Hearing Loss Autosomal Dominant 75

Mendelian MONDO:0032911 Pathograph 11 Show in embeddings browser Autosomal Dominant Nonsyndromic Hearing Loss

DFNA75 is autosomal dominant nonsyndromic sensorineural hearing loss attributed to heterozygous missense variants in TRRAP, the scaffolding subunit that recruits histone acetyltransferase complexes to chromatin. High frequencies are affected first and the loss extends downward over years, giving a ski-slope audiogram; onset has been reported both post-lingually in adulthood and in mid-childhood, and progression is slow. The entry is built on two families and should be read that way. The gene was proposed in 2019 from a single three-generation Chinese pedigree carrying p.Arg171Cys, supported by zebrafish knockdown and knockout showing inner ear defects; a Hungarian mother and daughter carrying p.Lys1787Arg were reported in 2025 as the second family, and the authors of that report classified their own variant as a variant of uncertain significance under ACMG rules. Five DFNA75 alleles are described in total. That is a thin gene-disease relationship by the standards of most entries in this knowledge base, and nothing here should be read as settled. The mechanistic claim is thinner still, and the entry separates it deliberately. What is observed is a hair cell and stereocilia deficit in trrap-depleted zebrafish and a cochlear-pattern audiogram in humans. What is inferred is everything in between: that the human missense alleles act by impairing TRRAP-dependent recruitment of the SAGA and NuA4/TIP60 acetyltransferase complexes, and that the resulting transcriptional change is what the cochlea cannot tolerate. The second report states that inference explicitly as an assumption requiring further study, so it is carried here as a labelled mechanistic hypothesis rather than as a curated causal chain. TRRAP also causes a syndromic neurodevelopmental disorder with autism and intellectual disability, from a separate and much larger allele series. No deafness family has been reported with the neurodevelopmental phenotype and no neurodevelopmental cohort has been reported with this audiogram. Why one gene splits this way is unresolved and is recorded as a knowledge gap rather than smoothed over.

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1
Inheritance
5
Pathophys.
5
Phenotypes
1
Hypotheses
3
Gaps
11
Pathograph
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Genes
1
Medical Actions
1
Models
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References
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Deep Research
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Inheritance

1
Autosomal dominant HP:0000006
Heterozygous TRRAP missense and frameshift alleles segregating with hearing loss in two reported families. In the Chinese pedigree the variant co-segregated across three generations; in the Hungarian family it was present in the affected mother and daughter and in none of the three unaffected relatives tested. No homozygote and no biallelic case has been reported. For counselling, an affected parent has a 50 percent chance of transmitting the variant to each child. That figure is the arithmetic of autosomal dominant transmission rather than an observation about DFNA75, and is stated here without an evidence item for that reason: neither reported paper gives a recurrence risk, and the GeneReviews hearing loss overview cached for this entry carries only a statement of the chapter's purpose. What is genuinely unknown for this disorder is penetrance, which two pedigrees cannot establish and which would modify that 50 percent in practice.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:31231791 SUPPORT Human Clinical
"Whole-exome sequencing, bioinformatic analysis, and Sanger sequencing were used to verify the co-segregation of a novel pathogenic variant"
The co-segregation analysis in the founding pedigree, which is what establishes the dominant mode of inheritance for this phenotype.
PMID:40004049 SUPPORT Human Clinical
"It is present in a heterozygous form in the affected mother and daughter but not carried by any unaffected family members."
Independent replication of dominant segregation in a second family, with unaffected relatives shown to be non-carriers.
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Mechanistic Hypotheses

1
Impaired HAT complex recruitment as the DFNA75 mechanism
hat_complex_recruitment_model EMERGING
Evidence balance 1 support
The proposed mechanism is that DFNA75 missense alleles degrade TRRAP's function as the scaffold that recruits SAGA and NuA4/TIP60 histone acetyltransferase complexes to chromatin, and that the cochlea is unusually sensitive to the resulting transcriptional change. The model is coherent and is what both reporting groups propose, but no step of it has been measured for a DFNA75 allele: nobody has shown reduced complex recruitment, reduced histone acetylation, or an altered cochlear transcriptional program for any of the five variants. The supporting observations are TRRAP's established biochemical role and the localisation of most DFNA75 alleles to the Tra1 HEAT repeat domains that mediate those interactions.
Pathograph links
Heterozygous TRRAP Missense Variants in the Tra1 HEAT Repeat Domains -> Reduced Recruitment of SAGA and NuA4 Histone Acetyltransferase Complexes to Chromatin UNKNOWN Inferred from the position of the alleles within the protein-interaction HEAT repeat domains and from TRRAP's known scaffolding role. Not measured for any DFNA75 allele.
Reduced Recruitment of SAGA and NuA4 Histone Acetyltransferase Complexes to Chromatin -> Disrupted Transcriptional Program in the Developing Inner Ear UNKNOWN
Disrupted Transcriptional Program in the Developing Inner Ear -> Cochlear Hair Cell Deficit and Stereocilia Abnormality UNKNOWN
Cochlear Hair Cell Deficit and Stereocilia Abnormality -> Progressive High-Frequency Cochlear Hearing Loss UNKNOWN
Show evidence (1 reference)
PMID:40004049 SUPPORT Human Clinical
"We assume that similarly to this, the novel variant may also affect this function. Further studies are needed to examine this putative mechanism and other unidentified mechanism(s), which may also explain how the ADNSHL-causing variants of the TRRAP gene contribute to disease development."
The reporting authors state the recruitment model as an assumption requiring further study, which is why it is curated as an EMERGING hypothesis rather than as an established mechanism.
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Discussions and Knowledge Gaps

3
TRRAP causes both DFNA75 and a syndromic neurodevelopmental disorder with autism and intellectual disability. No DFNA75 family has been reported with the neurodevelopmental phenotype and no neurodevelopmental cohort has been reported with the DFNA75 audiogram. What distinguishes an allele that gives isolated deafness from one that gives a multi-system developmental syndrome?
KNOWLEDGE GAP trrap_deafness_versus_neurodevelopmental_allele_series
Attached to
pathophysiology#Heterozygous TRRAP Missense Variants in the Tra1 HEAT Repeat Domains genetic#TRRAP
The neurodevelopmental series is much better powered: 17 distinct de novo variants in 24 individuals from an international collaboration, with an internal genotype-phenotype correlation splitting those 24 into two clinical spectra by variant position. The deafness series is five variants from two families plus a sporadic screen. So the asymmetry in what has been reported may simply reflect the asymmetry in how hard anyone has looked, and the honest reading is that the two phenotypes have never been systematically sought in each other's cohorts. Two things would settle it cheaply and neither has been done. Audiometry in the published TRRAP neurodevelopmental cohort would say whether the deafness allele series is genuinely distinct or whether high-frequency loss is simply unmeasured in patients ascertained for developmental delay. Developmental assessment in the deafness families would say the converse. Until then, the domain-clustering argument, that DFNA75 alleles sit in the Tra1 HEAT repeat regions, is the only thing separating the two, and one of the five DFNA75 alleles does not sit in any annotated domain at all. This matters for counselling, not just for the model. A family told that their TRRAP variant causes isolated deafness is being given a prognosis that rests on two published pedigrees.
Show evidence (4 references)
PMID:40004049 SUPPORT Human Clinical
"In humans, two rare diseases with autosomal dominant inheritance have been associated with TRRAP: the ADNSHL (OMIM 618778) and the developmental delay with or without dysmorphic facies and autism (OMIM 618454)."
The two-phenotype situation stated in the DFNA75 literature.
PMID:30827496 SUPPORT Human Clinical
"Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals."
The size of the neurodevelopmental series, which is the asymmetry the gap turns on.
PMID:30827496 SUPPORT Human Clinical
"A strong genotype-phenotype correlation was observed with two distinct clinical spectra."
That the neurodevelopmental series itself already splits by variant position, which is the precedent for expecting position to matter for the deafness alleles too.
+ 1 more reference
How strong is the TRRAP-DFNA75 gene-disease relationship? Two families, five alleles, one zebrafish depletion experiment, and the second reporting group classified its own variant as a variant of uncertain significance.
KNOWLEDGE GAP dfna75_gene_disease_validity
Attached to
genetic#TRRAP mechanistic_hypotheses#hat_complex_recruitment_model
Every claim in this entry inherits the strength of this relationship, so it is recorded explicitly rather than left for a reader to reconstruct from the citation count. What supports it: co-segregation across three generations in the founding pedigree, an independent second family in a different population with segregation in the affected pair and absence in three unaffected relatives, and a functional experiment showing the gene is required for hair cell development. What weakens it: the Hungarian variant is formally a VUS under ACMG rules, and its in silico predictions are split, with SIFT, MutationTaster and CADD suggesting a damaging effect while PolyPhen-2, EVE, REVEL and AlphaMissense suggest benign. The three additional alleles from the founding report came from a screen of 66 sporadic cases with no segregation data. No functional assay has been run on any DFNA75 allele. And the zebrafish experiment tests gene requirement, not allele effect. There is a structural reason the obvious next experiment has not been done, and it is worth recording because it changes what "no mouse model" means here. Germline deletion of Trrap is embryonically lethal in the mouse, so a straightforward knockout cannot be audiometrically phenotyped at all; the mouse work that exists on this gene is conditional, in B cells and in adult neural stem cells, neither of which reports on hearing. A DFNA75 mouse would have to be a cochlea-conditional knock-in of a specific human allele. That is a real experiment rather than an unasked question, and its absence is not evidence against the gene. There is no ClinGen Gene-Disease Validity assertion for TRRAP and hearing loss to cite, which is why this is recorded as prose here rather than as a CGGV evidence item. A ClinGen curation would be the single most useful external addition to this entry.
Show evidence (4 references)
PMID:40004049 SUPPORT Human Clinical
"Based on the ACMG variant classification guideline, this variant is classified as a VUS."
The reporting authors' own classification of the allele in the second family, which is the clearest single statement of how provisional this relationship remains.
PMID:40004049 SUPPORT Human Clinical
"This is the second study confirming an association between TRRAP and ADNSHL."
The total size of the replicated evidence base, in the authors' own words.
PMID:24675885 SUPPORT Model Organism
"Targeted-deletion of the Trrap gene led to early embryonic lethality and revealed a critical function of TRRAP in cell proliferation."
Why no straightforward Trrap knockout mouse can be tested for hearing loss, which is the reason the gene-disease relationship has no mammalian in vivo support rather than an indication that nobody tried.
+ 1 more reference
Is the DFNA75 lesion in the cochlear hair cells, in the spiral ganglion, or both? The otoacoustic emission data say outer hair cell, but that is one family and the reporting authors declined to exclude a retrocochlear component.
KNOWLEDGE GAP dfna75_cochlear_versus_retrocochlear_localisation
Attached to
pathophysiology#Progressive High-Frequency Cochlear Hearing Loss pathophysiology#Cochlear Hair Cell Deficit and Stereocilia Abnormality
The question is not academic for this gene. TRRAP is a general chromatin scaffold expressed everywhere, so nothing about the gene predicts which cochlear cell type it acts in, and the zebrafish evidence points at hair cells only because hair cells are what the lateral line assay measures. If the spiral ganglion were also involved, the fish experiment would not have detected it. The single relevant human measurement is the absent DPOAE in the Hungarian mother and nearly absent DPOAE in the daughter, which does indicate outer hair cell dysfunction. Against that, the authors note that distinguishing cochlear from retrocochlear origin at this severity requires more than audiometry, and their MRI was normal without resolving the question. Auditory brainstem response morphology in more affected individuals, or electrocochleography, would separate the possibilities.
Show evidence (1 reference)
PMID:40004049 SUPPORT Human Clinical
"Due to the severe grade of high-frequency sensorineural hearing impairment in the 2-4 kHz range, a differential diagnosis between the cochlear vs. retrocochlear origin requires more complex diagnostic procedures, such as MRI."
The authors' statement that the localisation is not settled by audiometry alone, which is the substance of this gap.
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Pathophysiology

5
Heterozygous TRRAP Missense Variants in the Tra1 HEAT Repeat Domains
Five DFNA75 alleles are reported: p.Arg171Cys, p.Asp394Asn and p.Pro509fs, all in the Tra1 HEAT repeat central region spanning residues 18-531; p.Glu2750Asp, which lies in no annotated domain; and p.Lys1787Arg in the Tra1 HEAT repeat ring region spanning residues 541-2011. The clustering in HEAT repeat regions is the main structural argument for the mechanism proposed below, and it is an argument from position rather than from a functional assay. The allelic spectrum is not uniform in consequence: p.Pro509fs is a frameshift while the rest are missense, and no study has established whether any DFNA75 allele acts by loss of function, dominant negative effect, or something else. This entry therefore records no functional impact category for them.
Impaired HAT complex recruitment as the DFNA75 mechanism
TRRAP hgnc:12347 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TRRAP (hgnc:12347). hgnc:12347 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Reduced Recruitment of SAGA and NuA4 Histone Acetyltransferase Complexes to Chromatin Inferred from the position of the alleles within the protein-interaction HEAT repeat domains and from TRRAP's known scaffolding role. Not measured for any DFNA75 allele. Impaired HAT complex recruitment as the DFNA75 mechanism
Show evidence (2 references)
PMID:40004049 SUPPORT Human Clinical
"Nearly all previously reported variants affect the same functional domain of the TRRAP protein, including the p.Arg171Cys, p.Asp394Asn, and p.Pro509fs variants, which all affect the Tra1 HEAT repeat central region domain (position from 18 to 531 amino acids), whereas the p.Glu2750Asp variant..."
The reported allelic spectrum and its domain distribution, including the one allele that does not fit the clustering argument.
PMID:40004049 SUPPORT Human Clinical
"the detected missense variant affects the Tra1 HEAT repeat ring region"
The domain assignment of the fifth and most recently reported allele.
Reduced Recruitment of SAGA and NuA4 Histone Acetyltransferase Complexes to Chromatin
Mechanism confidence: Hypothetical
TRRAP is a pseudokinase member of the phosphoinositide 3-kinase-related kinase family and the scaffolding subunit shared by the SAGA and NuA4/TIP60 histone acetyltransferase complexes; its HEAT repeat solenoids are the surfaces through which those complexes are assembled and delivered to chromatin. The node states the hypothesised consequence of a DFNA75 allele on that function. It is included as a node because the biochemistry of TRRAP is well established and because both reporting groups build their interpretation on it. It carries no direct evidence for DFNA75 alleles, which is why its incoming and outgoing edges are typed as hypothesised.
Impaired HAT complex recruitment as the DFNA75 mechanism
histone acetyltransferase activity GO:0004402 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased histone acetyltransferase activity (GO:0004402). GO:0004402 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Disrupted Transcriptional Program in the Developing Inner Ear Impaired HAT complex recruitment as the DFNA75 mechanism
Show evidence (3 references)
PMID:30827496 SUPPORT Human Clinical
"This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP)."
Establishes TRRAP's scaffolding role, which is the biochemical premise of this node. The citing paper is about the neurodevelopmental phenotype, not DFNA75, so it supports the protein's function and nothing about this disease.
PMID:40004049 SUPPORT Human Clinical
"TRRAP is a component of many histone acetyltransferase (HAT) complexes and plays a role in transcription and DNA repair by recruiting HAT complexes to chromatin"
The same scaffolding role stated in the DFNA75 literature itself.
PMID:34830324 SUPPORT Other
"TRRAP, as the only member lacking the enzymatic activity in this family, is an adaptor protein for several histone acetyltransferase (HAT) complexes and a scaffold protein for multiple transcription factors."
Why the mechanism has to run through recruitment rather than through catalysis: TRRAP is the one PIKK family member with no enzymatic activity of its own, so a DFNA75 allele cannot act by changing an enzyme rate. Evidence source is OTHER because this is a review of TRRAP biology rather than a study of this disease.
Disrupted Transcriptional Program in the Developing Inner Ear
Mechanism confidence: Hypothetical
The step at which a general chromatin defect becomes an ear-specific one. It is the weakest link in the chain and is labelled as such: no cochlear or otic transcriptomic data exist for any DFNA75 allele, in any species. What supports placing the lesion in the ear at all is the zebrafish result below, where depleting trrap produces a quantifiable sensory-epithelial deficit, and the human audiometric pattern, which is cochlear rather than middle-ear. Why a ubiquitously expressed chromatin scaffold should give isolated deafness for one allele series and a multi-system neurodevelopmental syndrome for another is not explained by anything in this node, and is recorded as a knowledge gap.
Impaired HAT complex recruitment as the DFNA75 mechanism
inner ear development GO:0048839 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased inner ear development (GO:0048839). GO:0048839 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Cochlear Hair Cell Deficit and Stereocilia Abnormality Impaired HAT complex recruitment as the DFNA75 mechanism
Show evidence (1 reference)
PMID:31231791 SUPPORT Model Organism
"Knockdown or knockout of TRRAP resulted in significant defects in the inner ear of zebrafish, indicating that TRRAP plays an important role in inner ear development."
The only experimental evidence that TRRAP is required for inner ear development. It is a depletion experiment in fish, so it supports the requirement rather than the consequence of a human missense allele.
Cochlear Hair Cell Deficit and Stereocilia Abnormality
Mechanism confidence: Provisional
The structural lesion, observed only in zebrafish. Depleting trrap reduces the number of lateral line neuromasts, reduces hair cells per neuromast, and leaves the surviving hair cells with abnormal stereocilia. The mammalian cochlea has never been examined for a TRRAP allele, and human cochlear histology is not obtainable, so this node is carried on cross-species inference from a mechanosensory organ that is not the cochlea.
Impaired HAT complex recruitment as the DFNA75 mechanism
cochlear outer hair cell CL:0000601 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlear outer hair cell (CL:0000601). CL:0000601 is a cell type from the Cell Ontology.
inner ear receptor cell stereocilium organization GO:0060122 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased inner ear receptor cell stereocilium organization (GO:0060122). GO:0060122 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
trrap-depleted zebrafish (morpholino knockdown and CRISPR/Cas9 knockout) Zebrafish partially recapitulates The model establishes that trrap is required for hair cell development and stereocilia integrity, which is the only experimental support anywhere for placing the DFNA75 lesion in the sensory epithelium.
Downstream
Progressive High-Frequency Cochlear Hearing Loss Impaired HAT complex recruitment as the DFNA75 mechanism
Show evidence (1 reference)
PMID:40004049 SUPPORT Model Organism
"In trrap knockdown and knockout, zebrafish had reduced lateral line neuromasts, decreased number of hair cells per neuromast, and abnormal stereocilia on the hair cells compared with WT zebrafish"
The specific structural findings behind this node, restated in the second report from the zebrafish work in the first.
Progressive High-Frequency Cochlear Hearing Loss
The clinical lesion. Both reported families show sensorineural loss that begins at high frequencies and extends downward, with normal middle ear function on tympanometry and normal inner ear anatomy on MRI. Distortion product otoacoustic emissions were absent or nearly absent in the Hungarian family, which points at the cochlea rather than the auditory nerve, though the reporting authors were careful to say the audiology does not exclude a retrocochlear component.
cochlea UBERON:0001844 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cochlea (UBERON:0001844). UBERON:0001844 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Progressive high-frequency sensorineural hearing loss
Absent otoacoustic emissions
Abnormal auditory brainstem response
Show evidence (1 reference)
PMID:40004049 SUPPORT Human Clinical
"the audiological findings partially support (on the contrary, do not exclude) the cochlear origin of hearing loss, and the cochlea may be the site of the lesion"
The authors' own hedged localisation of the lesion, quoted rather than firmed up because the hedge is the finding.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Hearing Loss Autosomal Dominant 75 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

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Ear 4
Progressive high-frequency sensorineural hearing loss High-frequency sensorineural hearing impairment HP:0001757 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High-frequency sensorineural hearing impairment (HP:0001757), qualified as course progressive. HP:0001757 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:40004049 SUPPORT Human Clinical
"the affected individuals exhibited sensorineural hearing loss with similar clinical symptoms, including initial impaired high frequencies that subsequently affected speech and lower frequencies"
The audiometric configuration and its direction of progression.
PMID:40004049 SUPPORT Human Clinical
"As the hearing threshold of the II/2 mother deteriorated only slightly over time, this slow progression may continue for decades."
The rate of progression, which bears directly on rehabilitation planning.
Bilateral sensorineural hearing impairment HP:0008619 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bilateral sensorineural hearing impairment (HP:0008619). HP:0008619 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40004049 SUPPORT Human Clinical
"MRI did not reveal any abnormalities in the inner ears of the affected mother and daughter"
Excludes a structural inner ear malformation, which is part of what makes this a sensorineural rather than anatomical phenotype.
Absent otoacoustic emissions HP:6000182 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absent otoacoustic emissions (HP:6000182). HP:6000182 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40004049 SUPPORT Human Clinical
"at 70/60 dB SPL stimulus intensity, the DP-grams showed absent otoacoustic emissions in both ears"
The distortion product otoacoustic emission result in the affected mother, which is what this phenotype records.
Absence of vestibular and neurological involvement EXCLUDED Abnormal vestibular function HP:0001751 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is absent Abnormal vestibular function (HP:0001751). HP:0001751 is a phenotype from the Human Phenotype Ontology.
∅ ABSENT
The absence is carried by `frequency: EXCLUDED`, which is what the HPOA exporter reads to emit a NOT-qualified row; `modifier: ABSENT` alone is not consulted by the export layer and documents intent only. The evidence is graded `SUPPORT` because the quoted observation supports the claim this node makes, which is that vestibular involvement is absent. Grading it `REFUTE` and relying on that to carry the negation would leave the export one added `SUPPORT` item away from silently asserting that DFNA75 features vestibular dysfunction, cited to a paper saying the opposite. See `Adult-Onset_Autosomal_Dominant_Demyelinating_Leukodystrophy.yaml` for the entry where that regression actually happened. The binding is `HP:0001751 Abnormal vestibular function` rather than `HP:0002321 Vertigo`, because what was examined and found absent was vestibular dysfunction rather than the single symptom of vertigo.
Show evidence (1 reference)
PMID:40004049 SUPPORT Human Clinical
"On examination, vestibular dysfunction and neurological abnormalities were not observed in the patients."
The examination finding that supports this exclusion. Graded SUPPORT because the claim the node makes is the absence, and the quote reports exactly that.
Nervous System 1
Abnormal auditory brainstem response Abnormal auditory evoked potentials HP:0006958 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal auditory evoked potentials (HP:0006958). HP:0006958 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40004049 SUPPORT Human Clinical
"At 90 dB nHL stimulus intensity from the right ear, the Vth wave was indefinably present. In contrast, from the left ear, the Vth wave was absent."
The auditory brainstem response finding this phenotype records.
🧬

Genetic Associations

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TRRAP
Gene: TRRAP hgnc:12347 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TRRAP (hgnc:12347). hgnc:12347 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:31231791 SUPPORT Human Clinical
"Additionally, three more novel variants of transformation/transcription domain associated protein (TRRAP) were detected in 66 sporadic cases of hearing loss."
The additional alleles from the sporadic screen in the founding report. Note this is a variant screen without segregation data, so it widens the allelic series without independently establishing causality for those alleles.
PMID:30827496 SUPPORT Human Clinical
"TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation."
Constraint context for interpreting DFNA75 missense alleles. Cited from the neurodevelopmental paper because that is where the constraint statement appears.
🗃️

External Assertions

1
OMIM deafness, autosomal dominant 75 record
OMIM disease record OMIM:618778
OMIM entry for DFNA75, the TRRAP-related autosomal dominant nonsyndromic hearing loss phenotype curated here. OMIM:618454 is the separate TRRAP neurodevelopmental phenotype and is deliberately not curated in this entry.
💊

Medical Actions

1
Conventional Hearing Amplification
Action: hearing rehabilitation with an amplification deviceNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hearing rehabilitation with an amplification device, annotated with Rehabilitation (NCIT:C15315), qualified as medical device hearing aid. NCIT:C15315 is a clinical intervention from the NCI Thesaurus. Ontology label: Rehabilitation NCIT:C15315
Platform: Device
Both reported families were managed with conventional hearing assistive devices. In the Hungarian family the reporting clinicians judged the progression slow enough that amplification was expected to remain adequate long term, and explicitly did not support an indication for cochlear implantation on the available data. That is a two-patient judgement, not a guideline, and it should not be generalised to a patient whose loss progresses faster.
Mechanism Target:
Progressive High-Frequency Cochlear Hearing Loss — Amplification compensates for the raised thresholds. It does not act on the molecular lesion, and nothing reported for DFNA75 does.
Show evidence (1 reference)
PMID:40004049 SUPPORT Human Clinical
"conventional hearing assistive solutions appear to provide stable and good rehabilitative effects over the long term. Based on the available data, an indication for cochlear implantation was not supported."
The reported management decision and its stated basis, including the negative recommendation on implantation.
🔬

Diagnosis

1
Exome sequencing within a dominant hearing loss workup
DFNA75 has no feature outside the ear and no audiometric finding that distinguishes it from the other forty-odd dominant nonsyndromic deafness genes, so it is not diagnosable without sequencing. Both reported families were solved by whole exome sequencing with Sanger confirmation and segregation testing in relatives; TRRAP is recent enough that an older targeted deafness panel may not include it. Two adjuncts are worth noting from the reported workups. Normal tympanometry excludes a conductive component, and inner ear MRI was normal in the Hungarian family, which does not diagnose anything but does rule out a structural malformation and was used there to approach the cochlear versus retrocochlear question.
Show evidence (2 references)
PMID:31231791 SUPPORT Human Clinical
"Whole-exome sequencing, bioinformatic analysis, and Sanger sequencing were used to verify the co-segregation of a novel pathogenic variant"
The diagnostic route in the founding family.
PMID:40004049 SUPPORT Human Clinical
"From the perspective of the clinical geneticist, we conclude that WES is an effective approach for establishing the genetic background of ADNSHL."
The reporting clinicians' own conclusion about which test to use, in a disorder whose genetic heterogeneity is what makes the choice non-obvious.
📊

Prevalence

1
Worldwide, published cases
Cases In Literature Ultra Rare
Two families and five alleles in total. Four alleles were reported in 2019 from Chinese patients, one pedigree with segregation and three from a screen of 66 sporadic cases; the fifth was reported in 2025 in a Hungarian mother and daughter. No population estimate exists, and the fifth allele is described as extremely rare in gnomAD.
Show evidence (1 reference)
PMID:40004049 SUPPORT Human Clinical
"This gene has been recently linked to ADNSHL, and its disease-causing variants (n = 4) have only been found in Chinese patients."
The size and ancestry of the reported literature before the second family, which is the whole quantitative statement available for this disorder.
🐁

Animal Models

1
trrap-depleted zebrafish (morpholino knockdown and CRISPR/Cas9 knockout)
The only animal work on this gene-disease relationship, produced in the founding report to support the genetic finding. Both morpholino knockdown and CRISPR knockout produce inner ear defects: fewer lateral line neuromasts, fewer hair cells per neuromast, and abnormal stereocilia on the hair cells that remain.
Species
Zebrafish
Genotype
trrap morpholino knockdown; trrap CRISPR/Cas9 knockout
Genes
TRRAP hgnc:12347 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns TRRAP (hgnc:12347). hgnc:12347 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:31231791
Pathograph links
Cochlear Hair Cell Deficit and Stereocilia Abnormality partially recapitulates fidelity: low observes: tissue The model establishes that trrap is required for hair cell development and stereocilia integrity, which is the only experimental support anywhere for placing the DFNA75 lesion in the sensory epithelium.
Limitations: Three separate gaps between this model and the human disease. First, allele: the model is a knockdown and a knockout, whereas every human DFNA75 allele except one frameshift is a heterozygous missense change of unestablished functional consequence, so the experiment tests gene requirement rather than variant effect. Second, organ: the readout is the lateral line neuromast, a mechanosensory organ zebrafish have and humans do not, rather than the cochlea. Third, timing: the fish phenotype is developmental, whereas the human phenotype is post-lingual or mid-childhood onset and progressive, so a developmental deficit is being used to explain a progressive degeneration.
Divergences from the human mechanism
species mismatch qualifying
The quantified structure is the zebrafish lateral line neuromast. Humans have no lateral line, and the cochlear organ of Corti that DFNA75 affects has a different cellular architecture, tonotopy and regenerative capacity from a neuromast.
proxy quantity invalidating
The model's manipulated quantity is trrap gene dosage, reduced to near zero. The disease's quantity is the activity of a heterozygous missense TRRAP protein whose functional consequence has never been measured. Complete depletion is not a proxy for a missense allele unless loss of function has been demonstrated, and it has not.
Readouts
Hair cells per lateral line neuromast
Direction: DECREASED
Interpretation: The quantitative sensory-cell deficit on which the developmental interpretation rests.
Show evidence (1 reference)
PMID:40004049 SUPPORT Model Organism
"In trrap knockdown and knockout, zebrafish had reduced lateral line neuromasts, decreased number of hair cells per neuromast, and abnormal stereocilia on the hair cells compared with WT zebrafish"
The measurement behind this readout. Quoted from the second report because it states the specific findings more precisely than the founding abstract does.
Show evidence (1 reference)
PMID:31231791 SUPPORT Model Organism
"Knockdown or knockout of TRRAP resulted in significant defects in the inner ear of zebrafish, indicating that TRRAP plays an important role in inner ear development."
The model's own auditory conclusion, which is what licenses linking it to this node at all.
{ }

Source YAML

click to show 
name: Hearing Loss Autosomal Dominant 75
category: Mendelian
creation_date: "2026-09-04T00:00:00Z"
synonyms:
- DFNA75
- deafness, autosomal dominant 75
- TRRAP-related autosomal dominant nonsyndromic hearing loss
description: >-
  DFNA75 is autosomal dominant nonsyndromic sensorineural hearing loss attributed to
  heterozygous missense variants in TRRAP, the scaffolding subunit that recruits histone
  acetyltransferase complexes to chromatin. High frequencies are affected first and the
  loss extends downward over years, giving a ski-slope audiogram; onset has been reported
  both post-lingually in adulthood and in mid-childhood, and progression is slow.

  The entry is built on two families and should be read that way. The gene was proposed
  in 2019 from a single three-generation Chinese pedigree carrying p.Arg171Cys, supported
  by zebrafish knockdown and knockout showing inner ear defects; a Hungarian mother and
  daughter carrying p.Lys1787Arg were reported in 2025 as the second family, and the
  authors of that report classified their own variant as a variant of uncertain
  significance under ACMG rules. Five DFNA75 alleles are described in total. That is a
  thin gene-disease relationship by the standards of most entries in this knowledge base,
  and nothing here should be read as settled.

  The mechanistic claim is thinner still, and the entry separates it deliberately. What is
  observed is a hair cell and stereocilia deficit in trrap-depleted zebrafish and a
  cochlear-pattern audiogram in humans. What is inferred is everything in between: that
  the human missense alleles act by impairing TRRAP-dependent recruitment of the SAGA and
  NuA4/TIP60 acetyltransferase complexes, and that the resulting transcriptional change is
  what the cochlea cannot tolerate. The second report states that inference explicitly as
  an assumption requiring further study, so it is carried here as a labelled mechanistic
  hypothesis rather than as a curated causal chain.

  TRRAP also causes a syndromic neurodevelopmental disorder with autism and intellectual
  disability, from a separate and much larger allele series. No deafness family has been
  reported with the neurodevelopmental phenotype and no neurodevelopmental cohort has been
  reported with this audiogram. Why one gene splits this way is unresolved and is recorded
  as a knowledge gap rather than smoothed over.
disease_term:
  preferred_term: hearing loss, autosomal dominant 75
  term:
    id: MONDO:0032911
    label: hearing loss, autosomal dominant 75
parents:
- Autosomal Dominant Nonsyndromic Hearing Loss
external_assertions:
- name: OMIM deafness, autosomal dominant 75 record
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:618778
  description: >-
    OMIM entry for DFNA75, the TRRAP-related autosomal dominant nonsyndromic hearing loss
    phenotype curated here. OMIM:618454 is the separate TRRAP neurodevelopmental phenotype
    and is deliberately not curated in this entry.
inheritance:
- name: Autosomal dominant
  description: >-
    Heterozygous TRRAP missense and frameshift alleles segregating with hearing loss in
    two reported families. In the Chinese pedigree the variant co-segregated across three
    generations; in the Hungarian family it was present in the affected mother and
    daughter and in none of the three unaffected relatives tested. No homozygote and no
    biallelic case has been reported.

    For counselling, an affected parent has a 50 percent chance of transmitting the variant
    to each child. That figure is the arithmetic of autosomal dominant transmission rather
    than an observation about DFNA75, and is stated here without an evidence item for that
    reason: neither reported paper gives a recurrence risk, and the GeneReviews hearing loss
    overview cached for this entry carries only a statement of the chapter's purpose. What
    is genuinely unknown for this disorder is penetrance, which two pedigrees cannot
    establish and which would modify that 50 percent in practice.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:31231791
    reference_title: "Novel TRRAP mutation causes autosomal dominant non-syndromic hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing, bioinformatic analysis, and Sanger sequencing were used to verify the co-segregation of a novel pathogenic variant"
    explanation: >-
      The co-segregation analysis in the founding pedigree, which is what establishes the
      dominant mode of inheritance for this phenotype.
  - reference: PMID:40004049
    reference_title: "Novel Pathogenic Variant of the TRRAP Gene Detected in a Hungarian Family with Autosomal Dominant Non-Syndromic Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is present in a heterozygous form in the affected mother and daughter but not carried by any unaffected family members."
    explanation: >-
      Independent replication of dominant segregation in a second family, with unaffected
      relatives shown to be non-carriers.
mechanistic_hypotheses:
- hypothesis_group_id: hat_complex_recruitment_model
  hypothesis_label: Impaired HAT complex recruitment as the DFNA75 mechanism
  status: EMERGING
  description: >-
    The proposed mechanism is that DFNA75 missense alleles degrade TRRAP's function as the
    scaffold that recruits SAGA and NuA4/TIP60 histone acetyltransferase complexes to
    chromatin, and that the cochlea is unusually sensitive to the resulting transcriptional
    change. The model is coherent and is what both reporting groups propose, but no step of
    it has been measured for a DFNA75 allele: nobody has shown reduced complex recruitment,
    reduced histone acetylation, or an altered cochlear transcriptional program for any of
    the five variants. The supporting observations are TRRAP's established biochemical role
    and the localisation of most DFNA75 alleles to the Tra1 HEAT repeat domains that mediate
    those interactions.
  evidence:
  - reference: PMID:40004049
    reference_title: "Novel Pathogenic Variant of the TRRAP Gene Detected in a Hungarian Family with Autosomal Dominant Non-Syndromic Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We assume that similarly to this, the novel variant may also affect this function. Further studies are needed to examine this putative mechanism and other unidentified mechanism(s), which may also explain how the ADNSHL-causing variants of the TRRAP gene contribute to disease development."
    explanation: >-
      The reporting authors state the recruitment model as an assumption requiring further
      study, which is why it is curated as an EMERGING hypothesis rather than as an
      established mechanism.
pathophysiology:
- name: Heterozygous TRRAP Missense Variants in the Tra1 HEAT Repeat Domains
  description: >-
    Five DFNA75 alleles are reported: p.Arg171Cys, p.Asp394Asn and p.Pro509fs, all in the
    Tra1 HEAT repeat central region spanning residues 18-531; p.Glu2750Asp, which lies in
    no annotated domain; and p.Lys1787Arg in the Tra1 HEAT repeat ring region spanning
    residues 541-2011. The clustering in HEAT repeat regions is the main structural
    argument for the mechanism proposed below, and it is an argument from position rather
    than from a functional assay.

    The allelic spectrum is not uniform in consequence: p.Pro509fs is a frameshift while
    the rest are missense, and no study has established whether any DFNA75 allele acts by
    loss of function, dominant negative effect, or something else. This entry therefore
    records no functional impact category for them.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: TRRAP
    term:
      id: hgnc:12347
      label: TRRAP
  downstream:
  - target: Reduced Recruitment of SAGA and NuA4 Histone Acetyltransferase Complexes to Chromatin
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - hat_complex_recruitment_model
    description: >-
      Inferred from the position of the alleles within the protein-interaction HEAT repeat
      domains and from TRRAP's known scaffolding role. Not measured for any DFNA75 allele.
  evidence:
  - reference: PMID:40004049
    reference_title: "Novel Pathogenic Variant of the TRRAP Gene Detected in a Hungarian Family with Autosomal Dominant Non-Syndromic Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nearly all previously reported variants affect the same functional domain of the TRRAP protein, including the p.Arg171Cys, p.Asp394Asn, and p.Pro509fs variants, which all affect the Tra1 HEAT repeat central region domain (position from 18 to 531 amino acids), whereas the p.Glu2750Asp variant does not affect any known functional domains of the protein"
    explanation: >-
      The reported allelic spectrum and its domain distribution, including the one allele
      that does not fit the clustering argument.
  - reference: PMID:40004049
    reference_title: "Novel Pathogenic Variant of the TRRAP Gene Detected in a Hungarian Family with Autosomal Dominant Non-Syndromic Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the detected missense variant affects the Tra1 HEAT repeat ring region"
    explanation: The domain assignment of the fifth and most recently reported allele.
- name: Reduced Recruitment of SAGA and NuA4 Histone Acetyltransferase Complexes to Chromatin
  mechanism_confidence: HYPOTHETICAL
  description: >-
    TRRAP is a pseudokinase member of the phosphoinositide 3-kinase-related kinase family
    and the scaffolding subunit shared by the SAGA and NuA4/TIP60 histone acetyltransferase
    complexes; its HEAT repeat solenoids are the surfaces through which those complexes are
    assembled and delivered to chromatin. The node states the hypothesised consequence of a
    DFNA75 allele on that function.

    It is included as a node because the biochemistry of TRRAP is well established and
    because both reporting groups build their interpretation on it. It carries no direct
    evidence for DFNA75 alleles, which is why its incoming and outgoing edges are typed as
    hypothesised.
  biological_scale: MOLECULAR
  molecular_functions:
  - preferred_term: histone acetyltransferase activity
    term:
      id: GO:0004402
      label: histone acetyltransferase activity
    modifier: DECREASED
  downstream:
  - target: Disrupted Transcriptional Program in the Developing Inner Ear
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - hat_complex_recruitment_model
  evidence:
  - reference: PMID:30827496
    reference_title: "Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP)."
    explanation: >-
      Establishes TRRAP's scaffolding role, which is the biochemical premise of this node.
      The citing paper is about the neurodevelopmental phenotype, not DFNA75, so it
      supports the protein's function and nothing about this disease.
  - reference: PMID:40004049
    reference_title: "Novel Pathogenic Variant of the TRRAP Gene Detected in a Hungarian Family with Autosomal Dominant Non-Syndromic Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TRRAP is a component of many histone acetyltransferase (HAT) complexes and plays a role in transcription and DNA repair by recruiting HAT complexes to chromatin"
    explanation: The same scaffolding role stated in the DFNA75 literature itself.
  - reference: PMID:34830324
    reference_title: "Beyond HAT Adaptor: TRRAP Liaisons with Sp1-Mediated Transcription."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TRRAP, as the only member lacking the enzymatic activity in this family, is an adaptor protein for several histone acetyltransferase (HAT) complexes and a scaffold protein for multiple transcription factors."
    explanation: >-
      Why the mechanism has to run through recruitment rather than through catalysis: TRRAP
      is the one PIKK family member with no enzymatic activity of its own, so a DFNA75
      allele cannot act by changing an enzyme rate. Evidence source is OTHER because this
      is a review of TRRAP biology rather than a study of this disease.
- name: Disrupted Transcriptional Program in the Developing Inner Ear
  mechanism_confidence: HYPOTHETICAL
  description: >-
    The step at which a general chromatin defect becomes an ear-specific one. It is the
    weakest link in the chain and is labelled as such: no cochlear or otic transcriptomic
    data exist for any DFNA75 allele, in any species. What supports placing the lesion in
    the ear at all is the zebrafish result below, where depleting trrap produces a
    quantifiable sensory-epithelial deficit, and the human audiometric pattern, which is
    cochlear rather than middle-ear.

    Why a ubiquitously expressed chromatin scaffold should give isolated deafness for one
    allele series and a multi-system neurodevelopmental syndrome for another is not
    explained by anything in this node, and is recorded as a knowledge gap.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: inner ear development
    term:
      id: GO:0048839
      label: inner ear development
    modifier: DECREASED
  downstream:
  - target: Cochlear Hair Cell Deficit and Stereocilia Abnormality
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - hat_complex_recruitment_model
  evidence:
  - reference: PMID:31231791
    reference_title: "Novel TRRAP mutation causes autosomal dominant non-syndromic hearing loss."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Knockdown or knockout of TRRAP resulted in significant defects in the inner ear of zebrafish, indicating that TRRAP plays an important role in inner ear development."
    explanation: >-
      The only experimental evidence that TRRAP is required for inner ear development. It
      is a depletion experiment in fish, so it supports the requirement rather than the
      consequence of a human missense allele.
- name: Cochlear Hair Cell Deficit and Stereocilia Abnormality
  mechanism_confidence: PROVISIONAL
  description: >-
    The structural lesion, observed only in zebrafish. Depleting trrap reduces the number
    of lateral line neuromasts, reduces hair cells per neuromast, and leaves the surviving
    hair cells with abnormal stereocilia. The mammalian cochlea has never been examined for
    a TRRAP allele, and human cochlear histology is not obtainable, so this node is carried
    on cross-species inference from a mechanosensory organ that is not the cochlea.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: cochlear outer hair cell
    term:
      id: CL:0000601
      label: cochlear outer hair cell
  biological_processes:
  - preferred_term: inner ear receptor cell stereocilium organization
    term:
      id: GO:0060122
      label: inner ear receptor cell stereocilium organization
    modifier: DECREASED
  downstream:
  - target: Progressive High-Frequency Cochlear Hearing Loss
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - hat_complex_recruitment_model
  evidence:
  - reference: PMID:40004049
    reference_title: "Novel Pathogenic Variant of the TRRAP Gene Detected in a Hungarian Family with Autosomal Dominant Non-Syndromic Hearing Loss."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In trrap knockdown and knockout, zebrafish had reduced lateral line neuromasts, decreased number of hair cells per neuromast, and abnormal stereocilia on the hair cells compared with WT zebrafish"
    explanation: >-
      The specific structural findings behind this node, restated in the second report from
      the zebrafish work in the first.
- name: Progressive High-Frequency Cochlear Hearing Loss
  description: >-
    The clinical lesion. Both reported families show sensorineural loss that begins at high
    frequencies and extends downward, with normal middle ear function on tympanometry and
    normal inner ear anatomy on MRI. Distortion product otoacoustic emissions were absent
    or nearly absent in the Hungarian family, which points at the cochlea rather than the
    auditory nerve, though the reporting authors were careful to say the audiology does not
    exclude a retrocochlear component.
  biological_scale: ORGANISM
  locations:
  - preferred_term: cochlea
    term:
      id: UBERON:0001844
      label: cochlea
  downstream:
  - target: Progressive high-frequency sensorineural hearing loss
    causal_link_type: DIRECT
  - target: Absent otoacoustic emissions
    causal_link_type: DIRECT
  - target: Abnormal auditory brainstem response
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:40004049
    reference_title: "Novel Pathogenic Variant of the TRRAP Gene Detected in a Hungarian Family with Autosomal Dominant Non-Syndromic Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the audiological findings partially support (on the contrary, do not exclude) the cochlear origin of hearing loss, and the cochlea may be the site of the lesion"
    explanation: >-
      The authors' own hedged localisation of the lesion, quoted rather than firmed up
      because the hedge is the finding.
phenotypes:
- name: Progressive high-frequency sensorineural hearing loss
  category: Auditory
  description: >-
    Bilateral sensorineural loss that starts in the 2-8 kHz range and later involves speech
    and lower frequencies, producing a ski-slope audiogram. Progression is slow: in the
    Hungarian mother the threshold deteriorated only slightly over years of follow-up.
  phenotype_term:
    preferred_term: High-frequency sensorineural hearing impairment
    term:
      id: HP:0001757
      label: High-frequency sensorineural hearing impairment
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:40004049
    reference_title: "Novel Pathogenic Variant of the TRRAP Gene Detected in a Hungarian Family with Autosomal Dominant Non-Syndromic Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the affected individuals exhibited sensorineural hearing loss with similar clinical symptoms, including initial impaired high frequencies that subsequently affected speech and lower frequencies"
    explanation: The audiometric configuration and its direction of progression.
  - reference: PMID:40004049
    reference_title: "Novel Pathogenic Variant of the TRRAP Gene Detected in a Hungarian Family with Autosomal Dominant Non-Syndromic Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As the hearing threshold of the II/2 mother deteriorated only slightly over time, this slow progression may continue for decades."
    explanation: The rate of progression, which bears directly on rehabilitation planning.
- name: Bilateral sensorineural hearing impairment
  category: Auditory
  description: >-
    The loss is sensorineural and bilateral in both reported families, with normal middle
    ear ventilation on tympanometry and no structural inner ear abnormality on MRI.
  phenotype_term:
    preferred_term: Bilateral sensorineural hearing impairment
    term:
      id: HP:0008619
      label: Bilateral sensorineural hearing impairment
  evidence:
  - reference: PMID:40004049
    reference_title: "Novel Pathogenic Variant of the TRRAP Gene Detected in a Hungarian Family with Autosomal Dominant Non-Syndromic Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MRI did not reveal any abnormalities in the inner ears of the affected mother and daughter"
    explanation: >-
      Excludes a structural inner ear malformation, which is part of what makes this a
      sensorineural rather than anatomical phenotype.
- name: Absent otoacoustic emissions
  category: Auditory
  description: >-
    Distortion product otoacoustic emissions were absent in the affected mother and nearly
    absent in the daughter, and the acoustic reflex threshold was absent at the tested
    frequencies in the mother. Loss of otoacoustic emissions indicates outer hair cell
    dysfunction, and it is the single measurement that places the DFNA75 lesion in the
    cochlea rather than in the auditory nerve.

    That makes it load-bearing for this entry's cochlear-versus-retrocochlear knowledge gap,
    which is why it is bound to the specific term rather than folded into a general
    abnormal-evoked-potential claim. Note this is the opposite finding to DFNA83, the other
    recently defined dominant deafness locus in this knowledge base's neighbourhood, where
    preserved emissions point at spiral ganglion neurons instead.
  phenotype_term:
    preferred_term: Absent otoacoustic emissions
    term:
      id: HP:6000182
      label: Absent otoacoustic emissions
  evidence:
  - reference: PMID:40004049
    reference_title: "Novel Pathogenic Variant of the TRRAP Gene Detected in a Hungarian Family with Autosomal Dominant Non-Syndromic Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "at 70/60 dB SPL stimulus intensity, the DP-grams showed absent otoacoustic emissions in both ears"
    explanation: >-
      The distortion product otoacoustic emission result in the affected mother, which is
      what this phenotype records.
- name: Abnormal auditory brainstem response
  category: Auditory
  description: >-
    Auditory brainstem response wave V was absent from the left ear and barely definable
    from the right in the affected mother, and the objective thresholds derived from it
    agreed with her pure tone audiogram. Recorded separately from the otoacoustic emission
    result above because the two are different measurements of different parts of the
    auditory pathway, and because separating them is what lets each carry its own ontology
    term.
  phenotype_term:
    preferred_term: Abnormal auditory evoked potentials
    term:
      id: HP:0006958
      label: Abnormal auditory evoked potentials
  evidence:
  - reference: PMID:40004049
    reference_title: "Novel Pathogenic Variant of the TRRAP Gene Detected in a Hungarian Family with Autosomal Dominant Non-Syndromic Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At 90 dB nHL stimulus intensity from the right ear, the Vth wave was indefinably
      present. In contrast, from the left ear, the Vth wave was absent.
    explanation: The auditory brainstem response finding this phenotype records.
- name: Absence of vestibular and neurological involvement
  category: Auditory
  frequency: EXCLUDED
  description: >-
    Neither reported family had vestibular dysfunction or neurological abnormality on
    examination. This is what makes DFNA75 nonsyndromic, and it is also the observation that
    separates it clinically from the TRRAP neurodevelopmental phenotype. It is a negative
    finding from clinical examination in two families, not from systematic phenotyping.
  notes: >-
    The absence is carried by `frequency: EXCLUDED`, which is what the HPOA exporter reads
    to emit a NOT-qualified row; `modifier: ABSENT` alone is not consulted by the export
    layer and documents intent only. The evidence is graded `SUPPORT` because the quoted
    observation supports the claim this node makes, which is that vestibular involvement is
    absent. Grading it `REFUTE` and relying on that to carry the negation would leave the
    export one added `SUPPORT` item away from silently asserting that DFNA75 features
    vestibular dysfunction, cited to a paper saying the opposite. See
    `Adult-Onset_Autosomal_Dominant_Demyelinating_Leukodystrophy.yaml` for the entry where
    that regression actually happened.

    The binding is `HP:0001751 Abnormal vestibular function` rather than `HP:0002321
    Vertigo`, because what was examined and found absent was vestibular dysfunction rather
    than the single symptom of vertigo.
  phenotype_term:
    preferred_term: Abnormal vestibular function
    term:
      id: HP:0001751
      label: Abnormal vestibular function
    modifier: ABSENT
  evidence:
  - reference: PMID:40004049
    reference_title: "Novel Pathogenic Variant of the TRRAP Gene Detected in a Hungarian Family with Autosomal Dominant Non-Syndromic Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On examination, vestibular dysfunction and neurological abnormalities were not observed in the patients."
    explanation: >-
      The examination finding that supports this exclusion. Graded SUPPORT because the claim
      the node makes is the absence, and the quote reports exactly that.

prevalence:
- population: Worldwide, published cases
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Two families and five alleles in total. Four alleles were reported in 2019 from Chinese
    patients, one pedigree with segregation and three from a screen of 66 sporadic cases;
    the fifth was reported in 2025 in a Hungarian mother and daughter. No population
    estimate exists, and the fifth allele is described as extremely rare in gnomAD.
  evidence:
  - reference: PMID:40004049
    reference_title: "Novel Pathogenic Variant of the TRRAP Gene Detected in a Hungarian Family with Autosomal Dominant Non-Syndromic Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This gene has been recently linked to ADNSHL, and its disease-causing variants (n =
      4) have only been found in Chinese patients.
    explanation: >-
      The size and ancestry of the reported literature before the second family, which is
      the whole quantitative statement available for this disorder.
genetic:
- name: TRRAP
  notes: >-
    The only gene reported for DFNA75. TRRAP is among the genes most intolerant to missense
    variation in the human genome, which is relevant to interpreting any missense allele in
    it: intolerance raises prior suspicion but does not by itself establish that a
    particular variant is causal.
  gene_term:
    preferred_term: TRRAP
    term:
      id: hgnc:12347
      label: TRRAP
  relationship_type: CAUSATIVE
  evidence:
  - reference: PMID:31231791
    reference_title: "Novel TRRAP mutation causes autosomal dominant non-syndromic hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additionally, three more novel variants of transformation/transcription domain associated protein (TRRAP) were detected in 66 sporadic cases of hearing loss."
    explanation: >-
      The additional alleles from the sporadic screen in the founding report. Note this is
      a variant screen without segregation data, so it widens the allelic series without
      independently establishing causality for those alleles.
  - reference: PMID:30827496
    reference_title: "Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation."
    explanation: >-
      Constraint context for interpreting DFNA75 missense alleles. Cited from the
      neurodevelopmental paper because that is where the constraint statement appears.
diagnosis:
- name: Exome sequencing within a dominant hearing loss workup
  description: >-
    DFNA75 has no feature outside the ear and no audiometric finding that distinguishes it
    from the other forty-odd dominant nonsyndromic deafness genes, so it is not diagnosable
    without sequencing. Both reported families were solved by whole exome sequencing with
    Sanger confirmation and segregation testing in relatives; TRRAP is recent enough that
    an older targeted deafness panel may not include it.

    Two adjuncts are worth noting from the reported workups. Normal tympanometry excludes a
    conductive component, and inner ear MRI was normal in the Hungarian family, which does
    not diagnose anything but does rule out a structural malformation and was used there to
    approach the cochlear versus retrocochlear question.
  evidence:
  - reference: PMID:31231791
    reference_title: "Novel TRRAP mutation causes autosomal dominant non-syndromic hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing, bioinformatic analysis, and Sanger sequencing were used to verify the co-segregation of a novel pathogenic variant"
    explanation: The diagnostic route in the founding family.
  - reference: PMID:40004049
    reference_title: "Novel Pathogenic Variant of the TRRAP Gene Detected in a Hungarian Family with Autosomal Dominant Non-Syndromic Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      From the perspective of the clinical geneticist, we conclude that WES is an effective
      approach for establishing the genetic background of ADNSHL.
    explanation: >-
      The reporting clinicians' own conclusion about which test to use, in a disorder whose
      genetic heterogeneity is what makes the choice non-obvious.
animal_models:
- name: trrap-depleted zebrafish (morpholino knockdown and CRISPR/Cas9 knockout)
  species: Zebrafish
  genotype: trrap morpholino knockdown; trrap CRISPR/Cas9 knockout
  publication: PMID:31231791
  description: >-
    The only animal work on this gene-disease relationship, produced in the founding report
    to support the genetic finding. Both morpholino knockdown and CRISPR knockout produce
    inner ear defects: fewer lateral line neuromasts, fewer hair cells per neuromast, and
    abnormal stereocilia on the hair cells that remain.
  genes:
  - preferred_term: TRRAP
    term:
      id: hgnc:12347
      label: TRRAP
  modeled_mechanisms:
  - target: Cochlear Hair Cell Deficit and Stereocilia Abnormality
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: TISSUE
    description: >-
      The model establishes that trrap is required for hair cell development and stereocilia
      integrity, which is the only experimental support anywhere for placing the DFNA75
      lesion in the sensory epithelium.
    limitations: >-
      Three separate gaps between this model and the human disease. First, allele: the
      model is a knockdown and a knockout, whereas every human DFNA75 allele except one
      frameshift is a heterozygous missense change of unestablished functional consequence,
      so the experiment tests gene requirement rather than variant effect. Second, organ:
      the readout is the lateral line neuromast, a mechanosensory organ zebrafish have and
      humans do not, rather than the cochlea. Third, timing: the fish phenotype is
      developmental, whereas the human phenotype is post-lingual or mid-childhood onset and
      progressive, so a developmental deficit is being used to explain a progressive
      degeneration.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        The quantified structure is the zebrafish lateral line neuromast. Humans have no
        lateral line, and the cochlear organ of Corti that DFNA75 affects has a different
        cellular architecture, tonotopy and regenerative capacity from a neuromast.
    - divergence_type: PROXY_QUANTITY
      materiality: INVALIDATING
      description: >-
        The model's manipulated quantity is trrap gene dosage, reduced to near zero. The
        disease's quantity is the activity of a heterozygous missense TRRAP protein whose
        functional consequence has never been measured. Complete depletion is not a proxy
        for a missense allele unless loss of function has been demonstrated, and it has
        not.
    readouts:
    - name: Hair cells per lateral line neuromast
      target: Cochlear Hair Cell Deficit and Stereocilia Abnormality
      direction: DECREASED
      interpretation: >-
        The quantitative sensory-cell deficit on which the developmental interpretation
        rests.
      evidence:
      - reference: PMID:40004049
        reference_title: "Novel Pathogenic Variant of the TRRAP Gene Detected in a Hungarian Family with Autosomal Dominant Non-Syndromic Hearing Loss."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "In trrap knockdown and knockout, zebrafish had reduced lateral line neuromasts, decreased number of hair cells per neuromast, and abnormal stereocilia on the hair cells compared with WT zebrafish"
        explanation: >-
          The measurement behind this readout. Quoted from the second report because it
          states the specific findings more precisely than the founding abstract does.
    evidence:
    - reference: PMID:31231791
      reference_title: "Novel TRRAP mutation causes autosomal dominant non-syndromic hearing loss."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Knockdown or knockout of TRRAP resulted in significant defects in the inner ear of zebrafish, indicating that TRRAP plays an important role in inner ear development."
      explanation: >-
        The model's own auditory conclusion, which is what licenses linking it to this node
        at all.
treatments:
- name: Conventional Hearing Amplification
  description: >-
    Both reported families were managed with conventional hearing assistive devices. In the
    Hungarian family the reporting clinicians judged the progression slow enough that
    amplification was expected to remain adequate long term, and explicitly did not support
    an indication for cochlear implantation on the available data. That is a two-patient
    judgement, not a guideline, and it should not be generalised to a patient whose loss
    progresses faster.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: hearing rehabilitation with an amplification device
    term:
      id: NCIT:C15315
      label: Rehabilitation
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: hearing aid
        term:
          id: NCIT:C183182
          label: Hearing Aid
  target_mechanisms:
  - target: Progressive High-Frequency Cochlear Hearing Loss
    description: >-
      Amplification compensates for the raised thresholds. It does not act on the molecular
      lesion, and nothing reported for DFNA75 does.
  evidence:
  - reference: PMID:40004049
    reference_title: "Novel Pathogenic Variant of the TRRAP Gene Detected in a Hungarian Family with Autosomal Dominant Non-Syndromic Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "conventional hearing assistive solutions appear to provide stable and good rehabilitative effects over the long term. Based on the available data, an indication for cochlear implantation was not supported."
    explanation: >-
      The reported management decision and its stated basis, including the negative
      recommendation on implantation.
discussions:
- discussion_id: trrap_deafness_versus_neurodevelopmental_allele_series
  kind: KNOWLEDGE_GAP
  prompt: >-
    TRRAP causes both DFNA75 and a syndromic neurodevelopmental disorder with autism and
    intellectual disability. No DFNA75 family has been reported with the neurodevelopmental
    phenotype and no neurodevelopmental cohort has been reported with the DFNA75 audiogram.
    What distinguishes an allele that gives isolated deafness from one that gives a
    multi-system developmental syndrome?
  attaches_to:
  - pathophysiology#Heterozygous TRRAP Missense Variants in the Tra1 HEAT Repeat Domains
  - genetic#TRRAP
  rationale: >-
    The neurodevelopmental series is much better powered: 17 distinct de novo variants in
    24 individuals from an international collaboration, with an internal genotype-phenotype
    correlation splitting those 24 into two clinical spectra by variant position. The
    deafness series is five variants from two families plus a sporadic screen. So the
    asymmetry in what has been reported may simply reflect the asymmetry in how hard anyone
    has looked, and the honest reading is that the two phenotypes have never been
    systematically sought in each other's cohorts.

    Two things would settle it cheaply and neither has been done. Audiometry in the
    published TRRAP neurodevelopmental cohort would say whether the deafness allele series
    is genuinely distinct or whether high-frequency loss is simply unmeasured in patients
    ascertained for developmental delay. Developmental assessment in the deafness families
    would say the converse. Until then, the domain-clustering argument, that DFNA75 alleles
    sit in the Tra1 HEAT repeat regions, is the only thing separating the two, and one of
    the five DFNA75 alleles does not sit in any annotated domain at all.

    This matters for counselling, not just for the model. A family told that their TRRAP
    variant causes isolated deafness is being given a prognosis that rests on two published
    pedigrees.
  evidence:
  - reference: PMID:40004049
    reference_title: "Novel Pathogenic Variant of the TRRAP Gene Detected in a Hungarian Family with Autosomal Dominant Non-Syndromic Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In humans, two rare diseases with autosomal dominant inheritance have been associated with TRRAP: the ADNSHL (OMIM 618778) and the developmental delay with or without dysmorphic facies and autism (OMIM 618454)."
    explanation: The two-phenotype situation stated in the DFNA75 literature.
  - reference: PMID:30827496
    reference_title: "Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals."
    explanation: >-
      The size of the neurodevelopmental series, which is the asymmetry the gap turns on.
  - reference: PMID:30827496
    reference_title: "Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A strong genotype-phenotype correlation was observed with two distinct clinical spectra."
    explanation: >-
      That the neurodevelopmental series itself already splits by variant position,
      which is the precedent for expecting position to matter for the deafness alleles too.
  - reference: PMID:41952423
    reference_title: "Long-Term Follow Up of Two Patients With Variants in the Cluster 1031-1159 of TRRAP Gene: Expanding the Phenotype of Developmental Delay With or Without Dysmorphic Facies and Autism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Strong genotype-phenotype correlation has been observed in DEDDFA, where missense variants located in the clustering between residues 1031-1159 result in more pronounced facial anomalies associated with a variable degree of intellectual disability."
    explanation: >-
      Names the residue window that drives the severe neurodevelopmental phenotype. This
      sharpens rather than closes the gap: no DFNA75 allele falls in 1031-1159, which is
      consistent with a positional split, but four of the five DFNA75 alleles lie in the
      Tra1 HEAT repeat central region and one lies in no annotated domain at all, so
      position does not yet predict which phenotype a novel TRRAP missense allele will give.
- discussion_id: dfna75_gene_disease_validity
  kind: KNOWLEDGE_GAP
  prompt: >-
    How strong is the TRRAP-DFNA75 gene-disease relationship? Two families, five alleles,
    one zebrafish depletion experiment, and the second reporting group classified its own
    variant as a variant of uncertain significance.
  attaches_to:
  - genetic#TRRAP
  - mechanistic_hypotheses#hat_complex_recruitment_model
  rationale: >-
    Every claim in this entry inherits the strength of this relationship, so it is recorded
    explicitly rather than left for a reader to reconstruct from the citation count.

    What supports it: co-segregation across three generations in the founding pedigree, an
    independent second family in a different population with segregation in the affected
    pair and absence in three unaffected relatives, and a functional experiment showing the
    gene is required for hair cell development.

    What weakens it: the Hungarian variant is formally a VUS under ACMG rules, and its in
    silico predictions are split, with SIFT, MutationTaster and CADD suggesting a damaging
    effect while PolyPhen-2, EVE, REVEL and AlphaMissense suggest benign. The three
    additional alleles from the founding report came from a screen of 66 sporadic cases
    with no segregation data. No functional assay has been run on any DFNA75 allele. And
    the zebrafish experiment tests gene requirement, not allele effect.

    There is a structural reason the obvious next experiment has not been done, and it is
    worth recording because it changes what "no mouse model" means here. Germline deletion
    of Trrap is embryonically lethal in the mouse, so a straightforward knockout cannot be
    audiometrically phenotyped at all; the mouse work that exists on this gene is
    conditional, in B cells and in adult neural stem cells, neither of which reports on
    hearing. A DFNA75 mouse would have to be a cochlea-conditional knock-in of a specific
    human allele. That is a real experiment rather than an unasked question, and its absence
    is not evidence against the gene.

    There is no ClinGen Gene-Disease Validity assertion for TRRAP and hearing loss to cite,
    which is why this is recorded as prose here rather than as a CGGV evidence item. A
    ClinGen curation would be the single most useful external addition to this entry.
  evidence:
  - reference: PMID:40004049
    reference_title: "Novel Pathogenic Variant of the TRRAP Gene Detected in a Hungarian Family with Autosomal Dominant Non-Syndromic Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Based on the ACMG variant classification guideline, this variant is classified as a VUS."
    explanation: >-
      The reporting authors' own classification of the allele in the second family, which
      is the clearest single statement of how provisional this relationship remains.
  - reference: PMID:40004049
    reference_title: "Novel Pathogenic Variant of the TRRAP Gene Detected in a Hungarian Family with Autosomal Dominant Non-Syndromic Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is the second study confirming an association between TRRAP and ADNSHL."
    explanation: The total size of the replicated evidence base, in the authors' own words.
  - reference: PMID:24675885
    reference_title: "Tissue-specific inactivation of HAT cofactor TRRAP reveals its essential role in B cells."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Targeted-deletion of the Trrap gene led to early embryonic lethality and revealed a critical function of TRRAP in cell proliferation."
    explanation: >-
      Why no straightforward Trrap knockout mouse can be tested for hearing loss, which is
      the reason the gene-disease relationship has no mammalian in vivo support rather than
      an indication that nobody tried.
  - reference: PMID:36618986
    reference_title: "TRRAP-mediated acetylation on Sp1 regulates adult neurogenesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here, we find that Trrap deletion compromises self-renewal and differentiation of aNSCs in mice and in cultures."
    explanation: >-
      The mouse work that does exist is conditional and neural, and reports on adult neural
      stem cells rather than on the cochlea. Cited to show what the mammalian evidence
      currently covers, not to support a claim about DFNA75.
- discussion_id: dfna75_cochlear_versus_retrocochlear_localisation
  kind: KNOWLEDGE_GAP
  prompt: >-
    Is the DFNA75 lesion in the cochlear hair cells, in the spiral ganglion, or both? The
    otoacoustic emission data say outer hair cell, but that is one family and the reporting
    authors declined to exclude a retrocochlear component.
  attaches_to:
  - pathophysiology#Progressive High-Frequency Cochlear Hearing Loss
  - pathophysiology#Cochlear Hair Cell Deficit and Stereocilia Abnormality
  rationale: >-
    The question is not academic for this gene. TRRAP is a general chromatin scaffold
    expressed everywhere, so nothing about the gene predicts which cochlear cell type it
    acts in, and the zebrafish evidence points at hair cells only because hair cells are
    what the lateral line assay measures. If the spiral ganglion were also involved, the
    fish experiment would not have detected it.

    The single relevant human measurement is the absent DPOAE in the Hungarian mother and
    nearly absent DPOAE in the daughter, which does indicate outer hair cell dysfunction.
    Against that, the authors note that distinguishing cochlear from retrocochlear origin
    at this severity requires more than audiometry, and their MRI was normal without
    resolving the question. Auditory brainstem response morphology in more affected
    individuals, or electrocochleography, would separate the possibilities.
  evidence:
  - reference: PMID:40004049
    reference_title: "Novel Pathogenic Variant of the TRRAP Gene Detected in a Hungarian Family with Autosomal Dominant Non-Syndromic Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Due to the severe grade of high-frequency sensorineural hearing impairment in the 2-4 kHz range, a differential diagnosis between the cochlear vs. retrocochlear origin requires more complex diagnostic procedures, such as MRI."
    explanation: >-
      The authors' statement that the localisation is not settled by audiometry alone,
      which is the substance of this gap.
references:
- reference: PMID:20301607
  title: "Genetic Hearing Loss Overview."
  tags:
  - GeneReviews
- reference: PMID:31231791
  title: "Novel TRRAP mutation causes autosomal dominant non-syndromic hearing loss."
- reference: PMID:40004049
  title: "Novel Pathogenic Variant of the TRRAP Gene Detected in a Hungarian Family with Autosomal Dominant Non-Syndromic Hearing Loss."
- reference: PMID:30827496
  title: "Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability."
- reference: PMID:41952423
  title: "Long-Term Follow Up of Two Patients With Variants in the Cluster 1031-1159 of TRRAP Gene: Expanding the Phenotype of Developmental Delay With or Without Dysmorphic Facies and Autism."
- reference: PMID:34830324
  title: "Beyond HAT Adaptor: TRRAP Liaisons with Sp1-Mediated Transcription."
- reference: PMID:24675885
  title: "Tissue-specific inactivation of HAT cofactor TRRAP reveals its essential role in B cells."
- reference: PMID:36618986
  title: "TRRAP-mediated acetylation on Sp1 regulates adult neurogenesis."
📚

References & Deep Research

References

8
PMID:20301607
Genetic Hearing Loss Overview.
No top-level findings curated for this source.
PMID:31231791
Novel TRRAP mutation causes autosomal dominant non-syndromic hearing loss.
No top-level findings curated for this source.
PMID:40004049
Novel Pathogenic Variant of the TRRAP Gene Detected in a Hungarian Family with Autosomal Dominant Non-Syndromic Hearing Loss.
No top-level findings curated for this source.
PMID:30827496
Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability.
No top-level findings curated for this source.
PMID:41952423
Long-Term Follow Up of Two Patients With Variants in the Cluster 1031-1159 of TRRAP Gene: Expanding the Phenotype of Developmental Delay With or Without Dysmorphic Facies and Autism.
No top-level findings curated for this source.
PMID:34830324
Beyond HAT Adaptor: TRRAP Liaisons with Sp1-Mediated Transcription.
No top-level findings curated for this source.
PMID:24675885
Tissue-specific inactivation of HAT cofactor TRRAP reveals its essential role in B cells.
No top-level findings curated for this source.
PMID:36618986
TRRAP-mediated acetylation on Sp1 regulates adult neurogenesis.
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 (1)

Create: Hearing Loss Autosomal Dominant 75 (DFNA75, TRRAP) · 2026-09-04T13:46:39Z · View source

De novo curation of DFNA75 (MONDO:0032911, OMIM:618778, TRRAP). Deep research: one OpenScientist run, committed as research/Hearing_Loss_Autosomal_Dominant_75-deep-research-openscientist.md. That run was invoked with --validate-references and --validate-terms but emitted neither a frontmatter block nor a report section; both were added afterwards with just validate-research-reference and just validate-research-terms. Retro-fitted reference validation: 16/16 identifiers resolved, 23/23 quoted claims found in source, one reference (PMID:41699244, cochlear implant complications) flagged as possibly off topic and not used. Retro-fitted term validation flagged three bad bindings in the report which were consequently not used: CL:0002218 offered as inner ear hair cell (it is immature dendritic epithelial T cell precursor), NCIT:C50072 offered as Hearing Aid (it is Modem Device), and obsolete GO:0016573. Entry content is built on the two primary human reports (PMID:31231791 Xia 2019, PMID:40004049 Nagy 2025) plus PMID:30827496 for the allelic neurodevelopmental disorder, and two references surfaced by the deep-research run (PMID:41952423 for the DEDDFA 1031-1159 cluster, PMID:34830324 for TRRAP scaffold biology). The HAT-recruitment mechanism is carried as an EMERGING mechanistic_hypotheses group with UNKNOWN causal_link_type edges and HYPOTHETICAL mechanism_confidence nodes, because no functional assay has been run on any DFNA75 allele. Three knowledge-gap discussions record the DFNA75/DEDDFA allele-series split, the gene-disease validity limits (two families, the second variant a VUS by the authors' own ACMG assessment), and the unresolved cochlear versus retrocochlear localisation. Validation: just validate passed with 28/28 snippets verified; check-entity-refs, check-causal-targets, check-duplicate-keys and check-qualifier-terms all clean. check-qualifier-terms-online caught a fabricated NCIT:C50075 binding for hearing aid (actually EKG or ECG Monitor Device) that the offline gate had passed; corrected to NCIT:C183182.

OpenScientist ▸
Hearing Loss Autosomal Dominant 75 (DFNA75): A Comprehensive Disease Characteristics Report
openscientist-autonomous 16 citations 2026-09-04T13:43:43.676825

Hearing Loss Autosomal Dominant 75 (DFNA75): A Comprehensive Disease Characteristics Report

Gene: TRRAP (Transformation/tRanscription domain-Associated Protein) · Disease OMIM: #618778 · Gene OMIM: 603015 · Category:* Mendelian (monogenic, autosomal dominant, nonsyndromic sensorineural hearing loss)

Summary

Hearing Loss Autosomal Dominant 75 (DFNA75; OMIM #618778) is a rare Mendelian, autosomal dominant, nonsyndromic sensorineural hearing loss (ADNSHL) caused by heterozygous pathogenic variants in TRRAP (Transformation/tRanscription domain-Associated Protein; HGNC:12347; NCBI Gene 8295; 7q22.1; OMIM 603015). The locus/phenotype was defined by Xia et al. (2019), who identified the co-segregating variant NM_001244580 c.511C>T, p.(Arg171Cys) across a three-generation Chinese family with post-lingual, progressive ADNSHL, plus three additional novel TRRAP variants in a screen of 66 sporadic hearing-loss cases. Functional validation in zebrafish (morpholino knockdown and CRISPR/Cas9 knockout of trrap*) produced significant inner-ear defects, establishing TRRAP as required for inner-ear development (PMID: 31231791).

Clinically, DFNA75 presents as bilateral, post-lingual (onset after speech acquisition), progressive cochlear sensorineural hearing loss. Because nonsyndromic hearing impairment is almost exclusively cochlear, the resulting deficit is sensorineural, and postlingual nonsyndromic forms typically follow an autosomal dominant trait — consistent with the DFNA (autosomal Dominant, NonsyndromicA) locus series to which DFNA75 belongs. There is no gene-specific or curative therapy; management is supportive, following the general SNHL pathway of hearing amplification for mild-to-moderate loss and cochlear implantation for severe-to-profound loss.

TRRAP is a biologically pivotal protein: the only enzymatically inactive member of the phosphatidylinositol 3-kinase–related kinase (PIKK) family, it functions as an adaptor/scaffold for multiple histone acetyltransferase (HAT) complexes (STAGA/SAGA with GCN5; TIP60/NuA4) and as a scaffold for key transcription factors (E2F1, c-Myc, p53, Sp1). Distinct TRRAP missense alleles cause the allelic multisystem neurodevelopmental disorder DEDDFA (Developmental delay with or without dysmorphic facies and autism; OMIM #618454), and recurrent somatic TRRAP mutations (p.Ser722Phe) act as oncogenic drivers in melanoma — illustrating that the clinical consequence of TRRAP perturbation is strongly dependent on the specific variant, its domain location, and germline versus somatic context.

Section 1 — Disease Information

Overview. DFNA75 is a form of autosomal dominant, nonsyndromic (isolated, no other organ system involvement) sensorineural hearing loss. It belongs to the large, genetically heterogeneous DFNA series of dominant nonsyndromic deafness loci. Hearing loss is the sole clinical manifestation; affected individuals do not have the multisystem features seen in TRRAP-related neurodevelopmental disorder.

Key identifiers.

Resource Identifier
OMIM (phenotype) #618778 (Deafness, autosomal dominant 75)
OMIM (gene) *603015 (TRRAP)
Gene symbol / HGNC TRRAP / HGNC:12347
NCBI Gene 8295
Ensembl ENSG00000196367
UniProt Q9Y4A5
Cytogenetic location 7q22.1
MONDO Corresponds to the OMIM #618778 concept ("autosomal dominant nonsyndromic hearing loss 75")

Synonyms / alternative names: DFNA75; Deafness, autosomal dominant 75; Autosomal dominant nonsyndromic sensorineural hearing loss type 75; TRRAP-related autosomal dominant hearing loss.

Information source. Disease-level knowledge here is aggregated from Mendelian genetics resources (OMIM) and the primary literature (a single index family plus sporadic-case screening), rather than from individual EHR data. The defining evidence is a family-based segregation and functional study (PMID: 31231791).

Section 2 — Etiology

Disease causal factors. DFNA75 is a monogenic, genetic disorder. The primary cause is a heterozygous pathogenic variant in TRRAP. There is no established infectious or environmental cause of the Mendelian disease itself, though general environmental insults (noise, ototoxic drugs, aging) can independently compound sensorineural hearing loss in any individual.

Genetic risk factors. The causal variant class is heterozygous coding variants in TRRAP. The index variant is c.511C>T, p.(Arg171Cys) (NM_001244580), which co-segregated with disease across three generations; three additional novel TRRAP variants were identified among 66 sporadic hearing-loss cases (PMID: 31231791). A subsequent report (PMID: 40004049) describes a further novel pathogenic TRRAP variant in ADNSHL, reinforcing TRRAP as a bona fide ADNSHL gene.

Environmental risk factors / protective factors / gene-environment interactions. No disease-specific environmental risk factors, protective factors, or gene-environment interactions have been characterized for DFNA75. As with other progressive SNHL, avoidance of additional cochlear insults (excessive noise exposure, ototoxic aminoglycosides/platinum agents) is a prudent, non-specific protective measure, but no DFNA75-specific modifier has been demonstrated. This is a knowledge gap.

Section 3 — Phenotypes

Core phenotype: sensorineural hearing loss. The defining and essentially sole phenotype of DFNA75 is bilateral sensorineural hearing loss. Because nonsyndromic hearing impairment is almost exclusively caused by cochlear defects, affected patients suffer sensorineural (rather than conductive) loss (PMID: 15850684).

Phenotype characteristics.

Characteristic DFNA75
Phenotype type Clinical sign / laboratory (audiometric) abnormality — sensorineural hearing loss
Age of onset Post-lingual (after speech development); adult/late-childhood onset
Severity Variable; progresses from milder to more severe over time
Progression Progressive (worsens with age)
Laterality Bilateral
Frequency among affected Essentially the defining feature of affected individuals

The index family is explicitly described as having "post-lingual progressive ADNSHL" (PMID: 31231791). Post-lingual onset means hearing and speech develop normally before decline, which typically preserves spoken-language competence and favors auditory rehabilitation outcomes.

Quality-of-life impact. Progressive bilateral SNHL impairs speech perception (particularly in noise), communication, education/occupational function, and social participation, and is associated with tinnitus in a subset of SNHL patients. Disease-specific QoL instruments for DFNA75 have not been reported; general SNHL QoL data apply.

Suggested HPO terms. - HP:0000407 — Sensorineural hearing impairment - HP:0000408 — Progressive sensorineural hearing impairment - HP:0008619 — Bilateral sensorineural hearing impairment - HP:0001730 — Progressive hearing impairment - HP:0000006 — Autosomal dominant inheritance - HP:0008527 — Congenital sensorineural hearing impairment (explicitly excluded; onset is post-lingual)

Section 4 — Genetic / Molecular Information

Causal gene. TRRAP (Transformation/tRanscription domain-Associated Protein), OMIM *603015; HGNC:12347; NCBI Gene 8295; Ensembl ENSG00000196367; UniProt Q9Y4A5; located at chromosome 7q22.1. The protein is large (~3,830 amino acids) and is the enzymatically inactive (pseudokinase) member of the PIKK family.

Pathogenic variants.

Variant (transcript NM_001244580) Protein Type Context Source
c.511C>T p.(Arg171Cys) Missense Germline, co-segregating in 3-generation family PMID: 31231791
3 additional novel variants (various) Missense (reported) Germline, sporadic hearing-loss cases PMID: 31231791
Novel pathogenic variant (reported) — Germline ADNSHL PMID: 40004049
  • Variant classification: the index variant was reported as pathogenic based on co-segregation, rarity/absence in population databases, and functional support in zebrafish. Per ACMG/AMP, classification would rest on segregation (PP1), rarity (PM2), and functional evidence (PS3-supporting via zebrafish modeling).
  • Variant type/class: predominantly missense.
  • Allele frequency: the causal variants are rare/absent in population databases (gnomAD), consistent with a highly disease-relevant, constrained gene.
  • Somatic vs germline: DFNA75 variants are germline. This is mechanistically distinct from somatic TRRAP mutations in cancer (see Section 6 and Finding F007).
  • Functional consequence: for DFNA75, the mechanism is inferred to be a dominant, dosage/scaffold-sensitive effect (haploinsufficiency or dominant-negative disruption of HAT-complex scaffolding); zebrafish trrap loss-of-function reproduces inner-ear defects, supporting reduced TRRAP function as pathogenic (PMID: 31231791).

Constraint. TRRAP is "evolutionarily conserved and is among the top five genes intolerant to missense variation" (PMID: 30827496), underscoring that even single missense changes can be pathogenic.

Modifier genes / epigenetic information / chromosomal abnormalities. No DFNA75-specific modifier genes, epigenetic marks, or chromosomal abnormalities have been reported (knowledge gap). Notably TRRAP itself is an epigenetic regulator (a HAT-complex scaffold), so the downstream consequence of TRRAP dysfunction is dysregulated histone acetylation.

Suggested ontology terms: MONDO (autosomal dominant nonsyndromic hearing loss 75); HGNC:12347 (TRRAP).

Section 5 — Environmental Information

DFNA75 is a purely genetic Mendelian condition. No environmental factors, lifestyle factors, or infectious agents are established as causal or triggering. As with all sensorineural hearing loss, generic ototoxic exposures (aminoglycoside/platinum chemotherapy, loud noise, aging) may additively worsen hearing but are not part of the disease's causal etiology. This is a not-applicable / knowledge-gap section for this disorder.

Section 6 — Mechanism / Pathophysiology

Ordered causal chain

  1. A heterozygous germline missense variant in TRRAP (e.g., c.511C>T, p.Arg171Cys) leads to an altered TRRAP protein in a gene extraordinarily intolerant to missense change.
  2. Altered/reduced TRRAP function results in impaired scaffolding of histone-acetyltransferase (HAT) complexes (STAGA/SAGA–GCN5; TIP60/NuA4) and of transcription-factor partners (Sp1, c-Myc, p53, E2F1). (Inferred from TRRAP's known molecular role; not yet directly demonstrated for the DFNA75 alleles.)
  3. Disrupted HAT recruitment leads to aberrant histone acetylation and dysregulated transcription of TRRAP/HAT-dependent gene programs governing cell proliferation and differentiation.
  4. In the developing inner ear, this transcriptional dysregulation results in defective proliferation/differentiation of inner-ear cell populations — demonstrated as significant inner-ear developmental defects in zebrafish trrap knockdown/knockout. (Demonstrated in model organism.)
  5. Impaired cochlear development/maintenance leads to progressive cochlear (sensorineural) dysfunction.
  6. Cochlear sensorineural dysfunction manifests as bilateral, post-lingual, progressive hearing loss (DFNA75).

Branch (allelic, not DFNA75): Different TRRAP missense alleles (e.g., clustering near residues 1031–1159) instead disrupt neurodevelopmental transcriptional programs → developmental delay, dysmorphic facies, autism/ID (DEDDFA). A separate somatic branch (p.Ser722Phe in melanocytes) drives oncogenesis.

Molecular detail

Molecular function / pathways. "TRRAP, as the only member lacking the enzymatic activity in this [PIKK] family, is an adaptor protein for several histone acetyltransferase (HAT) complexes and a scaffold protein for multiple transcription factors" (PMID: 34830324). It bridges transcription factors to chromatin-modifying enzymes: MYC contacts the human STAGA coactivator via multivalent interactions with the GCN5 and TRRAP subunits — "we identify both TRRAP and the GCN5 acetyltransferase as MYC TAD-interacting subunits within native STAGA" (PMID: 24705139). TRRAP also participates in the TIP60/NuA4 complex (e.g., Elk-1–recruited TIP60/NuA4 activating prolactin transcription; PMID: 24075908).

Cellular processes. TRRAP is fundamentally required for cell proliferation. Targeted deletion of Trrap causes early embryonic lethality, and tissue-specific ablation in B cells impairs development and drives proliferating cells into apoptosis: "cells induced to proliferate undergo apoptosis. Our findings demonstrate a central and general role of TRRAP in cell proliferation" (PMID: 24675885). In neural stem cells, TRRAP acts as a scaffold controlling Sp1 stability/acetylation to regulate microtubule dynamics and adult hippocampal neurogenesis (PMID: 36618986, PMID: 34830324).

Protein dysfunction. TRRAP is a giant scaffold pseudokinase; pathogenic missense changes are inferred to perturb protein–protein interfaces required for HAT-complex/transcription-factor assembly (loss of scaffold competence), rather than an enzymatic active site (TRRAP has none).

Suggested GO/CL terms. - GO:0016573 — histone acetylation - GO:0000123 — histone acetyltransferase complex - GO:0006357 — regulation of transcription by RNA polymerase II - GO:0008283 — cell population proliferation - GO:0060113 — inner ear receptor cell differentiation (developing ear) - CL:0000855 — sensory hair cell; CL:0002218 — inner ear hair cell (candidate affected cell types, inferred)

Section 7 — Anatomical Structures Affected

Organ level. Primary affected organ: the inner ear / cochlea (UBERON:0001846 internal ear; UBERON:0001844 cochlea). Body system: auditory / special sense (nervous) system. DFNA75 is nonsyndromic — there is no established secondary organ involvement.

Tissue and cell level. Nonsyndromic hearing impairment is "almost exclusively caused by cochlear defects" (PMID: 15850684); the affected tissue is the cochlear sensory epithelium (organ of Corti). Candidate targeted cells include cochlear sensory hair cells (inner/outer) and supporting cells; zebrafish inner-ear developmental defects indicate broader inner-ear cell populations are TRRAP-dependent (PMID: 31231791). Precise human cell-type localization within the DFNA75 cochlea has not been directly established (inferred).

Subcellular level. As a transcriptional/chromatin scaffold, TRRAP localizes to the nucleus (GO:0005634); its functional site is nuclear chromatin and HAT complexes (GO:0000123 histone acetyltransferase complex).

Localization / lateralization. Bilateral cochlear involvement. UBERON:0001846 (internal ear), UBERON:0001844 (cochlea), UBERON:0002227 (organ of Corti).

Section 8 — Temporal Development

Onset. Post-lingual (after normal speech acquisition); typically childhood-to-adult onset, insidious. Not congenital in the index family.

Progression. Progressive — hearing worsens over time. The index family is explicitly "post-lingual progressive" (PMID: 31231791). Progression rate and precise audiometric trajectory across the frequency range have not been quantified in detail (knowledge gap); course is chronic and lifelong.

Patterns. No spontaneous remission; hearing loss does not recover without intervention. The critical window for intervention is functional (amplification/implantation once thresholds warrant), rather than a developmental critical period, given post-lingual onset.

Section 9 — Inheritance and Population

Inheritance. Autosomal dominant (the "A" in DFNA75). Postlingual nonsyndromic hearing impairment "usually follows an autosomal dominant trait" (PMID: 15850684), consistent with DFNA75. Segregation was demonstrated across three generations (PMID: 31231791).

Penetrance / expressivity. Co-segregation across three generations is consistent with high penetrance in the index family; formal penetrance and expressivity estimates are not established given the small number of reported families (knowledge gap). Genetic anticipation, germline mosaicism, founder effects, consanguinity, and carrier frequency are not applicable/undocumented for this dominant, rare disorder.

Epidemiology. DFNA75 is very rare; precise prevalence/incidence are unknown. It is one of >40 genes underlying autosomal dominant nonsyndromic hearing loss. Genetic heterogeneity is substantial: "One percent of the total human genes, i.e. 300-500, are estimated to cause syndromic and nonsyndromic HIH" (PMID: 15850684).

Population demographics. Reported cases include a Chinese family and sporadic cases (PMID: 31231791) and a further ADNSHL report (PMID: 40004049). No ethnic predisposition, geographic clustering, or sex bias has been established (autosomal, so no expected sex skew).

Section 10 — Diagnostics

Genetic testing is the definitive diagnostic modality. In the index family and sporadic cases, diagnosis was achieved by whole-exome sequencing with Sanger confirmation of co-segregation: "Whole-exome sequencing, bioinformatic analysis, and Sanger sequencing were used to verify the co-segregation of a novel pathogenic variant" (PMID: 31231791).

Recommended approach. Because ADNSHL is highly genetically heterogeneous (>40 genes; hundreds of hearing-loss genes overall — PMID: 15850684), the practical diagnostic strategy is a comprehensive hearing-loss gene panel or whole-exome sequencing, not single-gene TRRAP testing. WGS/WES are useful when panels are negative. Chromosomal microarray, karyotyping, FISH, mtDNA testing, and repeat-expansion testing are not indicated for this SNP/indel-level dominant disorder.

Clinical tests. - Audiometry (pure-tone air and bone conduction) documents the bilateral, sensorineural, progressive pattern; speech audiometry and, in children, otoacoustic emissions/auditory brainstem response characterize cochlear function. - No specific blood/urine biomarker exists; the genetic variant is the diagnostic biomarker. - Imaging (temporal bone CT/MRI) is used to exclude structural/syndromic causes and for cochlear-implant planning, not for positive DFNA75 diagnosis.

Differential diagnosis. Other DFNA-series dominant nonsyndromic hearing losses, and acquired progressive SNHL (noise-induced, ototoxic, presbycusis). Distinguishing features: family history/segregation and gene panel result. Syndromic causes are excluded by the absence of extra-auditory features.

Screening. Cascade genetic testing of at-risk relatives once the familial variant is identified; no population newborn-screening program targets DFNA75 specifically (though universal newborn hearing screening detects hearing loss non-specifically).

Section 11 — Outcome / Prognosis

Survival/mortality. DFNA75 is not life-threatening; it does not affect survival or life expectancy. There is no disease-specific mortality.

Morbidity/function. The principal burden is communication disability from progressive bilateral SNHL, with attendant effects on education, employment, and social/psychological well-being, and tinnitus in a subset. Formal disability/QoL metrics specific to DFNA75 are not reported.

Disease course. Chronic, lifelong, progressive. Without intervention, hearing declines; there is no spontaneous recovery. With appropriate amplification or cochlear implantation, functional hearing and speech understanding can be substantially restored, particularly given post-lingual onset (preserved language).

Prognostic factors. Degree and rate of threshold progression determine timing of hearing-aid versus cochlear-implant candidacy. Post-lingual onset is generally favorable for auditory rehabilitation outcomes. No molecular prognostic biomarker beyond the genotype is established.

Section 12 — Treatment

No disease-specific or curative therapy exists for TRRAP-related hearing loss. Management follows the standard progressive-SNHL pathway.

Modality Indication NCIT concept
Hearing aids / amplification Mild-to-moderate loss Hearing Aid (NCIT:C50072)
Cochlear implantation Severe-to-profound loss Cochlear Implant / Cochlear Implantation
Aural rehabilitation, speech therapy, assistive listening Adjunctive across severities Rehabilitation Therapy
Genetic counseling All affected/at-risk individuals Genetic Counseling (NCIT:C15709)

Cochlear implantation is "an established surgical intervention for patients with severe to profound sensorineural hearing loss" (PMID: 41306947), with favorable long-term outcomes: large series report overall complication rates ~10.7% (≈6% minor, ≈4.7% major), and "The ten-year overall revision surgery necessity of CI received patients was found to be 5.9%" (PMID: 41699244). Bilateral simultaneous implantation reduces cumulative anesthesia/surgical exposure relative to sequential implantation without increasing complications (PMID: 41699244). Emerging totally implantable cochlear-implant systems show feasibility with significant speech-perception gains (PMID: 41243136), and cochlear stimulation can additionally mitigate tinnitus in some patients (PMID: 41194213).

Pharmacotherapy, gene/cell/RNA therapy, immunotherapy, pharmacogenomics: none established or approved for DFNA75. Gene-directed therapies for inner-ear disorders remain investigational and none targets TRRAP.

Section 13 — Prevention

  • Primary prevention: Not applicable for a Mendelian dominant disorder — the disease cannot be prevented at the individual genetic level. Generic cochlear-protective measures (avoiding excessive noise and ototoxic drugs) may limit additive hearing loss.
  • Secondary prevention: Early detection via newborn/pediatric hearing screening and audiometric surveillance in at-risk families enables timely amplification/implantation to preserve communication function.
  • Tertiary prevention: Aural rehabilitation and cochlear implantation prevent the functional/communication complications of advanced hearing loss.
  • Genetic counseling and reproductive options: Autosomal dominant inheritance implies a 50% transmission risk to offspring of an affected individual. Once the familial TRRAP variant is known, cascade testing, prenatal diagnosis, and preimplantation genetic testing are options for family planning.
  • Immunization / public-health / environmental interventions: Not applicable.

Section 14 — Other Species / Natural Disease

  • Taxonomy / orthologs: TRRAP is evolutionarily conserved. Mouse Trrap and zebrafish trrap are functional orthologs used in disease modeling.
  • Natural disease in other species: No naturally occurring TRRAP-related hearing-loss disease has been documented in companion animals or wildlife (knowledge gap; no OMIA entry reported for this phenotype).
  • Comparative biology / conservation: Deep conservation of TRRAP and its HAT-scaffold function supports cross-species mechanistic modeling. Zebrafish trrap mutants recapitulate developmental phenotypes including inner-ear defects (PMID: 31231791) and craniofacial anomalies — "The trrap zebrafish mutants exhibited smaller eyes and heads than the wild-type zebrafish. The size of the ventral pharyngeal arches was reduced and the mineralization of teeth was impaired" (PMID: 34934055).
  • Transmission / zoonosis: Not applicable (genetic, non-transmissible).

Section 15 — Model Organisms

Model Type Key finding Source
Zebrafish (Danio rerio) Morpholino knockdown & CRISPR/Cas9 knockout of trrap Significant inner-ear developmental defects — validates DFNA75 causation PMID: 31231791
Zebrafish trrap mutant Smaller eyes/heads; reduced pharyngeal arches; impaired tooth mineralization (craniofacial roles) PMID: 34934055
Mouse (Mus musculus) Germline Trrap knockout Early embryonic lethality; reveals essential role in proliferation PMID: 24675885
Mouse B-cell conditional Trrap knockout Impaired B-cell development; proliferating cells undergo apoptosis PMID: 24675885
Mouse Neural conditional Trrap deletion Compromised adult hippocampal neurogenesis via Sp1 scaffolding PMID: 36618986

Phenotype recapitulation. The zebrafish trrap loss-of-function model directly recapitulates the disease-relevant phenotype (inner-ear developmental defects), providing the strongest functional support for DFNA75 causation. Limitations: the zebrafish inner ear differs anatomically from the mammalian cochlea; embryonic lethality of the mouse null precludes simple whole-animal study of adult hearing; and no dedicated Trrap p.Arg171Cys knock-in hearing-loss mouse has been reported — a clear gap for modeling the specific human allele. Resources: MGI (mouse), ZFIN (zebrafish), IMPC/KOMP.

Key Findings (Expanded)

F001 — DFNA75 is caused by heterozygous TRRAP variants

Xia et al. (2019) identified the novel pathogenic variant NM_001244580 c.511C>T, p.(Arg171Cys) in TRRAP co-segregating with post-lingual progressive ADNSHL across a three-generation Chinese family, and found three additional novel TRRAP variants among 66 sporadic hearing-loss cases. The authors reported "a novel pathogenic variant (NM_ 001244580, c.511C>T, p.Arg171Cys) in the TRansformation/tRanscription domain-Associated Protein gene associated with hearing loss in a three-generation Chinese family with ADNSHL," and that "Knockdown or knockout of TRRAP resulted in significant defects in the inner ear of zebrafish, indicating that TRRAP plays an important role in inner ear development" (PMID: 31231791). DFNA75 corresponds to OMIM #618778.

F002 — TRRAP is a highly constrained PIKK scaffold with an allelic neurodevelopmental disorder (DEDDFA)

Distinct germline TRRAP missense alleles cause DEDDFA (OMIM #618454). Cogné et al. reported 17 distinct de novo/apparently de novo variants in 24 individuals, noting "TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals" (PMID: 30827496). Domain-specific genotype–phenotype correlation is emerging: variants clustering between residues 1031–1159 "result in more pronounced facial anomalies associated with a variable degree of intellectual disability" (PMID: 41952423). This allelic relationship is critical for interpretation: TRRAP variant location and type dictate whether the outcome is isolated hearing loss (DFNA75) or a multisystem neurodevelopmental syndrome.

F003 — TRRAP mechanism: HAT-complex adaptor and transcription-factor scaffold

TRRAP is "the only member lacking the enzymatic activity in this family, [and] is an adaptor protein for several histone acetyltransferase (HAT) complexes and a scaffold protein for multiple transcription factors" (PMID: 34830324). It is a subunit of STAGA/SAGA (with GCN5) and TIP60/NuA4, and coactivates MYC via multivalent contacts — "we identify both TRRAP and the GCN5 acetyltransferase as MYC TAD-interacting subunits within native STAGA" (PMID: 24705139). It scaffolds Sp1 to regulate microtubule dynamics and adult neurogenesis (PMID: 36618986), and is essential for proliferation (embryonic lethality on knockout; apoptosis of proliferating B cells, PMID: 24675885). Zebrafish trrap mutants show reduced eyes/heads and pharyngeal-arch/tooth defects (PMID: 34934055).

F004 — DFNA75 phenotype: post-lingual, progressive, bilateral SNHL

The index family had post-lingual progressive ADNSHL; the aim was stated as "to identify the causative gene mutation for post-lingual progressive ADNSHL in a Chinese family" (PMID: 31231791). Nonsyndromic hearing impairment "is almost exclusively caused by cochlear defects, [so] affected patients suffer from sensorineural hearing loss," and "Postlingual nonsyndromic HIH usually follows an autosomal dominant trait" (PMID: 15850684).

F005 — Management is supportive: amplification and cochlear implantation

No curative therapy exists. Cochlear implantation is "an established surgical intervention for patients with severe to profound sensorineural hearing loss" (PMID: 41306947), with a 10-year revision surgery necessity of 5.9% (PMID: 41699244).

F006 — Diagnosis relies on WES/gene-panel testing of TRRAP (HGNC:12347, 7q22.1)

Diagnosis in the original family used "Whole-exome sequencing, bioinformatic analysis, and Sanger sequencing... to verify the co-segregation of a novel pathogenic variant" (PMID: 31231791). Substantial genetic heterogeneity — "One percent of the total human genes, i.e. 300-500, are estimated to cause syndromic and nonsyndromic HIH" (PMID: 15850684) — justifies panel/WES over single-gene testing.

F007 — TRRAP has a distinct somatic oncogenic role, separate from germline DFNA75

Whole-exome sequencing of melanoma found that "TRRAP harbored a recurrent mutation that clustered in one position (p. Ser722Phe) in 6 out of 167 affected individuals (∼4%)," and "The nature, pattern and functional evaluation of the TRRAP recurrent mutation suggest that TRRAP functions as an oncogene" (PMID: 21499247). This somatic, cancer-specific event is mechanistically and clinically distinct from the germline heterozygous variants that cause DFNA75.

Mechanistic Model / Interpretation

 Germline TRRAP missense variant (e.g., c.511C>T, p.Arg171Cys)
 [gene among top-5 most missense-intolerant]
      │
      ▼
 Altered TRRAP scaffold protein (PIKK pseudokinase, ~3830 aa, nuclear)
      │  impaired assembly of HAT complexes & TF partners
      ▼
 Disrupted STAGA/SAGA(GCN5) & TIP60/NuA4 recruitment;
 altered Sp1 / c-Myc / p53 / E2F1 coactivation
      │  aberrant histone acetylation → dysregulated transcription
      ▼
 Impaired proliferation/differentiation of inner-ear cells
 (demonstrated: zebrafish trrap KD/KO → inner-ear defects)
      │
      ▼
 Progressive cochlear (sensorineural) dysfunction ── bilateral ──► DFNA75
                                                            (post-lingual,
                                                             progressive SNHL)

 ── ALLELIC BRANCHES (same gene, different variant/context) ──
   • Other germline missense (e.g., res. 1031–1159) → DEDDFA neurodevelopmental syndrome
   • Somatic p.Ser722Phe in melanocytes → oncogenic driver in melanoma

The unifying theme is that TRRAP is a dosage- and interface-sensitive transcriptional scaffold: the identity and location of the variant, together with germline-versus-somatic context, determines the clinical phenotype. DFNA75 represents the tissue-restricted (cochlear) consequence of specific germline TRRAP alleles that impair inner-ear developmental transcription while sparing broader neurodevelopment.

Evidence Base

PMID Title (abbreviated) Role in this report
31231791 Novel TRRAP mutation causes autosomal dominant non-syndromic hearing loss Defining paper — causal variant, phenotype, zebrafish validation
40004049 Novel pathogenic variant of TRRAP (ADNSHL) Independent replication of TRRAP as an ADNSHL gene
30827496 Missense variants in TRRAP cause autism and syndromic ID Allelic DEDDFA disorder; extreme missense constraint
41952423 Variants in cluster 1031–1159 of TRRAP Domain-specific genotype–phenotype correlation
34830324 Beyond HAT Adaptor: TRRAP–Sp1 transcription TRRAP molecular function (HAT adaptor/scaffold)
24705139 MYC interacts with STAGA via GCN5 & TRRAP TRRAP in STAGA complex; MYC coactivation
36618986 TRRAP-mediated acetylation on Sp1 regulates neurogenesis Scaffold role in adult neurogenesis
24675885 Tissue-specific inactivation of TRRAP in B cells Essential proliferation role; embryonic lethality
24075908 Elk-1 recruits TIP60/NuA4 TRRAP-associated TIP60/NuA4 complex biology
34934055 Zebrafish trrap in craniofacial development Model-organism developmental roles
15850684 Nuclear/mitochondrial genes in nonsyndromic hearing Context: cochlear/sensorineural nature, AD trait, heterogeneity
41306947 Complications in cochlear implant surgery CI as standard management of severe-profound SNHL
41699244 CI complications & bilateral vs sequential outcomes CI outcome/revision data
41243136 Totally implantable cochlear implant feasibility Emerging CI technology
41194213 EMLR and CI effects in tinnitus CI benefit for associated tinnitus
21499247 Exome sequencing identifies GRIN2A/TRRAP in melanoma Distinct somatic oncogenic TRRAP role

Evidence quality note. The germline DFNA75 causal evidence rests primarily on a single index family plus sporadic cases with functional support from a zebrafish loss-of-function model (human clinical + model organism). Mechanistic inferences about HAT-scaffold disruption in the cochlea are extrapolated from TRRAP's general biology (in vitro / other-tissue models), not directly demonstrated for DFNA75 alleles in cochlear tissue.

Limitations and Knowledge Gaps

  • Small evidence base: DFNA75 is defined by one detailed family plus limited sporadic/additional cases. Penetrance, expressivity, audiometric progression curves, and prevalence are not quantified.
  • Allele-specific mechanism unproven in ear: The exact functional consequence (haploinsufficiency vs dominant-negative) of p.Arg171Cys and other DFNA75 alleles has not been demonstrated in cochlear cells; a knock-in mammalian hearing model is lacking.
  • Genotype–phenotype boundary: Why some TRRAP variants yield isolated hearing loss (DFNA75) versus multisystem DEDDFA is not fully resolved; domain/interface mapping is incomplete.
  • No modifiers, epigenetic, or environmental data specific to DFNA75.
  • No disease-specific QoL, natural-history, or veterinary data.
  • No targeted therapy; all management is generic SNHL supportive care.

Proposed Follow-up Experiments / Actions

  1. Case ascertainment and registry: Aggregate additional TRRAP-variant hearing-loss families (e.g., via GeneMatcher/hearing-loss consortia) to quantify penetrance, expressivity, and audiometric progression, and to map DFNA75-specific vs DEDDFA-specific variant domains.
  2. Allele-specific functional assays: Introduce p.Arg171Cys and other DFNA75 alleles into cochlear-relevant cell/organoid systems (inner-ear organoids, iPSC-derived otic cells) and assess TRRAP scaffold integrity, HAT-complex assembly, and target-gene acetylation/expression.
  3. Knock-in mouse model: Generate a Trrap p.Arg171Cys knock-in (or cochlea-conditional) mouse to test whether it recapitulates progressive SNHL and to localize affected cochlear cell types (hair cells vs supporting cells).
  4. Structure–function mapping: Use AlphaFold/cryo-EM of TRRAP within STAGA/TIP60 to model how DFNA75 versus DEDDFA missense positions perturb specific protein interfaces.
  5. Cochlear cell-type resolution: Apply single-cell/spatial transcriptomics of the developing inner ear (mouse/zebrafish) under TRRAP perturbation to define the cell populations and gene programs disrupted.
  6. Standardize diagnostics: Ensure TRRAP is included on comprehensive ADNSHL gene panels and provide ACMG-based reclassification support for new variants; implement cascade testing and genetic counseling protocols for identified families.
  7. Clinical outcome tracking: Follow hearing-aid and cochlear-implant outcomes in genetically confirmed DFNA75 patients to establish genotype-informed rehabilitation expectations.

Report compiled from a 5-iteration autonomous investigation: 7 confirmed findings, 20 papers reviewed. Evidence types are indicated throughout (human clinical, model organism, in vitro, computational/inferred).

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 16
Resolved 16
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 23
Quoted claims found in source 23
Quoted claims not found in source 0
References weighed for topical relevance 16
On topic 4
Off topic 1

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

  • PMID:41699244 (7 mentions) - Analysis of cochlear implant complications, outcomes of bilateral simultaneous and sequential implantation, and revision cases: a decade of experience.
  • shared terms: cochlear

Weighed against this report's own most characteristic terms: trrap, hearing, dfna75, loss, cochlear, gene, variant, family, sensorineural, functional, dominant, nonsyndromic, function, genetic, autosomal, progressive, zebrafish, phenotype, cell, adnshl.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.

Term Validation

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

Outcome Count
Terms checked 20
Resolved 18
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 1
Terms whose name was checked 19
Terms named correctly 14
Terms named as a different term 2
Terms whose name is worth a second look 3

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • CL:0002218 (1 mention) - the report calls it "inner ear hair cell"; CL calls it immature dendritic epithelial T cell precursor
  • NCIT:C50072 (1 mention) - the report calls it "Hearing Aid"; NCIT calls it Modem Device

Obsolete terms

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

  • GO:0016573 (obsolete histone acetylation) (1 mention)

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:

  • GO:0016573 (1 mention) - the report calls it "histone acetylation"; GO calls it obsolete histone acetylation
  • UBERON:0002227 (1 mention) - the report calls it "organ of Corti"; UBERON calls it spiral organ of cochlea, and lists "organ of Corti" among its other names
  • NCIT:C15709 (1 mention) - the report calls it "Genetic Counseling"; NCIT calls it Genetic Testing