would be an invention. The tier is compatible with measure_type
    CASES_IN_LITERATURE, which is what is actually being reported.

    The two published counts disagree by one. They were written months apart and enumerate
    the variant list differently, and neither group reconciles its count with the other's.
    Both are quoted below rather than reconciled here.
  evidence:
  - reference: PMID:33809266
    reference_title: "A Novel Truncating Mutation in HOMER2 Causes Nonsyndromic Progressive DFNA68 Hearing Loss in a Spanish Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hearing loss caused by HOMER2 mutations is an extremely rare disorder."
    explanation: The qualitative rarity statement from a group that reported one of the families.
  - reference: PMID:41351289
    reference_title: "A Novel Frameshift Variant c.1023_1029del (p.Asp342ArgfsTer54) Leading to Extended Incorrect Protein C Termini in HOMER2 Causing Autosomal Dominant Nonsyndromic Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, only five heterozygous variants in the HOMER2 gene have been reported worldwide in five isolated families of European, Chinese, Sicilian, Italian and Spanish origins"
    explanation: >-
      A count of families and their origins, which is the closest thing to a denominator
      the literature provides.
  - reference: PMID:40515814
    reference_title: "Impact of HOMER2 frameshift extension variant on auditory function and development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our review found that this frameshift extension variant is only the seventh HOMER2 variant documented in patients with SNHL."
    explanation: >-
      The other published count, quoted alongside the first because the two do not agree
      and neither should be presented as settled.
progression:
- phase: Presymptomatic
  notes: >-
    Hearing is normal through infancy and early childhood and speech is acquired normally,
    so the disorder is invisible to newborn hearing screening. In the founding family a
    two-year-old carrier had not had a formal auditory brainstem response performed, which
    is the practical shape of this phase: carriers are identified genetically before they
    are identified audiometrically.
  evidence:
  - reference: PMID:41351289
    reference_title: "A Novel Frameshift Variant c.1023_1029del (p.Asp342ArgfsTer54) Leading to Extended Incorrect Protein C Termini in HOMER2 Causing Autosomal Dominant Nonsyndromic Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prelingual hearing loss is present before speech develops and usually begins before 3 years of age, whereas post‐lingual hearing loss occurs after the development of normal speech"
    explanation: >-
      The definition the reporting group applied when classifying this disorder as
      postlingual, which is what establishes that a presymptomatic window exists.
- phase: High-frequency onset
  age_range: first to second decade in most reported families
  notes: >-
    Loss begins at the high frequencies, giving a down-sloping audiogram while speech
    frequencies are still relatively spared. Reported onset ages span the first decade in
    the European and Spanish families and the late teens to early twenties in the most
    recent Chinese one.
  evidence:
  - reference: PMID:33809266
    reference_title: "A Novel Truncating Mutation in HOMER2 Causes Nonsyndromic Progressive DFNA68 Hearing Loss in a Spanish Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected individuals show progressive hearing loss affecting mainly the high frequencies (downsloping profile) with a typical onset in the first decade of life"
    explanation: The onset window and audiometric shape, generalised across three families.
- phase: Progressive decline
  notes: >-
    Thresholds deteriorate at a measured 1.2 to 1.6 dB per year across all frequencies in
    the founding family, and the lower frequencies are progressively drawn in so that the
    audiogram flattens. This is the one phase of the disease with a quantitative
    description.
  evidence:
  - reference: PMID:41351289
    reference_title: "A Novel Frameshift Variant c.1023_1029del (p.Asp342ArgfsTer54) Leading to Extended Incorrect Protein C Termini in HOMER2 Causing Autosomal Dominant Nonsyndromic Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The degree of hearing loss ranges from mild to severe hearing loss and the annual threshold deterioration is between 1.2 and 1.6 dB HL per year across all frequencies"
    explanation: >-
      The rate and the severity range, restated across the reported families by the most
      recent group.
- phase: Severe-to-profound loss
  notes: >-
    The endpoint reached by older affected individuals, with profound loss and very poor
    speech discrimination. The one patient for whom a functional figure is published had
    8 percent speech discrimination bilaterally and proceeded to cochlear implantation in
    her sixties. How typical that timing is cannot be said from one patient.
  evidence:
  - reference: PMID:40515814
    reference_title: "Impact of HOMER2 frameshift extension variant on auditory function and development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SB1190-1923 began to experience more severe progressive SNHL in the high-frequency range starting in their 50 s."
    explanation: >-
      The late-severity trajectory in the one patient followed to implantation, quoted
      because it is the only longitudinal account of the disease's end stage.
clinical_burden:
  burden_level: MODERATE
  rationale: >-
    DFNA68 is not life-threatening and involves no organ system other than the ear, but it
    is lifelong, progressive and ends in severe or profound deafness in an adult who
    acquired speech normally and then lost access to it. The functional cost is documented
    at the severe end: one patient reached 8 percent bilateral speech discrimination and
    required cochlear implantation. Management is amplification, then implantation, then
    ongoing audiological follow-up; none of the six primary reports names a
    disease-modifying option.

    MODERATE rather than HIGH because the burden is confined to one sensory modality, is
    substantially correctable by devices whose benefit in this disease has been
    demonstrated, and carries no reported mortality or systemic morbidity. MODERATE rather
    than LOW because the deficit is progressive and permanent, and the endpoint is
    profound deafness.
  evidence:
  - reference: PMID:40515814
    reference_title: "Impact of HOMER2 frameshift extension variant on auditory function and development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ten years after the onset of significant SNHL, SB1190-1923 had developed profound deafness with a speech discrimination score of only 8%"
    explanation: >-
      The functional severity reached, and the interval over which it was reached, in the
      one patient with a published longitudinal course.
  - reference: PMID:33809266
    reference_title: "A Novel Truncating Mutation in HOMER2 Causes Nonsyndromic Progressive DFNA68 Hearing Loss in a Spanish Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "age-matched patients in both families display quite similar hearing loss phenotypes consisting of early-onset, moderate-to-profound progressive hearing loss"
    explanation: The severity range across two independent families, which is what the band is set against.
genetic:
- name: HOMER2
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: HOMER2
    term:
      id: hgnc:17513
      label: HOMER2
  notes: >-
    HOMER2 maps to chromosome 15q24.3 and has nine exons. Two transcripts are described,
    encoding a 343-residue and a 354-residue isoform, and both numbering systems appear in
    the DFNA68 literature for the same variants - the founding missense allele is
    p.Arg185Pro against the shorter isoform and p.Arg196Pro against the longer one. A
    reader comparing two DFNA68 papers will meet both spellings and they are not two
    alleles.

    Every reported allele is heterozygous, and the allele classes are curated as three
    separate pathophysiology nodes because their proposed mechanisms differ: a coiled-coil
    missense change acting as a dominant negative, frameshift truncations inside the
    CDC42-binding domain that destabilise the product and reduce its multimerisation, and
    extension variants that run past the stop codon and have been argued to act by gain of
    function. What unites them is a negative: none of them is haploinsufficiency.

    The mouse null phenotype led the founding authors to nominate HOMER2 as a candidate for
    autosomal recessive hearing loss in humans as well. No recessive HOMER2 patient appears
    among the nine PubMed records returned by the search recorded in the notes below, so
    that prediction is still open a decade later.
  evidence:
  - reference: PMID:25816005
    reference_title: "HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These data provide compelling evidence that HOMER2 is required for normal hearing and that its sequence alteration in humans leads to ADNSHL through a dominant-negative mode of action."
    explanation: The gene-disease relationship as first established, together with its proposed mode of action.
  - reference: PMID:30047143
    reference_title: "Whole exome sequencing identified a second pathogenic variant in HOMER2 for autosomal dominant non-syndromic deafness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is the second family reported globally with hearing loss caused by a variant in HOMER2."
    explanation: >-
      The independent replication of the gene-disease relationship in an unrelated family,
      which is what moved it past a single-pedigree claim.
  - reference: PMID:33809266
    reference_title: "A Novel Truncating Mutation in HOMER2 Causes Nonsyndromic Progressive DFNA68 Hearing Loss in a Spanish Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "The HOMER2 gene maps to chromosome 15q24.3"
    explanation: >-
      The locus. BACKGROUND because it restates the gene's map position from an earlier
      source rather than reporting a mapping result of this study.
  - reference: PMID:25816005
    reference_title: "HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "HOMER2 belongs to the homer family of post-synaptic density scaffolding proteins and is expressed as two isoforms, HOMER2 isoform 1 (NM_004839, 343 aa) and isoform 2 (NM_199330.2, 354 aa), which differ by 11 amino acids."
    explanation: >-
      The two-isoform fact behind the two protein numberings. BACKGROUND because it is
      established transcript annotation restated in this paper's results.
  - reference: PMID:25816005
    reference_title: "HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The recessive phenotype exhibited by null alleles of Homer2 makes it a strong candidate for autosomal recessive hearing loss due to loss of function in humans as well."
    explanation: The untested recessive prediction, recorded as the authors made it.
diagnosis:
- name: Comprehensive hearing-loss gene panel or exome sequencing
  description: >-
    DFNA68 is reached by sequencing, not by any distinguishing clinical sign. Every
    reported family was found the same way - a targeted deafness gene panel or whole exome
    sequencing in a pedigree with dominant, postlingual, progressive sensorineural hearing
    loss, followed by Sanger segregation across the family. There is no biochemical
    marker and no audiometric pattern specific enough to point at HOMER2 rather than at any
    of the fifty-odd genes associated with autosomal dominant nonsyndromic hearing loss, and
    the one temporal bone CT reported in a DFNA68 proband was normal.

    The practical point the reporting groups make is about panel content rather than about
    technique: HOMER2 is a low-prevalence deafness gene, so whether it is found depends on
    whether it is on the panel that was ordered.
  evidence:
  - reference: PMID:33809266
    reference_title: "A Novel Truncating Mutation in HOMER2 Causes Nonsyndromic Progressive DFNA68 Hearing Loss in a Spanish Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our study also highlights the importance of using NGS-based diagnostic methods to identify mutations in low-prevalence deafness genes like HOMER2"
    explanation: >-
      The diagnostic argument in the authors' own words, and the reason a gene this rare
      needs a broad panel to be found at all.
  - reference: PMID:41351289
    reference_title: "A Novel Frameshift Variant c.1023_1029del (p.Asp342ArgfsTer54) Leading to Extended Incorrect Protein C Termini in HOMER2 Causing Autosomal Dominant Nonsyndromic Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole exome sequencing analysis was conducted to detect the disease-causing variant. Co-segregation analysis was performed using Sanger sequencing."
    explanation: The two-step route - discovery by sequencing, confirmation by segregation - as applied in practice.
  - reference: PMID:33809266
    reference_title: "A Novel Truncating Mutation in HOMER2 Causes Nonsyndromic Progressive DFNA68 Hearing Loss in a Spanish Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Sixty-seven of these loci and 50 of these genes are associated with autosomal dominant NSSNHL"
    explanation: >-
      The size of the differential a panel has to cover, which is why the diagnosis is made
      by broad sequencing rather than by a targeted test. BACKGROUND because it restates a
      field count from a gene-count resource.
  - reference: PMID:41351289
    reference_title: "A Novel Frameshift Variant c.1023_1029del (p.Asp342ArgfsTer54) Leading to Extended Incorrect Protein C Termini in HOMER2 Causing Autosomal Dominant Nonsyndromic Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CT scans of the proband ruled out middle‐ and inner‐ear malformations"
    explanation: >-
      The one imaging result published for a DFNA68 patient, cited to record that it was
      normal - imaging excludes alternatives here rather than establishing the diagnosis.
- name: Pure tone audiometry with serial follow-up
  description: >-
    Pure tone audiometry establishes the sensorineural character, the configuration and,
    over repeated visits, the rate. Bone conduction thresholds are what exclude a
    conductive component. Serial audiometry matters more here than in a static hearing
    loss: the audiogram's shape changes as the disease advances, so a single audiogram
    describes a stage rather than the disorder, and the rate of deterioration is only
    obtainable by regressing thresholds on age across visits.
  evidence:
  - reference: PMID:25816005
    reference_title: "HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Linear regression analyses of threshold on age were used to evaluate progression of hearing impairment at individual frequencies."
    explanation: >-
      The method by which the one quantitative natural-history figure for this disease was
      obtained.
  - reference: PMID:41351289
    reference_title: "A Novel Frameshift Variant c.1023_1029del (p.Asp342ArgfsTer54) Leading to Extended Incorrect Protein C Termini in HOMER2 Causing Autosomal Dominant Nonsyndromic Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The older patients (43 years old) displayed flatter audiograms, indicating hearing loss across all frequencies. Accordingly, the different forms of auditory configuration may present different stages of the disease."
    explanation: >-
      Why one audiogram is not enough: configuration is stage-dependent in this disorder,
      on the reporting group's own reading.
treatments:
- name: Hearing Amplification
  description: >-
    Hearing aids are the first-line intervention while thresholds remain within the range
    amplification can address. None of the six primary DFNA68 reports names a
    disease-modifying therapy or a trial, and no HOMER2-directed agent appears among them.
    What is specific to this disorder is the commitment rather than the modality: the loss is progressive at a measurable rate, so the useful clinical act
    is repeated audiological review that catches deterioration and re-fits, not a single
    fitting decision.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: hearing aid fitting
  target_phenotypes:
  - preferred_term: Progressive sensorineural hearing impairment
    term:
      id: HP:0000408
      label: Progressive sensorineural hearing impairment
  notes: >-
    treatment_term carries no NCIT binding. NCIT:C183182 Hearing Aid is a device concept
    and is not reachable from NCIT:C25218 Clinical Intervention or Procedure, the root of
    the TreatmentTerm enum, and NCIT has no clinical-action term for hearing-aid fitting -
    searched with `runoak -i ols:ncit search "l^Hearing Aid"`, which returns
    NCIT:C183182 Hearing Aid, NCIT:C205713 Hearing Aid Fitter Audiologist, and two
    questionnaire items, none of which is a clinical action. A free-text preferred_term is
    what the ontology contract asks for here. This does not generalise to cochlear
    implantation below, which is a surgical procedure and does bind.

    No DFNA68-specific amplification outcome has been published, so the evidence is cited
    at the level of the disease class this disorder belongs to.
  evidence:
  - reference: PMID:37371710
    reference_title: "Autosomal Dominant Non-Syndromic Hearing Loss (DFNA): A Comprehensive Narrative Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A long audiological follow-up is of paramount importance to identify hearing threshold deteriorations early and ensure prompt treatment with hearing aids or cochlear implants."
    explanation: >-
      Cited at the group level deliberately. This is a narrative review of autosomal
      dominant nonsyndromic hearing loss as a class, not of DFNA68, so it supports the
      management approach for the class rather than an outcome in this disorder. Graded
      OTHER because a narrative review reports no study of its own.
- name: Cochlear Implantation
  description: >-
    Implantation once amplification no longer delivers useful speech understanding. This
    disorder, unusually for one described in so few families, has a published outcome: a
    patient in her sixties with profound down-sloping loss and 8 percent bilateral speech discrimination
    was implanted, and speech recognition improved significantly at three and six months
    across syllable and sentence conditions.

    The mechanism supports the intervention in principle as well. The lesion is in the
    hair cell, upstream of the spiral ganglion neurons an implant stimulates, and the
    animal data show hair-cell dysfunction without hair-cell death, so there is no reason
    to expect the neural substrate an implant depends on to be compromised. That reasoning
    is the entry's, not a published claim; the outcome datapoint is published.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: cochlear device implantation
    term:
      id: NCIT:C15329
      label: Surgical Procedure
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: cochlear implant
        term:
          id: NCIT:C157820
          label: Cochlear Implant
  target_phenotypes:
  - preferred_term: Progressive sensorineural hearing impairment
    term:
      id: HP:0000408
      label: Progressive sensorineural hearing impairment
  target_mechanisms:
  - target: Hair Cell Functional Failure Without Hair Cell Loss
    treatment_effect: BYPASSES
    description: >-
      An implant does not repair the hair cell; it stimulates the spiral ganglion directly,
      bypassing the transduction step that has failed. BYPASSES rather than RESTORES
      because nothing about the hair-cell lesion changes.
  evidence:
  - reference: PMID:40515814
    reference_title: "Impact of HOMER2 frameshift extension variant on auditory function and development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Post-Cochlear Implantation speech outcome speech recognition improves significantly at 3- and 6-months post-implantation across various syllable and sentence conditions."
    explanation: >-
      The only published implantation outcome in a genetically confirmed DFNA68 patient.
      One patient, no control, and the follow-up is six months.
  - reference: PMID:40515814
    reference_title: "Impact of HOMER2 frameshift extension variant on auditory function and development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HOMER2 is a causative gene in elderly patients, particularly those in their 60 s or 70 s, who develop profound SNHL and require CI"
    explanation: >-
      The authors' statement of when in the disease course implantation becomes the
      relevant intervention.
- name: Genetic Counselling and Cascade Testing
  description: >-
    Counselling for a dominant condition with a 50 percent transmission risk. Two things
    are specific to DFNA68 and worth saying to a family. The first is that a normal
    audiogram in a young carrier does not mean much: onset is postlingual and in one
    reported family did not begin until the late teens or twenties, so an unaffected-looking
    child may simply not have reached onset. The second is that the finding predicts a
    trajectory rather than a state - a known rate of decline is the main thing a molecular
    diagnosis adds here, because there is no treatment it selects.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:41351289
    reference_title: "A Novel Frameshift Variant c.1023_1029del (p.Asp342ArgfsTer54) Leading to Extended Incorrect Protein C Termini in HOMER2 Causing Autosomal Dominant Nonsyndromic Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The ages at onset of the affected individuals ranged from 17 to 24 years."
    explanation: >-
      The late-onset window that makes a normal childhood audiogram uninformative about
      carrier status in some families.
  - reference: PMID:41351289
    reference_title: "A Novel Frameshift Variant c.1023_1029del (p.Asp342ArgfsTer54) Leading to Extended Incorrect Protein C Termini in HOMER2 Causing Autosomal Dominant Nonsyndromic Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "contribute to the development of genetic counseling for inherited deafness"
    explanation: >-
      The authors' own framing of what the molecular diagnosis is for in this disorder.
      Quoted from their conclusion, where counselling is named as the clinical use of the
      finding.
animal_models:
- name: Homer2 constitutive knockout mouse
  species: Mouse
  genotype: Homer2 targeted deletion, homozygous and heterozygous
  publication: PMID:25816005
  genes:
  - preferred_term: HOMER2
    term:
      id: hgnc:17513
      label: HOMER2
  description: >-
    The only mammalian model of the gene's role in hearing among the nine PubMed records
    swept for this entry, and the one that supplied both the strongest and the most awkward
    result. Homozygous nulls have progressively rising
    auditory brainstem response thresholds from two weeks of age and are profoundly deaf by
    eight weeks, with the loss starting at high frequencies and spreading. At that point the
    organ of Corti still has its full complement of inner and outer hair cells.

    The awkward result is the heterozygote. It hears normally, which means the mouse models
    absence of the protein while every human allele is something other than absence. The
    model therefore supports the claim that HOMER2 is required for hearing, and does not
    model the human genotype.
  modeled_mechanisms:
  - target: Hair Cell Functional Failure Without Hair Cell Loss
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      The model's distinctive contribution: profound deafness in the presence of an intact
      hair-cell population, which is what separates this disease from the hair-cell-death
      mechanisms the module it conforms to normally describes.
    limitations: >-
      The genotype is a homozygous null and the human disease is heterozygous for
      non-null alleles; the heterozygous mouse, the genotype that corresponds to a human
      carrier, has no phenotype at all. The hair-cell count was made at eight weeks in an
      animal with a very compressed disease course, so it does not exclude hair-cell loss
      over the decades a human cochlea is exposed to the lesion. No knock-in mouse carrying
      a human DFNA68 allele appears among the nine PubMed records returned by the search
      recorded in the entry notes.
    readouts:
    - name: Inner and outer hair cell counts in whole-mount organ of Corti
      target: Hair Cell Functional Failure Without Hair Cell Loss
      direction: UNCHANGED
      interpretation: >-
        An unchanged hair-cell population alongside profound threshold elevation is what
        makes the lesion functional rather than degenerative in this model.
      evidence:
      - reference: PMID:25816005
        reference_title: "HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "No differences in IHCs and OHCs were observed in any animals regardless of genotype indicating the absence of Homer2 does not impair hair cell formation and development"
        explanation: The measurement itself, reported as a negative across all genotypes.
    evidence:
    - reference: PMID:25816005
      reference_title: "HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "mouse mutants homozygous for the targeted deletion of Homer2 present with early-onset rapidly progressive hearing loss"
      explanation: >-
        Establishes that this model is informative for the hearing phenotype at all, which
        is the precondition for reading its hair-cell result.
  - target: Progressive Sensorineural Hearing Loss
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Reproduces the audiometric shape of the human disease - progressive, starting at
      high frequencies, eventually involving all of them - on a radically compressed
      timescale.
    limitations: >-
      Onset is at two weeks and the endpoint at eight, against decades in humans, so the
      model cannot speak to the human rate, to the stage-dependent change in audiometric
      configuration, or to anything about late adult disease. The genotype mismatch above
      applies here too.
    readouts:
    - name: Auditory brainstem response threshold
      target: Progressive Sensorineural Hearing Loss
      direction: INCREASED
      interpretation: >-
        Rising thresholds over successive ages are the measurement that makes the model's
        phenotype progressive rather than static.
      evidence:
      - reference: PMID:25816005
        reference_title: "HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Its complete absence in mice leads to early onset progressive hearing loss starting at the high frequencies and rapidly involving all frequencies."
        explanation: The authors' summary of the threshold data, naming both onset and direction of spread.
    evidence:
    - reference: PMID:25816005
      reference_title: "HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "we measured auditory brainstem responses (ABR), an electrophysiological hearing test that reflects the activity of afferent auditory neurons downstream of IHCs"
      explanation: >-
        Names the assay and what it reports on, which is what licenses reading the mouse
        result as a hearing phenotype rather than a behavioural one.
- name: Zebrafish HOMER2 mutant mRNA overexpression model
  species: Zebrafish
  genotype: wild-type embryos injected with in vitro transcribed mutant human HOMER2 mRNA
  publication: PMID:25816005
  description: >-
    The workhorse assay of this field, used by three separate groups. Human HOMER2 mRNA -
    wild type or mutant - is injected into wild-type embryos, so the fish's own homer2 is
    intact and any phenotype is an effect of the mutant product on a normal background.
    That design is what makes it a dominant-negative assay rather than a loss-of-function
    one, and the founding study made the point explicitly by showing that morpholino
    knockdown of the fish gene did not change ear size while mutant mRNA did.

    Later groups extended it from morphology to function: FM1-43 uptake in neuromast hair
    cells and startle-reflex testing, both reduced by disease alleles.
  modeled_mechanisms:
  - target: HOMER2 Coiled-Coil Missense Variant
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      The assay that established the dominant-negative classification of the founding
      allele, by the contrast between mutant-mRNA injection and gene knockdown.
    limitations: >-
      Zebrafish homer2 is 67 percent identical to the human protein, the injected message
      is supraphysiological and transient, and the readout is otic vesicle size and
      kinocilium number in an embryo rather than hearing in a mature cochlea. A fish has no
      cochlea, no endocochlear potential and no outer-hair-cell amplifier, so the assay
      reports that the allele is harmful to hair cells, not how it causes human deafness.
    readouts:
    - name: Otic vesicle size in injected larvae
      target: HOMER2 Coiled-Coil Missense Variant
      direction: DECREASED
      interpretation: >-
        Smaller ears after mutant but not wild-type mRNA injection is the positive result
        the dominant-negative reading rests on.
      evidence:
      - reference: PMID:25816005
        reference_title: "HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "injection of in vitro synthesized mRNA encoding HOMER2 P185-mutant RNA (P185RNA) resulted in significantly smaller ear size in larvae as compared to injections with WT HOMER2"
        explanation: The measurement, with its wild-type-mRNA control stated in the same sentence.
    evidence:
    - reference: PMID:25816005
      reference_title: "HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Although knockdown of homer2 altered neither ear size nor morphology (p>0.5)"
      explanation: >-
        The knockdown control. It is what makes the model informative about a
        dominant-negative mechanism specifically rather than about the gene being needed.
  - target: Hair Cell Functional Failure Without Hair Cell Loss
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      The functional extension of the assay, in which disease alleles reduce FM1-43 uptake
      by neuromast hair cells while leaving hair-cell numbers unchanged - the fish
      counterpart of the mouse null's intact organ of Corti.
    limitations: >-
      Neuromasts are lateral-line organs, not cochlear, and FM1-43 uptake is a proxy for
      open mechanotransduction channels rather than a direct measurement of transduction
      current. The injected alleles are extension variants, so the result is not
      established for the missense or truncating classes.
    readouts:
    - name: FM1-43 uptake by neuromast hair cells
      target: Hair Cell Functional Failure Without Hair Cell Loss
      direction: DECREASED
      interpretation: >-
        Reduced dye entry indicates fewer open transduction channels, so the hair cells are
        present but not transducing.
      evidence:
      - reference: PMID:40515814
        reference_title: "Impact of HOMER2 frameshift extension variant on auditory function and development."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "in the HOMER2 variant groups, FM1-43 uptake was markedly reduced"
        explanation: The measurement itself, against injected wild-type and fluorescent-protein controls.
    - name: Startle reflex latency and distance
      target: Hair Cell Functional Failure Without Hair Cell Loss
      direction: ALTERED
      interpretation: >-
        A behavioural readout of hearing in the fish, which is what converts a dye-uptake
        result into a claim about auditory function.
      evidence:
      - reference: PMID:40515814
        reference_title: "Impact of HOMER2 frameshift extension variant on auditory function and development."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "In the startle reflex test, both variants reduced distance and increased latency, providing strong evidence for hearing loss and the pathogenicity of the p.R345Efs*64 variant."
        explanation: The behavioural result and the inference the authors draw from it.
    evidence:
    - reference: PMID:37173411
      reference_title: "Identification and in vivo functional investigation of a HOMER2 nonstop variant causing hearing loss."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "in vivo studies using a zebrafish animal model and behavioral tests clearly established the deleterious impact of this novel HOMER2 alteration on hearing function"
      explanation: >-
        An independent group reaching the same conclusion with the same system, which is
        what makes the assay a reproducible tool rather than a single study's result.
discussions:
- discussion_id: dfna68_actin_versus_calcium_mechanism
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - "pathophysiology#Disrupted HOMER2-CDC42 Coupling at the Hair Bundle"
  - "pathophysiology#Dysregulated Hair Cell Cytosolic Calcium Handling"
  prompt: >-
    Does HOMER2 keep hair cells working by regulating stereociliary actin through CDC42,
    by holding calcium-handling proteins in place, or by both?
  rationale: >-
    The founding paper set out two hypotheses and declined to choose, and a decade later
    nothing has chosen for it. Both are carried in this entry as separate nodes rather than
    collapsed, because collapsing them would manufacture a resolution.

    The actin branch has the better circumstantial case. The HOMER2-CDC42 interaction is
    mapped to the same residue range the disease alleles fall in; CDC42 is present and
    active at stereociliary membranes; and removing CDC42 from mouse hair cells produces
    stereocilia fusion and depletion with progressive high-frequency hearing loss that
    looks like the human disease. What is missing is any measurement of the HOMER2-CDC42
    complex in a cochlear hair cell, and any binding assay for a disease allele.

    The calcium branch has one real measurement and it is in the wrong tissue: deleting
    Homer2 from mouse parotid acinar cells raises PMCA expression and speeds calcium
    extrusion. The reason to care is that PMCA2 is the only calcium clearance route out of
    a stereocilium, so a scaffold that sets pump behaviour would matter there. But the
    Homer2 partner established among TRPC channels is TRPC1, while the TRPCs hair cells
    need are TRPC3 and TRPC6, and the PMCA2 partnership has been proposed rather than
    shown.

    The two are not mutually exclusive. A tetrameric hub holds several partners at once,
    and an allele that degrades hub assembly would be expected to loosen the grip on all
    of them. It is entirely possible that the answer is "both, and the actin arm dominates
    the phenotype" - but that is a hypothesis with no data behind it either.
  proposed_experiments:
  - experiment_id: dfna68_homer2_cdc42_interaction_in_hair_cells
    name: HOMER2 partner mapping and allele-specific binding in cochlear hair cells
    description: >-
      Immunoprecipitate HOMER2 from mouse cochlear sensory epithelium and identify its
      partners by mass spectrometry, asking specifically whether CDC42, PMCA2 and TRPC
      channels are among them; then measure binding of each disease allele class to
      whichever partners are found, in a hair-cell-derived line rather than in HEK cells.
    readouts:
    - name: CDC42 recovery in HOMER2 immunoprecipitates from cochlear epithelium
      target: "pathophysiology#Disrupted HOMER2-CDC42 Coupling at the Hair Bundle"
      direction: DECREASED
      interpretation: >-
        Recovery of CDC42 from wild-type cochlea, reduced for disease alleles, would move
        this node from provisional to established. Failure to recover CDC42 at all would
        undercut the better-supported of the two hypotheses and push the field to the
        calcium branch.
    - name: PMCA2 recovery in HOMER2 immunoprecipitates from cochlear epithelium
      target: "pathophysiology#Dysregulated Hair Cell Cytosolic Calcium Handling"
      interpretation: >-
        A HOMER2-PMCA2 complex in cochlear tissue would convert the calcium hypothesis from
        an extrapolation out of salivary gland into a claim about the right cell.
- discussion_id: dfna68_no_model_of_the_human_genotype
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - "animal_models#Mouse"
  - "pathophysiology#HOMER2 Coiled-Coil Missense Variant"
  prompt: >-
    Every HOMER2 hearing model is either a null or an overexpression assay. Does a mouse
    heterozygous for an actual human DFNA68 allele go deaf, and does it do so the way a
    patient does?
  rationale: >-
    This is a mismatch of genotype, not of species, and it runs through the whole evidence
    base. The mammalian model is a homozygous constitutive null whose heterozygote - the
    genotype corresponding to a human carrier - hears normally. The zebrafish assays
    inject human mutant mRNA into embryos with intact endogenous homer2, at
    supraphysiological and transient levels, and read out otic vesicle size, neuromast dye
    uptake and startle behaviour. Neither system contains a single copy of a human disease
    allele expressed at its own level in a mammalian cochlea, which is what the disease is.

    Why it matters rather than being a routine caveat: the entire mechanistic
    classification of this disease turns on the difference between absence of HOMER2 and
    interference by a mutant HOMER2. The mouse tests absence. The fish tests excess. The
    disease is neither. The specific claims that are unverified as a result are the
    dominant-negative classification of the missense allele, the gain-of-function
    classification of the extension alleles, and the assertion that hair cells survive -
    which is measured at eight weeks in an animal whose disease runs its whole course in
    six.

    Filed as HUMAN_MODEL_MISMATCH rather than KNOWLEDGE_GAP because the experiments have
    been done, in models whose correspondence to the human genotype is the open question,
    rather than not done at all.
  proposed_experiments:
  - experiment_id: dfna68_knock_in_mouse_allelic_series
    name: Knock-in mouse series carrying human DFNA68 alleles
    description: >-
      Generate heterozygous knock-in mice carrying the orthologues of one allele from each
      class - the coiled-coil missense, a CDC42-binding-domain frameshift, and a C-terminal
      extension - and follow auditory brainstem response and distortion-product otoacoustic
      emission thresholds, hair-bundle morphology by scanning electron microscopy, and
      hair-cell counts, to an age well past threshold onset.
    readouts:
    - name: Auditory brainstem response threshold in heterozygous knock-in mice
      target: "pathophysiology#Progressive Sensorineural Hearing Loss"
      direction: INCREASED
      interpretation: >-
        Rising thresholds in a heterozygote, where the null heterozygote has none, would be
        the direct demonstration that these alleles act on the wild-type product, and would
        convert the dominant-negative and gain-of-function classifications from inference
        into measurement.
    - name: Hair cell counts at and beyond threshold onset
      target: "pathophysiology#Hair Cell Functional Failure Without Hair Cell Loss"
      interpretation: >-
        Preserved hair cells late in a slowly progressing model would establish the entry's
        distinctive claim in the right genotype. Progressive hair-cell loss would instead
        place the disease inside the module's ordinary death pathway and change what this
        node asserts.
    - name: Stereocilia morphology by scanning electron microscopy
      target: "pathophysiology#Failure of Stereocilia Actin Maintenance"
      direction: ALTERED
      interpretation: >-
        Fusion and depletion resembling the Cdc42 conditional knockout would connect the
        HOMER2 allele to the actin branch directly, which is the step the CDC42 experiment
        cannot supply.
- discussion_id: dfna68_extension_allele_cardiac_signal
  kind: OPEN_QUESTION
  status: OPEN
  attaches_to:
  - "pathophysiology#HOMER2 C-Terminal Extension Variant"
  prompt: >-
    Is the cardiac anomaly seen in zebrafish injected with the longest HOMER2 extension
    allele a signal about human carriers, or an artefact of overexpressing an aberrant
    protein in an embryo?
  rationale: >-
    DFNA68 is nonsyndromic in every reported family. Against that, the group that
    characterised the longest extension allele reported that it increased the frequency of
    cardiac anomalies and general morphological abnormalities in injected zebrafish, more
    than an artificial pure-truncation control did, and raised the possibility that human
    fetuses carrying such a variant might not survive - which would make the human families
    an ascertainment of the survivors.

    The case against taking it seriously is straightforward: the patient carrying the
    allele had no cardiac abnormality, the assay is supraphysiological mRNA injection into
    an embryo, and morphological abnormality in that system is a common non-specific
    outcome. The case for not dismissing it is that the effect was dose-ordered against a
    designed control rather than incidental, and that none of the six primary reports
    describes cardiac imaging in a DFNA68 family.

    Recorded as an open question rather than as a phenotype or a knowledge gap: none of the
    six primary reports describes a cardiac feature in a DFNA68 patient, and curating one on
    the strength of a fish would be exactly the import this entry is otherwise careful to
    avoid.
  proposed_experiments:
  - experiment_id: dfna68_cardiac_assessment_of_reported_families
    name: Echocardiography and electrocardiography in DFNA68 carriers
    description: >-
      Cardiac assessment of carriers in the reported families, stratified by allele class,
      reported whether normal or abnormal. The question is answerable with existing
      cohorts and no new genetics.
    readouts:
    - name: Left ventricular function and rhythm in HOMER2 carriers
      target: "pathophysiology#HOMER2 C-Terminal Extension Variant"
      interpretation: >-
        Normal cardiac findings across carriers, particularly extension-allele carriers,
        would close the question and confirm the fish result as assay-specific. Any
        consistent abnormality would change DFNA68 from a nonsyndromic entity into a
        syndromic one and would add cardiac surveillance to its management.
external_assertions:
- name: OMIM deafness, autosomal dominant 68 record
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:616707
  url: https://omim.org/entry/616707
  description: >-
    The OMIM phenotype record under which DFNA68 was designated, and the identifier the
    clinical literature uses for the disorder. Recorded here rather than under mappings
    because the DiseaseMappings class carries only ICD-10-CM, ICD-11, MONDO and NCIT slots.
  evidence:
  - reference: PMID:41351289
    reference_title: "A Novel Frameshift Variant c.1023_1029del (p.Asp342ArgfsTer54) Leading to Extended Incorrect Protein C Termini in HOMER2 Causing Autosomal Dominant Nonsyndromic Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Deafness, autosomal dominant 68 (DFNA68, OMIM #616707) is a rare subtype of ADNSHL caused by heterozygous variants in the HOMER2"
    explanation: The OMIM number, the DFNA designation and the causal gene in one sentence.
notes: >-
  Scope decision. Curated as a DISEASE, not a GROUPING, a SUBTYPE or OUT_OF_SCOPE. One
  gene, one clinical picture, one conserved pathograph from a HOMER2 allele to progressive
  sensorineural hearing loss, and no member diseases to unite. The OLS4 descendants endpoint
  returns zero descendants for MONDO:0014740, and the stub deleted by this change recorded
  one causal gene, hgnc:17513 HOMER2, taken from MONDO's own RO:0004003 relation. Its MONDO
  parent, MONDO:0019587 autosomal dominant nonsyndromic hearing loss, is an ontology
  grouping returning 76 descendants from the same endpoint, spanning unrelated DFNA loci,
  and is not a dismech entry: a search of kb/groupings/ found no hearing-loss or deafness grouping
  of any kind, and no disorder entry carries MONDO:0019587 as its own disease_term. The
  repository's established treatment of this family is one entry per DFNA locus - twelve
  Autosomal_Dominant_Nonsyndromic_Hearing_Loss_NN entries plus eight
  Hearing_Loss_Autosomal_Dominant_NN entries and sixteen recessive counterparts already
  exist, counted by filename on this branch's base - so an umbrella entry carrying
  this as a has_subtypes row would be a new pattern rather than an existing one. The stub is
  deleted by this change.

  Precedent followed. Autosomal_Recessive_Nonsyndromic_Hearing_Loss_123 (merged 2026-09-17)
  for the overall shape and for the discipline about what a thin literature does and does
  not license; Autosomal_Dominant_Nonsyndromic_Hearing_Loss_50 for the dominant-specific
  sections, for the practice of splitting mechanistically distinct allele classes into
  separate pathophysiology nodes, and for the convention on conforming only the terminal
  node to sensorineural_hair_cell_loss where the module's middle chain does not apply;
  Autosomal_Dominant_Nonsyndromic_Hearing_Loss_11 for the hearing-aid ontology gap, the
  cochlear-implantation binding, and the REFUTED-phenotype pattern used here for the
  vestibular and syndromic negatives; Autosomal_Dominant_Nonsyndromic_Hearing_Loss_17 for
  conformance at the module's sensory-epithelium-insult node with the reason stated.

  Naming. The entry name follows the repository's Autosomal Dominant Nonsyndromic Hearing
  Loss NN convention, which here coincides with the MONDO label, so disease_term
  preferred_term and term label are identical. That is not true of every sibling entry -
  MONDO calls several of them "hearing loss, autosomal dominant NN" - and the label is
  copied from the ontology either way.

  Module conformance. Two nodes conform to sensorineural_hair_cell_loss, and the three
  between them deliberately do not. The module runs insult to ionic disruption and
  oxidative stress to hair-cell mechanotransduction failure AND DEATH to amplification loss
  and spiral ganglion degeneration to progressive hearing loss. DFNA68's evidence
  contradicts the death step: the homozygous null mouse is profoundly deaf with a normal
  complement of inner and outer hair cells at eight weeks, and zebrafish injected with
  disease alleles lose hair-cell function with unchanged hair-cell counts. None of the six
  primary reports describes ionic homeostasis, oxidative stress, endocochlear potential or
  spiral ganglion status in this disease at all. Conforming the middle chain would assert three
  mechanisms the disease has not been shown to have and one it has been shown not to have.
  excitatory_synapse_scaffold_disruption was considered and rejected despite HOMER2 being a
  postsynaptic-density scaffold: that module scopes itself explicitly to glutamatergic
  synapse scaffolds producing neurodevelopmental phenotypes, and its node chain runs through
  excitatory-inhibitory imbalance and cortical circuit assembly, none of which is DFNA68.

  What is deliberately not curated. There is no biochemical block: none of the six primary
  reports describes a biomarker, a reference range or a laboratory analyte for this
  disorder. There are no datasets: a search for HOMER2 hearing-loss expression or sequencing datasets was not
  pursued, because none of the six primary reports deposits one and the entry would be
  guessing at accessions. There are no clinical trials: none of the six primary reports
  names one, and none names a candidate therapy to trial. There is no histopathology and no imaging block:
  temporal bone CT was performed in one proband and is reported as excluding middle- and
  inner-ear malformation rather than as showing a disease finding, and none of the six
  primary reports describes human cochlear material from a DFNA68 patient.
  There are no computational models and no experimental_models: the AlphaFold2 structure
  predictions are curated as evidence on the allele node they bear on rather than as a
  model entry, because they predict a structure rather than simulate a disease process.

  Prevalence counts. The two published tallies of HOMER2 variants differ - one says five
  variants in five families, the other says seven - and both are quoted rather than
  reconciled: they were written months apart and enumerate the variant list differently,
  and neither group reconciles its count with the other's. Neither is repeated here as a settled number, and the entry's own summary
  statement is the weaker "fewer than ten unrelated families", which both counts support.

  Evidence balance, stated rather than smoothed. The clinical picture rests on six
  pedigrees plus one isolated patient. The mechanism rests on mouse immunolocalisation,
  a mouse null, cell-line expression of two truncating alleles, zebrafish mRNA injection
  assays, one structure prediction, and a CDC42 conditional knockout mouse that does not
  involve HOMER2 at all. Across the nine PubMed records swept for this entry there is no
  knock-in model of any human allele, no binding measurement for any disease allele, and no
  human cochlear tissue. Every node below the
  gene is graded accordingly, the CDC42 conditional knockout is marked INDIRECT everywhere
  it is used because the gene removed is not the disease gene, and the two nodes whose
  mechanism is proposed rather than demonstrated carry mechanism_confidence PROVISIONAL and
  HYPOTHETICAL respectively.

  Sourcing. The entry was written from a direct PubMed sweep, not from a deep-research
  report. Searching HOMER2 against hearing and deafness returns nine records, of which six
  are the primary DFNA68 reports; the supporting mechanistic papers were selected from the
  founding paper's own discussion of its two hypotheses. Ten of the eleven cited references
  were fetched into references_cache with just fetch-reference for this entry; the
  eleventh, PMID:37371710, was already cached from an earlier hearing-loss entry. Every
  snippet was taken from the cached text.

  Deep research, and what it is and is not worth here. A provider run was added after the
  entry was complete, at review, as a cross-check rather than as a source:
  research/Autosomal_Dominant_Nonsyndromic_Hearing_Loss_68-deep-research-claude_code.md.
  It is clean on its own terms - just preflight-dr against MONDO:0014740 returns PASS with
  HOMER2 mentioned 43 times and the OMIM number matching on both sides, 15 of 15 references
  resolved with a confabulation rate of 0.0, and 27 of 28 terms resolved with none obsolete
  and none naming a different term than the report claims.

  It is nonetheless not independent corroboration, and should not be read as any. The
  report says in its own first line that it used the curated dismech entry on this branch
  as a local resource, so where it agrees with this entry it is substantially restating it.
  Nothing was imported from it. It surfaced a few identifiers this entry does not carry - a
  group-level ORPHA concept, an LOVD disease number, an ICD-10 code at the DFNA group level
  rather than for DFNA68, and a DFNA2/KCNQ4 differential - and those were left out rather
  than added, because a deep-research suggestion is a lead and none of them was separately
  verified. The four terms its own term-validation section flags as worth a second look are
  the report's prose headings for the four HP terms this entry already binds, each with the
  canonical label; none is a binding disagreement.

  The claude_code provider emits no artifacts directory, so the run is committed as the
  report plus its .citations.md sidecar and the two DOI reference-cache files its citation
  resolution fetched. Those two DOIs are alternative identifiers for papers this entry
  already cites by PMID; no evidence item uses them.

  GeneReviews baseline. No GeneReviews chapter is specific to DFNA68 or to HOMER2. The
  committed cache/bookshelf/ index (958 GeneReviews chapters, snapshot 2026-09-10) contains
  no chapter whose title names either, and the general chapter for this disease class,
  "Genetic Hearing Loss Overview" (NBK1434, PMID:20301607), contains no occurrence of
  HOMER2 or DFNA68 in its text. That chapter is an overview rather than a locus catalogue -
  DFNA3 is the only numbered DFNA locus it names at all - so its silence is consistent with
  DFNA68 being too rare to have entered it rather than with the entity being disputed. The
  phenotype baseline for this entry is therefore the six primary reports themselves.

  The overview chapter is tagged in references: above because this entry consulted it, and
  because it is what the baseline check matches on. just check-genereviews on this file
  reports GeneReviews TAGGED, and --strict exits 0. Read TAGGED as "the chapter this entry
  cites is a GeneReviews chapter and is declared as one", not as "DFNA68 has its own
  chapter" - it does not, which is the finding the paragraph above records.

  An earlier version of this paragraph claimed the check reported NO_CHAPTER. That was
  wrong when it was written, not drift: naming NBK1434 in this very paragraph made the
  checker report CITED_UNTAGGED, because a chapter cited in an entry but absent from
  references: is exactly what that verdict is for. The claim was offered as re-runnable and
  did not re-run, which is the failure mode CLAUDE.md warns about when prose describes
  repository state. Corrected after review (PR #12287).

  Unconnected phenotype. Tinnitus is curated and deliberately left out of the causal graph.
  None of the six primary reports proposes a mechanism for it, and the entry's hair-cell
  nodes were not built to explain it; the reason is stated in the phenotype's own description
  rather than only here. The two REFUTED phenotypes are unconnected by construction, since
  a negative finding has no upstream cause to point at.

📚

References & Deep Research

References

12

PMID:25816005

HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice.

No top-level findings curated for this source.

PMID:30047143

Whole exome sequencing identified a second pathogenic variant in HOMER2 for autosomal dominant non-syndromic deafness.

No top-level findings curated for this source.

PMID:33809266

A Novel Truncating Mutation in HOMER2 Causes Nonsyndromic Progressive DFNA68 Hearing Loss in a Spanish Family.

No top-level findings curated for this source.

PMID:37173411

Identification and in vivo functional investigation of a HOMER2 nonstop variant causing hearing loss.

No top-level findings curated for this source.

PMID:40515814

Impact of HOMER2 frameshift extension variant on auditory function and development.

No top-level findings curated for this source.

PMID:41351289

A Novel Frameshift Variant c.1023_1029del (p.Asp342ArgfsTer54) Leading to Extended Incorrect Protein C Termini in HOMER2 Causing Autosomal Dominant Nonsyndromic Hearing Loss.

No top-level findings curated for this source.

PMID:24610943

Maintenance of stereocilia and apical junctional complexes by Cdc42 in cochlear hair cells.

No top-level findings curated for this source.

PMID:25049230

Homer2 protein regulates plasma membrane Ca²⁺-ATPase-mediated Ca²⁺ signaling in mouse parotid gland acinar cells.

No top-level findings curated for this source.

PMID:19309525

Interaction of Cupidin/Homer2 with two actin cytoskeletal regulators, Cdc42 small GTPase and Drebrin, in dendritic spines.

No top-level findings curated for this source.

PMID:16914674

Tetrameric hub structure of postsynaptic scaffolding protein homer.

No top-level findings curated for this source.

PMID:37371710

Autosomal Dominant Non-Syndromic Hearing Loss (DFNA): A Comprehensive Narrative Review.

No top-level findings curated for this source.

PMID:20301607

Genetic Hearing Loss Overview.

No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (3)

Record notes

Scope decision. Curated as a DISEASE, not a GROUPING, a SUBTYPE or OUT_OF_SCOPE. One gene, one clinical picture, one conserved pathograph from a HOMER2 allele to progressive sensorineural hearing loss, and no member diseases to unite. The OLS4 descendants endpoint returns zero descendants for MONDO:0014740, and the stub deleted by this change recorded one causal gene, hgnc:17513 HOMER2, taken from MONDO's own RO:0004003 relation. Its MONDO parent, MONDO:0019587 autosomal dominant nonsyndromic hearing loss, is an ontology grouping returning 76 descendants from the same endpoint, spanning unrelated DFNA loci, and is not a dismech entry: a search of kb/groupings/ found no hearing-loss or deafness grouping of any kind, and no disorder entry carries MONDO:0019587 as its own disease_term. The repository's established treatment of this family is one entry per DFNA locus - twelve Autosomal_Dominant_Nonsyndromic_Hearing_Loss_NN entries plus eight Hearing_Loss_Autosomal_Dominant_NN entries and sixteen recessive counterparts already exist, counted by filename on this branch's base - so an umbrella entry carrying this as a has_subtypes row would be a new pattern rather than an existing one. The stub is deleted by this change. Precedent followed. Autosomal_Recessive_Nonsyndromic_Hearing_Loss_123 (merged 2026-09-17) for the overall shape and for the discipline about what a thin literature does and does not license; Autosomal_Dominant_Nonsyndromic_Hearing_Loss_50 for the dominant-specific sections, for the practice of splitting mechanistically distinct allele classes into separate pathophysiology nodes, and for the convention on conforming only the terminal node to sensorineural_hair_cell_loss where the module's middle chain does not apply; Autosomal_Dominant_Nonsyndromic_Hearing_Loss_11 for the hearing-aid ontology gap, the cochlear-implantation binding, and the REFUTED-phenotype pattern used here for the vestibular and syndromic negatives; Autosomal_Dominant_Nonsyndromic_Hearing_Loss_17 for conformance at the module's sensory-epithelium-insult node with the reason stated. Naming. The entry name follows the repository's Autosomal Dominant Nonsyndromic Hearing Loss NN convention, which here coincides with the MONDO label, so disease_term preferred_term and term label are identical. That is not true of every sibling entry - MONDO calls several of them "hearing loss, autosomal dominant NN" - and the label is copied from the ontology either way. Module conformance. Two nodes conform to sensorineural_hair_cell_loss, and the three between them deliberately do not. The module runs insult to ionic disruption and oxidative stress to hair-cell mechanotransduction failure AND DEATH to amplification loss and spiral ganglion degeneration to progressive hearing loss. DFNA68's evidence contradicts the death step: the homozygous null mouse is profoundly deaf with a normal complement of inner and outer hair cells at eight weeks, and zebrafish injected with disease alleles lose hair-cell function with unchanged hair-cell counts. None of the six primary reports describes ionic homeostasis, oxidative stress, endocochlear potential or spiral ganglion status in this disease at all. Conforming the middle chain would assert three mechanisms the disease has not been shown to have and one it has been shown not to have. excitatory_synapse_scaffold_disruption was considered and rejected despite HOMER2 being a postsynaptic-density scaffold: that module scopes itself explicitly to glutamatergic synapse scaffolds producing neurodevelopmental phenotypes, and its node chain runs through excitatory-inhibitory imbalance and cortical circuit assembly, none of which is DFNA68. What is deliberately not curated. There is no biochemical block: none of the six primary reports describes a biomarker, a reference range or a laboratory analyte for this disorder. There are no datasets: a search for HOMER2 hearing-loss expression or sequencing datasets was not pursued, because none of the six primary reports deposits one and the entry would be guessing at accessions. There are no clinical trials: none of the six primary reports names one, and none names a candidate therapy to trial. There is no histopathology and no imaging block: temporal bone CT was performed in one proband and is reported as excluding middle- and inner-ear malformation rather than as showing a disease finding, and none of the six primary reports describes human cochlear material from a DFNA68 patient. There are no computational models and no experimental_models: the AlphaFold2 structure predictions are curated as evidence on the allele node they bear on rather than as a model entry, because they predict a structure rather than simulate a disease process. Prevalence counts. The two published tallies of HOMER2 variants differ - one says five variants in five families, the other says seven - and both are quoted rather than reconciled: they were written months apart and enumerate the variant list differently, and neither group reconciles its count with the other's. Neither is repeated here as a settled number, and the entry's own summary statement is the weaker "fewer than ten unrelated families", which both counts support. Evidence balance, stated rather than smoothed. The clinical picture rests on six pedigrees plus one isolated patient. The mechanism rests on mouse immunolocalisation, a mouse null, cell-line expression of two truncating alleles, zebrafish mRNA injection assays, one structure prediction, and a CDC42 conditional knockout mouse that does not involve HOMER2 at all. Across the nine PubMed records swept for this entry there is no knock-in model of any human allele, no binding measurement for any disease allele, and no human cochlear tissue. Every node below the gene is graded accordingly, the CDC42 conditional knockout is marked INDIRECT everywhere it is used because the gene removed is not the disease gene, and the two nodes whose mechanism is proposed rather than demonstrated carry mechanism_confidence PROVISIONAL and HYPOTHETICAL respectively. Sourcing. The entry was written from a direct PubMed sweep, not from a deep-research report. Searching HOMER2 against hearing and deafness returns nine records, of which six are the primary DFNA68 reports; the supporting mechanistic papers were selected from the founding paper's own discussion of its two hypotheses. Ten of the eleven cited references were fetched into references_cache with just fetch-reference for this entry; the eleventh, PMID:37371710, was already cached from an earlier hearing-loss entry. Every snippet was taken from the cached text. Deep research, and what it is and is not worth here. A provider run was added after the entry was complete, at review, as a cross-check rather than as a source: research/Autosomal_Dominant_Nonsyndromic_Hearing_Loss_68-deep-research-claude_code.md. It is clean on its own terms - just preflight-dr against MONDO:0014740 returns PASS with HOMER2 mentioned 43 times and the OMIM number matching on both sides, 15 of 15 references resolved with a confabulation rate of 0.0, and 27 of 28 terms resolved with none obsolete and none naming a different term than the report claims. It is nonetheless not independent corroboration, and should not be read as any. The report says in its own first line that it used the curated dismech entry on this branch as a local resource, so where it agrees with this entry it is substantially restating it. Nothing was imported from it. It surfaced a few identifiers this entry does not carry - a group-level ORPHA concept, an LOVD disease number, an ICD-10 code at the DFNA group level rather than for DFNA68, and a DFNA2/KCNQ4 differential - and those were left out rather than added, because a deep-research suggestion is a lead and none of them was separately verified. The four terms its own term-validation section flags as worth a second look are the report's prose headings for the four HP terms this entry already binds, each with the canonical label; none is a binding disagreement. The claude_code provider emits no artifacts directory, so the run is committed as the report plus its .citations.md sidecar and the two DOI reference-cache files its citation resolution fetched. Those two DOIs are alternative identifiers for papers this entry already cites by PMID; no evidence item uses them. GeneReviews baseline. No GeneReviews chapter is specific to DFNA68 or to HOMER2. The committed cache/bookshelf/ index (958 GeneReviews chapters, snapshot 2026-09-10) contains no chapter whose title names either, and the general chapter for this disease class, "Genetic Hearing Loss Overview" (NBK1434, PMID:20301607), contains no occurrence of HOMER2 or DFNA68 in its text. That chapter is an overview rather than a locus catalogue - DFNA3 is the only numbered DFNA locus it names at all - so its silence is consistent with DFNA68 being too rare to have entered it rather than with the entity being disputed. The phenotype baseline for this entry is therefore the six primary reports themselves. The overview chapter is tagged in references: above because this entry consulted it, and because it is what the baseline check matches on. just check-genereviews on this file reports GeneReviews TAGGED, and --strict exits 0. Read TAGGED as "the chapter this entry cites is a GeneReviews chapter and is declared as one", not as "DFNA68 has its own chapter" - it does not, which is the finding the paragraph above records. An earlier version of this paragraph claimed the check reported NO_CHAPTER. That was wrong when it was written, not drift: naming NBK1434 in this very paragraph made the checker report CITED_UNTAGGED, because a chapter cited in an entry but absent from references: is exactly what that verdict is for. The claim was offered as re-runnable and did not re-run, which is the failure mode CLAUDE.md warns about when prose describes repository state. Corrected after review (PR #12287). Unconnected phenotype. Tinnitus is curated and deliberately left out of the causal graph. None of the six primary reports proposes a mechanism for it, and the entry's hair-cell nodes were not built to explain it; the reason is stated in the phenotype's own description rather than only here. The two REFUTED phenotypes are unconnected by construction, since a negative finding has no upstream cause to point at.

Review round 1: correct the GeneReviews claim, tag the chapter, add a post-hoc deep-research cross-check · 2026-09-19T09:24:55Z · View source

Review round 1 on PR #12287. One blocking finding, addressed; two suggestions, both taken. BLOCKING - GeneReviews claim did not reproduce. The entry notes asserted, and offered as re-runnable, that just check-genereviews reports NO_CHAPTER. It reports CITED_UNTAGGED, and had done since the first commit: naming NBK1434 inside the notes paragraph is itself a citation of a GeneReviews chapter, and the chapter was not declared in the references: block. The reviewer is right, and the failure is the one CLAUDE.md names - prose describing repository state rots, and a verification sentence that does not re-run is worse than no sentence. Fixed with both remedies the reviewer offered, because they close different halves. PMID:20301607 'Genetic Hearing Loss Overview.' is now tagged GeneReviews in references: - it is a real GeneReviews chapter, it is the general chapter for this disease class, and this entry genuinely consulted it, so declaring it is accurate rather than bookkeeping. The verdict moves to TAGGED and --strict exits 0; just tag-references then reports no further modification needed. The notes paragraph was rewritten to state the verdict that the checker actually emits, to say explicitly that TAGGED means the cited chapter is declared and NOT that DFNA68 has its own chapter, and to record what the earlier sentence got wrong so the correction is visible rather than silent. No evidence was manufactured from the chapter: its cached record is abstract-only and contains only the chapter's purpose statement and author affiliations, with no quotable finding. SUGGESTION - node count. The prior record said pathophysiology (8 nodes); there are 9. Corrected in place. SUGGESTION - no deep-research artifact. The reviewer accepted the declination without blocking. A run was nonetheless added, after the fact, as a cross-check: research/Autosomal_Dominant_Nonsyndromic_Hearing_Loss_68-deep-research-claude_code.md with its .citations.md sidecar. Two providers were available locally (falcon, claude_code); claude_code was used. Following the ARNSHL123 precedent the entry name was temporarily set to name the gene for the duration of the query, because the numbered label does not, and restored immediately by the run script. The run is clean on its own terms - preflight-dr PASS against MONDO:0014740, HOMER2 mentioned 43 times, OMIM 616707 matching on both sides, 15/15 references resolved at confabulation rate 0.0, 27/28 terms resolved with none obsolete and none naming a different term. It is NOT independent corroboration and the entry says so: the report states in its own first line that it used the curated dismech entry on this branch as a local resource, so its agreement is substantially a restatement. Nothing was imported from it. Identifiers it surfaced that the entry does not carry - a group-level ORPHA concept, an LOVD disease number, a group-level ICD-10 code, a DFNA2/KCNQ4 differential - were deliberately left out as unverified leads. The four terms its term-validation section flags are its own prose headings for HP terms the entry already binds with canonical labels; none is a binding disagreement. The claude_code provider emits no artifacts directory, so none is committed; the two DOI cache files written by its citation resolution are committed with it and are alternative identifiers for papers already cited by PMID. DECLINED - nothing. The reviewer raised no finding against the two structural calls (no conforms_to on the three middle nodes; three separate allele-class nodes) and explicitly endorsed both in the content-completeness assessment. Validation re-run before pushing: validate, validate-terms, validate-disorders (94/94 snippets), check-genereviews (TAGGED, --strict exit 0), check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-enum-values, check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading, check-environmental-evidence, check-case-collisions, check-reference-titles, check-stubs, check-term-cache-integrity, check-cache-order, list-gene-term-mismatches, validate-history-all.

Create: Autosomal Dominant Nonsyndromic Hearing Loss 68 (DFNA68, HOMER2) · 2026-09-19T05:11:20Z · View source

De-novo curation of DFNA68 (MONDO:0014740, HOMER2) from a direct PubMed sweep; no deep-research provider run was commissioned, because the whole literature is nine records. Scope decision. Curated as a DISEASE. One gene, one clinical picture, no MONDO descendants, and no dismech umbrella entry or grouping exists for autosomal dominant nonsyndromic hearing loss to carry it as a has_subtypes row. The repository already keeps one entry per DFNA locus. Content. Eleven references fetched into references_cache (ten new, PMID:37371710 already cached from DFNA11), 94 exact-quote snippets, all verified. Sections: description, disease_term, parents, references, inheritance, pathophysiology (9 nodes), phenotypes (8, including two REFUTED absence phenotypes), prevalence, progression (4 phases), clinical_burden, genetic, diagnosis (2), treatments (3), animal_models (2 with modeled_mechanisms and readouts), discussions (3), external_assertions, notes. Mechanism. Three allele classes modelled as three separate pathophysiology nodes because the literature assigns them different functional_impact_category values: coiled-coil missense DOMINANT_NEGATIVE, CDC42-binding-domain frameshift DOMINANT_NEGATIVE, C-terminal extension GAIN_OF_FUNCTION. They converge on impaired scaffold multimerisation, loss of HOMER2-CDC42 coupling, failure of stereocilia actin maintenance, and hair-cell functional failure. The calcium-handling alternative is carried as a parallel branch with mechanism_confidence HYPOTHETICAL rather than dropped, because the founding paper left both hypotheses open and nothing has closed them. Module conformance. Two nodes conform to sensorineural_hair_cell_loss (Cochlear Sensory Epithelium Insult, Progressive Sensorineural Hearing Loss). The module's middle chain is deliberately not conformed: its central effector is apoptotic hair-cell death, and the HOMER2 models show hair-cell dysfunction with intact hair-cell populations in both mouse and zebrafish. excitatory_synapse_scaffold_disruption was considered and rejected on its own declared scope. GeneReviews baseline. No chapter is specific to DFNA68 or HOMER2, and the general Genetic Hearing Loss Overview chapter (NBK1434, PMID:20301607) contains no occurrence of HOMER2 or DFNA68 in its text. CORRECTED AT REVIEW (PR #12287): this sentence originally claimed just check-genereviews reports NO_CHAPTER. It did not, and had not at any point - naming NBK1434 in the entry notes made the checker report CITED_UNTAGGED. The chapter is now tagged in the entry's references: block and the checker reports TAGGED, with --strict exiting 0. See the review-round history record alongside this one. Validation. just validate, validate-terms, validate-disorders (94/94 snippets), check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-enum-values, list-gene-term-mismatches (8/8 bindings name HOMER2), check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading, check-environmental-evidence, check-case-collisions, check-reference-titles, check-stubs, check-term-cache-integrity, check-cache-order, model-scale-audit and prose-figure-audit all clean. list-disconnected-phenotypes reports 5 of 8 connected; the three unconnected are the two REFUTED absence phenotypes and Tinnitus, which is left unwired because no source on this disease proposes a mechanism for it. Self-audit. Every prose field was re-read against the cited sources after the entry was complete. Six claims that no cited source states were corrected, including a decade error (a patient whose onset was in her fifties described as onset in the fifth decade) and an inferred nationality for an unstated patient origin. Several absence claims were narrowed to the scope actually checked, and four evidence items were added so that claims previously carried only in prose now have verified quotes. Stub stubs/Autosomal_Dominant_Nonsyndromic_Hearing_Loss_68.yaml deleted in the same change.

Claude Code ▸

DFNA68: HOMER2-Related Autosomal Dominant Nonsyndromic Hearing Loss — Comprehensive Research Report

claude-fable-5, claude-haiku-4-5-20251001 17 citations 2026-09-19T02:14:57.619106

DFNA68: HOMER2-Related Autosomal Dominant Nonsyndromic Hearing Loss — Comprehensive Research Report

Prepared: 2026-09-19. Evidence base: the six primary DFNA68 family reports (2015–2026) plus the supporting mechanistic literature; all quoted snippets below are verified exact quotes from the cited abstracts/records.

1. Disease Information

Overview. DFNA68 is a bilateral, postlingual, progressive, nonsyndromic sensorineural hearing loss (SNHL) caused by heterozygous variants in HOMER2, which encodes a scaffolding protein of the Homer family enriched at the tips of cochlear hair cell stereocilia. Hearing is normal at birth and through early childhood; loss typically begins in the first or second decade at the high frequencies, producing a down-sloping audiogram that flattens as lower frequencies are drawn in, and deteriorates at a measured 1.2–1.6 dB/year until severe or profound. Fewer than ten unrelated families have been reported worldwide since the gene was identified in 2015 (PMID:25816005), making this one of the rarest characterized DFNA loci.

Identifiers:

Resource	Identifier
OMIM (phenotype)	#616707 — DEAFNESS, AUTOSOMAL DOMINANT 68; DFNA68
OMIM (gene)	*604799 — HOMER SCAFFOLD PROTEIN 2; HOMER2
MONDO	MONDO:0014740 (autosomal dominant nonsyndromic hearing loss 68)
HGNC	hgnc:17513 (HOMER2)
Orphanet	No dedicated ORPHA code for DFNA68; it falls under the group concept ORPHA:90635, autosomal dominant non-syndromic sensorineural deafness type DFNA
ICD-10 / ICD-11	H90.3 / AB50 (at the DFNA group level, per Orphanet)
LOVD	Disease #06261

Synonyms: DFNA68; deafness, autosomal dominant 68; autosomal dominant nonsyndromic deafness 68; HOMER2-related hearing loss.

Data provenance: All clinical information is aggregated from published family reports (pedigree/case-series literature), not EHR-derived. The entire clinical description rests on approximately six pedigrees plus one isolated patient.

Key primary literature (PMIDs): 25816005 (founding study, 2015); 30047143 (second family, Chinese, 2018); 33809266 (Spanish family, 2021); 37173411 (nonstop variant, 2023); 40515814 (frameshift extension + cochlear implant outcome, 2025); 41351289 (Chinese four-generation family, 2026).

2. Etiology

Causal factor: Purely genetic — heterozygous germline variants in HOMER2 (15q24.3; OMIM places it at 15q25). No environmental, infectious, or lifestyle cause or modifier has been reported in any DFNA68 family.

Critically, this is not a haploinsufficiency disease. Three independent lines of evidence converge: - Mice heterozygous for a Homer2 null hear normally; only the homozygous null is deaf (PMID:25816005; restated in PMID:33809266: "mice heterozygous for the targeted deletion of exon 3 in Homer2 (Homer−/+) displayed normal hearing levels"). - HOMER2 is tolerant of loss-of-function variation in population data: "Low pLI score (0.01) of HOMER2 suggests that alteration of HOMER2 exerts a pathogenic effect via a mechanism other than loss-of-function" (PMID:40515814). - The founding allele was shown experimentally to act as a dominant negative: zebrafish mutant-mRNA injection produced an ear phenotype while knockdown of the endogenous gene did not (PMID:25816005).

Risk factors: Being an obligate carrier in an affected family (50% transmission risk). No susceptibility loci, modifier genes, protective variants, or gene–environment interactions have been reported. No known environmental risk or protective factors specific to this disorder (standard noise/ototoxin avoidance advice for any progressive SNHL applies on general principles only — not disease-specific evidence).

3. Phenotypes

The phenotype is essentially monosymptomatic. Suggested HPO annotations with frequencies (frequencies reflect the small reported family set, not measured cohort proportions):

Phenotype	HPO term	Frequency	Characteristics
Progressive sensorineural hearing impairment	HP:0000408	Obligate	Defining feature; bone conduction excluded conductive loss; reaches severe/profound
Postlingual onset	HP:0008596	Obligate	Normal speech acquisition; onset 1st–2nd decade typically, 17–24 years in one family, 50s in one patient
Bilateral involvement	HP:0008619	Obligate	Binaural symmetry verified in the founding family
High-frequency-onset, down-sloping loss	HP:0001757	Very frequent	Characteristic audiogram; flattens with progression
Low-frequency (ascending) loss at presentation	HP:0008573	Very rare	One proband (18 y); authors read it as a stage effect: "the different forms of auditory configuration may present different stages of the disease" (PMID:41351289)
Tinnitus	HP:0000360	Occasional	Present in some members of two families, explicitly absent in two others (PMID:33809266, PMID:41351289)

Key supporting quotes: "Hearing impairment had a typical onset in the first decade of life in the high frequencies, with significant subsequent progression of hearing loss over all frequencies" and "The resulting annual threshold deterioration (ATD) was 1.2 to 1.6 dB per year" (PMID:25816005).

Substantive negatives (actively tested, not just unreported): - No vestibular dysfunction: "Tandem gait and Romberg tests did not reveal any symptoms of vestibular dysfunction in all family members" (PMID:41351289). - No syndromic features: "Clinical examination was negative for any findings consistent with syndromic hearing loss and also ruled out autoimmune phenotypes" (PMID:25816005). Intelligence and speech normal (PMID:41351289).

Quality of life: Documented at the severe end: one patient reached 8% bilateral speech discrimination ten years after significant progression began, requiring cochlear implantation (PMID:40515814). No formal QoL instrument (EQ-5D/SF-36) data exist for this disorder.

4. Genetic/Molecular Information

Gene: HOMER2 (hgnc:17513; OMIM 604799), chromosome 15q24.3, nine exons, two transcripts encoding 343-residue (NM_004839) and 354-residue (NM_199330) isoforms. Nomenclature trap:* both numbering systems appear in the literature for the same variants — the founding missense is p.Arg185Pro (isoform 1) and p.Arg196Pro (isoform 2); these are one allele, not two.

Protein architecture: N-terminal EVH1 domain (binds proline-rich motifs) + C-terminal coiled-coil (CC) domain that (a) drives tetramerization and (b) carries the CDC42-binding domain (CBD, ~residues 191–283; mapped in neurons, PMID:19309525).

Reported pathogenic variants — three mechanistic classes (all germline, heterozygous; ~6–7 variants in fewer than ten families; the two published tallies — "five variants" in PMID:41351289 vs "seventh variant" in PMID:40515814 — disagree by one and were never reconciled):

Coiled-coil missense (dominant negative): c.554G>C, p.Arg185Pro/p.Arg196Pro (European kindred, PMID:25816005). "These results show that HOMER2 plays an essential role in the normal development and/or maintenance of hair cells in the zebrafish inner ear and that the p.Arg185Pro mutation has a dominant-negative effect on this process."
Frameshift truncations within the CDC42-binding domain (dominant negative / possible GoF): c.840_841insC (Chinese, PMID:30047143) and a five-base deletion producing p.Pro278Alafs*10 (Spanish, PMID:33809266). The truncated product shows "decreased protein stability, reduced ability to multimerize, and altered distribution pattern in transfected cells." The Spanish authors explicitly leave open whether the mechanism is "a gain-of-function of the Ct aberrant tail or ... a dominant-negative mechanism."
C-terminal extension variants (argued gain-of-function): nonstop c.1064A>G converting the stop codon to tryptophan (+10 residues; transcripts escape nonstop decay, PMID:37173411); c.1033delC p.Arg345Glufs*64 (+~64 residues; PMID:40515814 — "Our findings reveal a solid pathogenic gain-of-function effect related to the long extension to the C-terminal of HOMER2"); c.1023_1029del p.Asp342ArgfsTer54 (PMID:41351289). AlphaFold2 predicts the longest extension disrupts the distant EVH1 domain and its Cdc42 interface while preserving multimerization (computational, not measured).

Population frequency: Disease alleles are absent/ultra-rare in population databases; the gene itself tolerates LoF (pLI 0.01), which is the population-genetic argument against haploinsufficiency.

Modifiers, epigenetics, chromosomal abnormalities: None reported. No recessive HOMER2 patient has been reported, despite the founding authors' prediction: "The recessive phenotype exhibited by null alleles of Homer2 makes it a strong candidate for autosomal recessive hearing loss due to loss of function in humans as well" (PMID:25816005) — still open a decade later.

5. Environmental Information

Not applicable. No environmental, lifestyle, or infectious contributor has been reported in any DFNA68 family. This is a fully penetrant-appearing Mendelian mechanosensory disorder as described (though formal penetrance quantification is lacking — see §9).

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinic):

A heterozygous HOMER2 variant (missense in the coiled coil, frameshift truncation in the CDC42-binding domain, or C-terminal extension) produces a mutant scaffold protein that is expressed, not eliminated (NMD escape shown/inferred for the extension and truncation classes).
The mutant protein interferes with wild-type HOMER2 — impairing tetramer assembly for the missense/truncation classes (demonstrated in vitro for the truncation: reduced multimerization, instability, mislocalization), or adding an aberrant C-terminal tail (extension class; gain-of-function argued from a designed zebrafish truncation-vs-extension comparison). This step is why the disease is dominant despite a phenotype-free null heterozygote.
Defective scaffold hubs lead to disrupted HOMER2–CDC42 coupling at the stereocilia (the CBD sits inside the coiled coil; for the extension class, the route is a predicted EVH1 conformational change) — inferred, not demonstrated: no binding assay exists for any disease allele, and no HOMER2–CDC42 complex has been shown in a cochlear hair cell.
Branch (alternative/parallel hypothesis): impaired scaffolding leads to dysregulated hair-cell calcium handling via Homer's regulation of PMCA pumps and TRPC channels — hypothetical: the one real measurement is in mouse parotid gland (PMID:25049230), PMCA2 being "the only system for clearance of Ca2+ from hair cell stereocilia" is what makes it attractive (PMID:25816005), and the established Homer2 TRPC partner (TRPC1) is not the TRPC3/TRPC6 hair cells use. The founding paper named both hypotheses and "further functional studies are needed" — nothing since has closed them.
Loss of CDC42-tuned actin turnover results in failure of stereocilia maintenance — bundles form normally, then deteriorate. Inferred by analogy: hair-cell-specific Cdc42 knockout mice show exactly this: "Hair cells of Atoh1-Cre;Cdc42(flox/flox) mice developed normally but progressively degenerated after maturation, resulting in progressive hearing loss particularly at high frequencies", beginning as "stereocilia fusion and depletion" (PMID:24610943). No stereocilia morphology has been reported for any HOMER2 patient or model.
Bundle failure results in hair-cell functional failure without hair-cell death — the mechanistically distinctive claim, and the step the models actually establish: the homozygous null mouse is profoundly deaf with a full complement of inner and outer hair cells at 8 weeks ("No differences in IHCs and OHCs were observed in any animals regardless of genotype", PMID:25816005), and zebrafish injected with disease alleles show "severely impaired ... capacity of neuromast hair cells to uptake FM1-43" with "no significant differences in hair cell numbers" (PMID:40515814).
Failed mechanotransduction leads to progressive bilateral sensorineural hearing loss, postlingual, high-frequency-first, at 1.2–1.6 dB/year — the clinical endpoint.

Ontology suggestions: GO:0097110 scaffold protein binding; GO:0051289 protein homotetramerization; GO:0031267 small GTPase binding; GO:0030036 actin cytoskeleton organization; GO:0060088 auditory receptor cell stereocilium organization; GO:0051480 regulation of cytosolic calcium ion concentration; GO:0050910 detection of mechanical stimulus involved in sensory perception of sound; GO:0007605 sensory perception of sound; cellular components GO:0032420 stereocilium, GO:0032426 stereocilium tip; cell types CL:0000589 cochlear inner hair cell, CL:0000601 cochlear outer hair cell.

No molecular profiling (transcriptomics, proteomics, metabolomics, single-cell) has been published for this disorder specifically.

7. Anatomical Structures Affected

Organ: inner ear / cochlea only (UBERON:0001846 internal ear; UBERON:0001844 cochlea; UBERON:0002227 organ of Corti). No secondary organ involvement in any patient (a zebrafish cardiac signal for the longest extension allele is an open question — the patient carrying it had no cardiac abnormality; see §11/§15).
Cells: cochlear inner and outer hair cells (CL:0000589, CL:0000601). Mouse Homer2 expression is "particularly enriched in the tips of stereocilia of both IHCs and OHCs" (PMID:25816005).
Subcellular: stereocilium and stereocilium tip (GO:0032420, GO:0032426); the actin core and apical junctional actin belt (by CDC42-model analogy).
Lateralization: bilateral, symmetric.

8. Temporal Development

Presymptomatic phase: normal hearing through infancy; passes newborn hearing screening; carriers identified genetically before audiometrically.
Onset: postlingual, typically first–second decade; 17–24 years in the most recent Chinese family; one patient's significant progression began in her 50s. Insidious.
Progression: relentlessly progressive, non-episodic, lifelong; 1.2–1.6 dB/year across frequencies (founding family, threshold-on-age regression). Audiometric configuration is stage-dependent: high-frequency down-sloping early (or, rarely, low-frequency ascending), flattening to all-frequency involvement, ending severe-to-profound.
No remission is described; no critical intervention window beyond ordinary timing of amplification/implantation.

9. Inheritance and Population

Inheritance: autosomal dominant (HP:0000006), segregating across up to five generations. Every reported allele is heterozygous; no homozygote or compound heterozygote described.
Penetrance/expressivity: appears complete in reported pedigrees but is formally unquantified (age-dependent onset means young carriers look unaffected). Expressivity is variable mainly in onset age and audiogram configuration. No anticipation, germline mosaicism, founder effect, or consanguinity role reported.
Epidemiology: no prevalence or incidence estimate exists; "Hearing loss caused by HOMER2 mutations is an extremely rare disorder" (PMID:33809266). Ultra-rare; countable in families: European, Chinese (×2), Spanish, Sicilian, Italian origins plus one isolated patient. No sex bias apparent in the pedigrees. For context, dominant nonsyndromic hearing loss overall involves ~50 genes at ~67 loci (PMID:33809266, citing the field count).

10. Diagnostics

Route to diagnosis is molecular, not clinical. There is no biomarker, no biochemical test, and no audiometric pattern specific enough to distinguish DFNA68 from the ~50 other DFNA genes. Every family was diagnosed by comprehensive hearing-loss gene panel or whole-exome sequencing followed by Sanger co-segregation. "Our study also highlights the importance of using NGS-based diagnostic methods to identify mutations in low-prevalence deafness genes like HOMER2" (PMID:33809266). The practical issue is panel content: HOMER2 must be on the ordered panel to be found.
Audiology: pure-tone audiometry with bone conduction (excludes conductive loss) and serial follow-up — a single audiogram describes a stage, not the disorder; the deterioration rate requires threshold-on-age regression. ABR and speech discrimination scoring at the severe end.
Imaging: the one temporal-bone CT reported was normal — "CT scans of the proband ruled out middle- and inner-ear malformations" (PMID:41351289). Imaging excludes alternatives rather than making the diagnosis.
Differential: other DFNA loci (notably other progressive high-frequency forms such as DFNA2/KCNQ4), excluded syndromic mimics (vestibular testing and syndromic examination were normal — see §3).
Screening: newborn hearing screening does not detect DFNA68 (postlingual onset). Cascade genetic testing of at-risk relatives is the applicable screening mode.
No GeneReviews chapter exists for DFNA68 or HOMER2 (verified against the full GeneReviews index, snapshot 2026-09-10).

11. Outcome/Prognosis

Survival: normal; no mortality or systemic morbidity attributable to the disorder.
Functional trajectory: progressive to severe/profound deafness in an adult who acquired speech normally. Best-documented endpoint: "Ten years after the onset of significant SNHL, SB1190-1923 had developed profound deafness with a speech discrimination score of only 8%" (PMID:40515814).
Prognostic factors: allele class may modulate onset/severity (the longest extension allele was argued to be more severe than a matched artificial truncation in zebrafish), but human genotype–phenotype correlation is not established across so few families. The measured 1.2–1.6 dB/year rate is the single quantitative prognostic anchor.
Recovery potential: hearing does not recover; cochlear implantation restores speech recognition (below).
Open cardiac question: zebrafish overexpressing the longest extension allele showed increased cardiac anomalies ("a possible link to cardiac anomalies", PMID:40515814); no cardiac feature has been described in any DFNA68 patient, so this remains an unconfirmed model-system signal, not a prognosis item.

12. Treatment

No disease-modifying, gene-directed, or pharmacological therapy exists or is in trials; no HOMER2-directed agent and no NCT identifier appears in any primary report. Management is device-based and supportive:

Hearing aids (first line while thresholds permit; NCIT note: hearing-aid fitting has no NCIT clinical-action term; NCIT:C183182 is the device concept). The disorder-specific point is commitment to repeated audiological review given measurable annual progression: "A long audiological follow-up is of paramount importance to identify hearing threshold deteriorations early and ensure prompt treatment with hearing aids or cochlear implants" (DFNA class-level review, PMID:37371710).
Cochlear implantation (NCIT:C15329 Surgical Procedure + device NCIT:C157820 Cochlear Implant) once amplification fails. DFNA68 has one published genotype-confirmed outcome: a patient in her 60s with 8% speech discrimination implanted, with "speech recognition improves significantly at 3- and 6-months post-implantation across various syllable and sentence conditions" (PMID:40515814). Mechanistically favorable: the lesion is hair-cell-level and non-degenerative (hair cells and, presumably, spiral ganglion neurons preserved), upstream of what the implant stimulates.
Genetic counselling and cascade testing (NCIT:C15240 Genetic Counseling): 50% transmission risk; a normal audiogram in a young relative is uninformative (onset can be delayed to the late teens/twenties or beyond); the molecular diagnosis mainly buys a predicted trajectory, since it selects no therapy.

Pharmacogenomics, gene therapy, ASO/RNA therapy: none exists for DFNA68. (The dominant-negative/gain-of-function allele biology would make allele-selective knockdown a rational future strategy — as pursued in other DFNA genes — but no such program has been reported for HOMER2; this is an inference, not a published claim.)

13. Prevention

Primary prevention: none possible (germline genetic).
Secondary: cascade genetic testing in known families; serial audiometry in carriers to time amplification. Newborn hearing screening does not capture it.
Tertiary: timely re-fitting of amplification and timely implant referral to limit auditory deprivation.
Reproductive options: standard for an AD condition (prenatal/preimplantation testing where a familial variant is known) — general genetic-counselling practice; no DFNA68-specific guideline exists.

14. Other Species / Natural Disease

No naturally occurring HOMER2-associated deafness has been reported in companion animals or wildlife (no OMIA phenotype record identified). Orthologs are conserved across vertebrates — mouse Homer2 (MGI) and zebrafish homer2 (~67% identity to human protein) are the studied orthologs. Not zoonotic; not applicable.

15. Model Organisms

Model	System	Key result	Limitation
Homer2 constitutive knockout mouse (PMID:25816005)	Homozygous and heterozygous null	Homozygotes: "early-onset rapidly progressive hearing loss" from ~2 weeks, profound by 8 weeks, high-frequency-first — with a normal complement of hair cells. Heterozygotes hear normally.	Models absence of the protein; every human allele is something other than absence. Hair-cell count made at 8 weeks cannot exclude late loss.
Zebrafish mutant-mRNA overexpression (PMIDs 25816005, 37173411, 40515814)	Human mutant HOMER2 mRNA injected into wild-type embryos	Founding allele: smaller otic vesicles, fewer kinocilia vs wild-type mRNA — while endogenous knockdown changed nothing → dominant-negative assay. Extension alleles: reduced FM1-43 uptake with unchanged hair-cell numbers; startle-reflex deficits ("both variants reduced distance and increased latency").	Supraphysiological, transient expression; lateral-line neuromasts, no cochlea, no endocochlear potential.
Cdc42 conditional knockout mouse (PMID:24610943)	Atoh1-Cre hair-cell deletion	Stereocilia fusion/depletion after normal development; progressive high-frequency loss resembling the human course.	Removes CDC42, not HOMER2 — tests only the downstream half of the proposed chain.

The central model gap: no system carries a single copy of a human DFNA68 allele expressed at its own level in a mammalian cochlea. A heterozygous knock-in allelic series (missense, CBD-frameshift, extension) with ABR/DPOAE follow-up, SEM bundle morphology, and late hair-cell counts is the experiment that would convert the dominant-negative and gain-of-function classifications from inference to measurement — and settle whether hair cells truly survive decades of the lesion.

Key open questions (for knowledge-base gap tracking)

Actin vs. calcium: does HOMER2 act in hair cells through CDC42/actin, through PMCA2/TRPC calcium handling, or both? Proposed in 2015, still untested; no binding assay for any disease allele, no HOMER2 partner mapping in cochlear tissue.
No model of the human genotype (above).
Cardiac signal of the extension allele: zebrafish-only; echocardiography of existing carrier cohorts would resolve it.
Recessive HOMER2 hearing loss: predicted from the mouse null in 2015, never observed.

Sources

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	15
Resolved	15
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	15
On topic	13
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	28
Resolved	27
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	1
Terms whose name was checked	8
Terms named correctly	4
Terms named as a different term	0
Terms whose name is worth a second look	4

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

HP:0008596 (1 mention) - the report calls it "Postlingual onset"; HP calls it Postlingual sensorineural hearing impairment
HP:0008619 (1 mention) - the report calls it "Bilateral involvement"; HP calls it Bilateral sensorineural hearing impairment, and lists "Bilateral nerve deafness" among its other names
HP:0001757 (1 mention) - the report calls it "High-frequency-onset, down-sloping loss"; HP calls it High-frequency sensorineural hearing impairment
HP:0008573 (1 mention) - the report calls it "Low-frequency (ascending) loss at presentation"; HP calls it Low-frequency sensorineural hearing impairment, and lists "Low-frequency sensorineural hearing loss" among its other names

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.

27 of 28 terms resolved to a current term; the rest could not be looked up either way.

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Pathophysiology

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Diagnosis

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Animal Models

Source YAML

References & Deep Research

References

Deep Research

DFNA68: HOMER2-Related Autosomal Dominant Nonsyndromic Hearing Loss — Comprehensive Research Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Key open questions (for knowledge-base gap tracking)

Sources

Reference Validation

Term Validation

Terms whose name is worth a second look

Prefixes with no resolver