Autosomal Recessive Nonsyndromic Hearing Loss 35

Mendelian MONDO:0012060 Pathograph 26 Show in embeddings browser Autosomal Recessive Nonsyndromic Hearing Loss

DFNB35 is autosomal recessive bilateral sensorineural hearing loss caused by biallelic pathogenic variants in ESRRB, encoding the orphan nuclear receptor ERR-beta (NR3B2). Reported families usually have prelingual severe-to-profound loss, although moderate severity, asymmetry and progression occur. The reported missense predominance does not establish residual function for every allele. The recurrent p.Arg382Cys variant impaired protein stability and reporter activity in cultured cells but remained a variant of uncertain significance in the 2024 study. Mouse loss-of-function experiments implicate defective strial marginal-cell differentiation and ion-transporter expression, with secondary intermediate-cell and capillary abnormalities. Developmental mouse RNA localization and postnatal rat immunohistochemistry also place ESRRB in nonsensory and neural cochlear compartments. Absent otoacoustic emissions in two affected Turkish relatives support outer-hair-cell dysfunction; the proposed secondary origin is inferred from rodent expression rather than demonstrated in human cochlear tissue. Vestibular findings vary across small reports: two Turkish adults had normal caloric testing, whereas a pediatric implant-candidate series reported abnormal cervical vestibular evoked myogenic potentials in its one ESRRB-associated case. Severe caries was reported in affected and heterozygous members of a Turkish family, whereas the affected Czech child was caries-free at age four. Its frequency and an ESRRB-specific enamel mechanism remain uncertain.

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1
Inheritance
10
Pathophys.
7
Phenotypes
3
Gaps
26
Pathograph
1
Genes
10
Variants
4
Medical Actions
1
Datasets
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Models
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References
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Deep Research
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Inheritance

1
Autosomal recessive HP:0000007
Biallelic ESRRB variants. Most reported pedigrees are consanguineous and homozygous - Turkish, Pakistani, Tunisian, Czech - with unaffected heterozygous parents. The compound heterozygous configuration is the exception and has been documented in a Korean family and a Han Chinese family, both carrying p.Arg382Cys in trans with a second allele.
Autosomal recessive inheritance
Show evidence (3 references)
PMID:18179891 SUPPORT DIRECT Human Clinical
"Mutation analysis of ESRRB, a candidate gene in the overlapping region, revealed a homozygous 7 bp duplication in exon 8 in all affected individuals."
Homozygosity in every affected member of the consanguineous Turkish family that defined the gene, which is the recessive pattern.
PMID:22951369 SUPPORT DIRECT Human Clinical
"Mutation p.R291L in a homozygous state was found in the deaf child, the parents were heterozygous."
Segregation in the Czech family: homozygous in the affected child, heterozygous and unaffected in both parents.
PMID:39261511 SUPPORT DIRECT Human Clinical
"Consequently, the majority of reported cases exhibited homozygous zygosity except the p.(Arg382Cys) variant, which presented as a compound heterozygous variant in trans with either c.16A>G in a Han Chinese family or c.397 + 2T>G in a South Korean family."
States the zygosity distribution across the whole reported literature, and names the two compound heterozygous exceptions.
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Discussions and Knowledge Gaps

3
Does loss of ERR-beta actually raise hearing thresholds in a mouse, and by how much?
HUMAN MODEL MISMATCH dfnb35_strial_failure_to_threshold
Attached to
pathophysiology#Impaired Endolymph Homeostasis
Mouse loss-of-function evidence supports defective strial development, and the 2008 gene-discovery paper summarizes defective hearing, balance and endolymph production in rescued or conditional-null mice. The available records do not provide a verified quantitative genotype-dependent ABR, DPOAE or endocochlear-potential comparison. Human missense alleles should not be assumed to retain function without assay evidence. Comparing null and defined missense alleles would clarify dose dependence; human vestibular results include both normal caloric testing and a single abnormal cVEMP report.
Proposed experiments
Auditory brainstem response and endocochlear potential in a conditional Esrrb inner-ear knockout
dfnb35_exp_abr_ep_conditional_ko
Measure longitudinal ABR, DPOAE, endocochlear potential and vestibular responses in conditional-null animals and a defined human-variant knock-in such as p.Arg382Cys, including the variant in trans with a null allele. This tests the proposed hypomorphic mechanism without assuming it.
Would support
pathophysiology#Impaired Endolymph Homeostasis
Would refute
pathophysiology#Impaired Endolymph Homeostasis
Supporting outcome
  • Elevated ABR thresholds together with a reduced endocochlear potential and reduced endolymphatic potassium, with the missense knock-in showing an intermediate deficit.
Refuting outcome
  • Normal endocochlear potential and normal ABR thresholds despite the documented marginal cell fate defect, which would mean the fate conversion is compensated and the deafness arises somewhere else.
Does ESRRB dysfunction increase caries susceptibility beyond age, dental care and environmental influences?
KNOWLEDGE GAP dfnb35_is_it_really_nonsyndromic
Attached to
phenotypes#Increased Dental Caries Experience
The Turkish pedigree had severe caries in six affected homozygotes and four heterozygotes, while the Czech affected child was caries-free at four years. Telephone histories and unequal dental-care access limit interpretation. Normal mouse ameloblast expression and common-SNP associations do not establish a DFNB35-specific enamel defect. Standardized dental examination across genotypes is needed to assess this association.
Proposed experiments
DMFT scoring in reported DFNB35 pedigrees
dfnb35_exp_dmft_pedigrees
Score decayed, missing and filled teeth in affected homozygotes, heterozygous relatives and unaffected relatives across the reported DFNB35 families, controlling for age and access to dental care, which is the obvious confounder in consanguineous cohorts from different countries.
Would support
phenotypes#Increased Dental Caries Experience
Would refute
phenotypes#Increased Dental Caries Experience
Supporting outcome
  • Higher DMFT in biallelic carriers than in their unaffected relatives across multiple independent pedigrees.
Refuting outcome
  • No DMFT difference between biallelic carriers and relatives once age and dental access are matched, which would make the two-family observation a confound of socioeconomic ascertainment.
How often is vestibular function affected in ESRRB-related hearing loss, and does it depend on genotype or the vestibular test used?
KNOWLEDGE GAP dfnb35_absent_vestibular_phenotype
Attached to
phenotypes#
Vestibular function is not uniformly unexamined or uniformly abnormal. Collin et al. reported normal caloric testing in two Turkish adults; Wang et al. reported abnormal cVEMP but normal rotary-chair testing in one pediatric ESRRB-associated case. The latter finding is tabulated rather than individually discussed in the narrative. Different tests sample different vestibular end organs, and these small reports cannot define penetrance or establish a simple species discordance with null mice.
Proposed experiments
Vestibular testing in molecularly confirmed DFNB35 patients
dfnb35_exp_vestibular_testing
Video head impulse testing, cervical and ocular VEMPs and caloric testing in biallelic ESRRB patients, who are largely already in contact with cochlear implant programmes where such testing is routine.
Would support
pathophysiology#Failure of the Strial Marginal Cell Secretory Programme
Would refute
pathophysiology#Failure of the Strial Marginal Cell Secretory Programme
Supporting outcome
  • Reduced VEMP responses or caloric hypofunction in a substantial fraction of DFNB35 patients, which would extend the dark cell arm of the mechanism into the clinic.
Refuting outcome
  • Consistently normal results across canal and otolith tests in a larger genotype-defined series would argue against a common vestibular deficit, while not negating the existing single-case result.
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Pathophysiology

10
ESRRB Loss of Function
Mechanism confidence: Established
Biallelic ESRRB variants impair the function of an orphan nuclear-receptor transcription factor. Reported alleles include missense substitutions in the DNA-binding and ligand-binding domains, frameshift, nonsense, splice and in-frame variants. The founding c.1018_1024dupGAGTTTG allele predicts p.Val342GlyfsTer44; nonsense-mediated decay or an abnormal truncated protein were alternative hypotheses in the original paper. Exon-4 skipping and transcript stabilization by cycloheximide support nonsense-mediated decay for c.397+2T>G. Missense status alone does not establish a hypomorphic effect, and residual function has not been measured across the allelic spectrum.
ESRRB hgnc:3473 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ESRRB (hgnc:3473). hgnc:3473 is a gene from the HUGO Gene Nomenclature Committee.
ERR-beta nuclear receptor transcription factor activity GO:0004879 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased ERR-beta nuclear receptor transcription factor activity, annotated with nuclear receptor activity (GO:0004879). GO:0004879 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Failure of the Strial Marginal Cell Secretory Programme ERR-beta is the transcription factor that installs and maintains the endolymph secretory programme in strial marginal cells, so reduced ERR-beta activity is read out directly as failure of that programme.
Partial Marginal Cell Fate Transformation Null marginal cells partially shift epithelial identity in the mouse model.
Secondary Strial Intermediate Cell Expression Changes Loss of Nr3b2 in marginal cells produces a non-cell-autonomous intermediate-cell response in mosaic mice.
Local Strial Capillary Loss Mosaic null marginal-cell regions show local capillary loss; the intervening signal is unresolved.
Reduced Stability of ESRRB Arg382Cys Protein The p.Arg382Cys allele specifically reduced protein stability in overexpression assays; this consequence is not assigned to all ESRRB variants.
Show evidence (4 references)
PMID:18179891 SUPPORT DIRECT Human Clinical
"Sequence analysis of the ESRRB gene in the affected individuals of the original DFNB35 family and in three other DFNB35-linked consanguineous families from Pakistan revealed four missense mutations."
Establishes that the founding DFNB35 alleles are predominantly missense rather than truncating.
PMID:18179891 SUPPORT INDIRECT Computational
"Molecular modeling of this nuclear receptor showed that the missense mutations are likely to affect the structure and stability of these domains."
The original mechanistic argument for these missense alleles was structural modelling, not an assay - graded COMPUTATIONAL and INDIRECT for that reason.
PMID:39261511 SUPPORT DIRECT Human Clinical
"Of the 19 coding variants, all were located in functional domains except for one variant (c.16A>G:p.Arg6Gly). Nine were resided in the LBD while the remaining 9 were positioned in the DNA binding domain (DBD)."
The domain distribution of the reported coding alleles, which is the basis for describing DFNB35 as a domain-restricted loss of transcription factor function.
+ 1 more reference
Reduced Stability of ESRRB Arg382Cys Protein
Mechanism confidence: Established
Overexpressed ESRRB p.Arg382Cys protein had reduced stability in cycloheximide-chase assays in HEI-OC1 and HEK293T cells. Nuclear localization was not significantly altered. These assay findings do not establish clinical pathogenicity or a shared effect of every ESRRB allele.
Downstream
Reduced ERR-beta Transcriptional Output at Target Promoters Reduced stability is a proposed contributor to lower reporter output; the experiments did not isolate it from other effects of the variant.
Show evidence (2 references)
PMID:39261511 SUPPORT DIRECT In Vitro
"Consistent with molecular modeling and dynamics studies, the stability of the ESRRB p.(Arg382Cys) variant was significantly reduced compared to that of the wild-type"
Cycloheximide chase showed reduced mutant protein stability in HEI-OC1 and HEK293T cells. Its contribution to reduced reporter activity is plausible but was not separated experimentally from other functional effects.
PMID:39261511 SUPPORT DIRECT In Vitro
"However, immunocytochemistry data showed that there was no significant difference in the translocation ability of ESRRB into the nucleus between the mutant and the wild type"
No significant difference in nuclear localization was detected under the tested overexpression conditions; this does not exclude every possible trafficking defect.
Reduced ERR-beta Transcriptional Output at Target Promoters
Mechanism confidence: Established
ESRRB p.Arg382Cys reduced SMAD7-promoter reporter activation in HEI-OC1 and HEK293T cells. Wild-type overexpression produced 2.09-fold and 2.21-fold activity relative to the internal control, whereas mutant values of 1.19-fold and 1.24-fold were not significantly different from that control. This supports impaired transcriptional output in the assay systems without proving zero residual activity or clinical pathogenicity. In family-derived lymphoblastoid cells, ATP1B1 and EGR1 were lower in the proband and the unaffected mother than in the father; NRP1, TBX3 and SPARC were lower in the proband and father than in the mother. These comparisons do not establish direct promoter binding or corresponding changes in the intact inner ear.
regulation of transcription by ERR-beta at target promoters GO:0006355 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased regulation of transcription by ERR-beta at target promoters, annotated with regulation of DNA-templated transcription (GO:0006355). GO:0006355 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Failure of the Strial Marginal Cell Secretory Programme Reduced transcription of ion-handling genes provides a candidate route from ESRRB dysfunction to strial failure. The human-variant reporter and lymphoblastoid experiments did not test marginal-cell differentiation or secretion.
Show evidence (2 references)
PMID:39261511 SUPPORT DIRECT In Vitro
"Transient overexpression of the ESRRB wild-type significantly increased luciferase activity, demonstrating a 2.09-fold increase relative to the internal control in HEI-OC1 cells (p < 0.01) and 2.21-fold in HEK293T cells (p < 0.01). However, the luciferase activity of ESRRB mutant did not exhibit..."
Wild-type overexpression activated the SMAD7 reporter; mutant activity was not significantly above the internal control. This is not a measurement of complete loss of endogenous transcription.
PMID:39261511 SUPPORT DIRECT In Vitro
"we observed marked decreases in mRNA levels of ATP1B1 and EGR1 (decreased 55.1% and 45.4% respectively)"
The reductions of ATP1B1 and EGR1 were measured in proband lymphoblastoid cells relative to the father; the unaffected mother also showed reductions. They are not measurements in strial tissue.
Failure of the Strial Marginal Cell Secretory Programme
Mechanism confidence: Established
Loss of Nr3b2/Esrrb in mouse strial marginal cells prevents expression of multiple ion-channel and transporter genes required for the endolymph-producing epithelial program. ERR-beta also acts in vestibular dark cells. This node describes the gene-expression defect; the partial cell-fate change and secondary strial effects are modeled separately.
strial marginal cell CL:0002492 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves strial marginal cell (CL:0002492). CL:0002492 is a cell type from the Cell Ontology. vestibular dark cell CL:0000846 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves vestibular dark cell (CL:0000846). CL:0000846 is a cell type from the Cell Ontology.
potassium ion transport into endolymph GO:0006813 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased potassium ion transport into endolymph, annotated with potassium ion transport (GO:0006813). GO:0006813 is a biological process from the Gene Ontology. ↓ DECREASED
stria vascularis of the cochlear duct UBERON:0002282 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in stria vascularis of the cochlear duct, annotated with stria vascularis of cochlear duct (UBERON:0002282). UBERON:0002282 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Nr3b2 (Esrrb) null mouse, including genetically mosaic animals Mouse recapitulates Null mouse marginal cells fail to express multiple ion-channel and transporter genes. This directly models the secretory gene-expression node.
Downstream
Impaired Endolymph Homeostasis The marginal cells are the endolymph-producing epithelium; a marginal cell that never acquires its transporter repertoire cannot secrete.
Show evidence (2 references)
PMID:17765677 SUPPORT DIRECT Model Organism
"We show here that estrogen-related receptor beta (ERR-beta; NR3B2), an orphan nuclear receptor, is specifically expressed in and controls the development of the endolymph-producing cells of the inner ear: the strial marginal cells in the cochlea and the vestibular dark cells in the ampulla and utricle."
Localises ERR-beta function to exactly these two cell types, which is what puts the DFNB35 lesion in the lateral wall rather than in the hair cell.
PMID:17765677 SUPPORT DIRECT Model Organism
"Nr3b2(-/-) strial marginal cells fail to express multiple ion channel and transporter genes"
The null marginal cells lose expression of the secretory machinery. This is a mouse result, not a direct measurement in human strial tissue.
Partial Marginal Cell Fate Transformation
Mechanism confidence: Established
Nr3b2-null mouse strial marginal cells partially acquire the identity of neighboring Pendrin-expressing epithelial cells. This is a partial fate transformation, not evidence that every marginal cell disappears or becomes an identical mature neighboring cell.
strial marginal cell CL:0002492 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves strial marginal cell (CL:0002492). CL:0002492 is a cell type from the Cell Ontology.
stria vascularis of the cochlear duct UBERON:0002282 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in stria vascularis of the cochlear duct, annotated with stria vascularis of cochlear duct (UBERON:0002282). UBERON:0002282 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Nr3b2 (Esrrb) null mouse, including genetically mosaic animals Mouse recapitulates Nr3b2-null mouse strial marginal cells partially acquire the identity of neighboring Pendrin-expressing epithelial cells. This is a partial fate transformation, not evidence that every marginal cell disappears or becomes an identical mature neighboring cell.
Show evidence (1 reference)
PMID:17765677 SUPPORT DIRECT Model Organism
"they show a partial transformation toward the fate of the immediately adjacent Pendrin-expressing epithelial cells"
The authors distinguish a partial identity change from loss of transporter expression.
Secondary Strial Intermediate Cell Expression Changes
Mechanism confidence: Established
In genetically mosaic mice, Nr3b2-null marginal cells induce secondary changes in gene expression in the underlying intermediate-cell layer. This establishes a local non-cell-autonomous effect, without identifying a specific intercellular signal.
strial intermediate cell CL:0002486 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves strial intermediate cell (CL:0002486). CL:0002486 is a cell type from the Cell Ontology.
stria vascularis of the cochlear duct UBERON:0002282 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in stria vascularis of the cochlear duct, annotated with stria vascularis of cochlear duct (UBERON:0002282). UBERON:0002282 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Nr3b2 (Esrrb) null mouse, including genetically mosaic animals Mouse recapitulates In genetically mosaic mice, Nr3b2-null marginal cells induce secondary changes in gene expression in the underlying intermediate-cell layer. This establishes a local non-cell-autonomous effect, without identifying a specific intercellular signal.
Show evidence (1 reference)
PMID:17765677 SUPPORT DIRECT Model Organism
"Nr3b2(-/-) strial marginal cells produce secondary alterations in gene expression in the underlying intermediate cells"
Mosaic analysis links mutant marginal cells to altered expression in the neighboring strial layer.
Local Strial Capillary Loss
Mechanism confidence: Established
Local loss of strial capillaries accompanies Nr3b2-null marginal-cell regions in mosaic mice. The primary abstract reports the vascular consequence without establishing its temporal order relative to intermediate-cell expression changes or specifying the vascular signaling mechanism.
stria vascularis of the cochlear duct UBERON:0002282 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in stria vascularis of the cochlear duct, annotated with stria vascularis of cochlear duct (UBERON:0002282). UBERON:0002282 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Nr3b2 (Esrrb) null mouse, including genetically mosaic animals Mouse recapitulates Local loss of strial capillaries accompanies Nr3b2-null marginal-cell regions in mosaic mice. The primary abstract reports the vascular consequence without establishing its temporal order relative to intermediate-cell expression changes or specifying the vascular signaling mechanism.
Show evidence (1 reference)
PMID:17765677 SUPPORT DIRECT Model Organism
"In genetically mosaic mice, Nr3b2(-/-) strial marginal cells produce secondary alterations in gene expression in the underlying intermediate cells and a local loss of strial capillaries."
The capillary finding is separated from the intermediate-cell expression phenotype; no serial causal order between them is inferred.
Impaired Endolymph Homeostasis
Mechanism confidence: Provisional
Defective marginal-cell differentiation and ion-transporter expression are proposed to impair cochlear endolymph production and ionic homeostasis. The 2008 gene-discovery paper summarizes disturbed endolymph production with defective hearing and balance in conditional-null mice. The available cached primary abstract establishes strial cellular abnormalities but supplies no numerical endocochlear potential, endolymph potassium or volume measurement. Quantitative extrapolation to human variants remains unresolved.
strial marginal cell CL:0002492 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves strial marginal cell (CL:0002492). CL:0002492 is a cell type from the Cell Ontology.
potassium ion homeostasis of endolymph GO:0055075 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated potassium ion homeostasis of endolymph, annotated with potassium ion homeostasis (GO:0055075). GO:0055075 is a biological process from the Gene Ontology. ↕ DYSREGULATED
stria vascularis of the cochlear duct UBERON:0002282 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in stria vascularis of the cochlear duct, annotated with stria vascularis of cochlear duct (UBERON:0002282). UBERON:0002282 is an anatomical location from the Uberon multi-species anatomy ontology. endolymph UBERON:0001852 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in endolymph (UBERON:0001852). UBERON:0001852 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Nr3b2 (Esrrb) null mouse, including genetically mosaic animals Mouse partially recapitulates The 2008 gene-discovery paper summarizes impaired endolymph production and defective hearing and balance in conditional-null Esrrb mice.
Downstream
Secondary Outer Hair Cell Dysfunction Disturbed ionic support is a candidate explanation for secondary sensory dysfunction. The full human sequence has not been measured.
Show evidence (1 reference)
PMID:18179891 SUPPORT INDIRECT Model Organism
"Disturbed endolymph production in these mice results in an aberrant inner-ear fluid homeostasis and as a consequence in defective hearing and balance."
The human gene-discovery paper summarizes earlier conditional mouse experiments; this is indirect evidence for their physiological outcome.
Secondary Outer Hair Cell Dysfunction
Mechanism confidence: Provisional
Absent transiently evoked otoacoustic emissions in two affected Turkish relatives indicate outer-hair-cell dysfunction. Collin et al. proposed a secondary origin because ESRRB was not detected in rodent cochlear sensory hair cells. The upstream cause is inferred from animal localization and human audiology; neither hair-cell death nor the precise strial-to-hair-cell mechanism was measured in these patients.
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.
Downstream
Absent Otoacoustic Emissions Loss of measurable outer-hair-cell emissions is the functional readout observed in the Turkish relatives.
Bilateral Sensorineural Hearing Impairment Reduced outer-hair-cell function can contribute to cochlear hearing impairment; the proportion of DFNB35 severity attributable to this process is not established.
Show evidence (3 references)
PMID:18179891 SUPPORT DIRECT Human Clinical
"Transient otoacoustic emission spectra (TEOAEs) were absent in two individuals"
The two tested Turkish relatives had absent emissions, supporting impaired outer-hair-cell function.
PMID:18179891 SUPPORT DIRECT Model Organism
"No ESRRB expression was detected in the sensory cells in the organ of Corti, but only in the supporting cells"
P4 rat immunohistochemistry supports a nonsensory localization under the tested conditions; it does not directly demonstrate the origin of human dysfunction.
PMID:18179891 SUPPORT INDIRECT Other
"Because ESRRB is not expressed in these cells, the loss of outer hair cell function is probably a secondary effect."
The proposed secondary mechanism is the authors' inference combining human audiology with rodent localization.
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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 Autosomal Recessive Nonsyndromic Hearing Loss 35 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 6
Bilateral Sensorineural Hearing Impairment OBLIGATE 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.
Bound to the bilateral term because no unilateral DFNB35 case has been reported. The first quoted sentence establishes the sensorineural type across the literature but not laterality; laterality rests on the individual pedigree audiograms, of which the Iranian family is one.
Show evidence (2 references)
PMID:39261511 SUPPORT DIRECT Human Clinical
"In all affected DFNB35 patients, the type of hearing loss was identified as SNHL."
A statement across the whole reported DFNB35 literature that the loss is sensorineural in every case.
PMID:35101039 SUPPORT DIRECT Human Clinical
"Our study evaluated the genetic cause of bilateral severe to profound HL in an Iranian family with Azeri Turkish ethnicity."
Bilaterality stated for an individual DFNB35 family, which is what the cross-literature sentence above does not supply.
Severe to Profound Hearing Impairment Severe sensorineural hearing impairment HP:0008625 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe sensorineural hearing impairment (HP:0008625). HP:0008625 is a phenotype from the Human Phenotype Ontology.
The node is named "Severe to Profound" but the binding is HP:0008625, *Severe* sensorineural hearing impairment, which is the narrower of the two. That direction is deliberate: HPO has no combined severe-to-profound term, and binding to the profound term instead would over-state severity for the patients at the severe end. The broader range is carried by `preferred_term` and by the description, which the term contract permits.
Show evidence (3 references)
PMID:39261511 SUPPORT DIRECT Human Clinical
"The majority of hearing loss phenotypes exhibited symmetry, prelingual onset, and severe-to-profound SNHL, whereas our proband showed asymmetric hearing loss with a progressive nature."
Describes the majority pattern and the documented exception without supplying a population frequency estimate.
PMID:32681043 SUPPORT INDIRECT Human Clinical
"A missense variant in ESRRB was implicated for recessively inherited moderate to severe hearing loss."
A sporadic Pakistani case at the moderate-to-severe rather than profound end. Indirect for this phenotype because it qualifies the severity range rather than asserting the severe-to-profound majority.
PMID:35101039 SUPPORT DIRECT Human Clinical
"The audiograms show bilateral severe to profound hearing loss in (a) V4, (b) V5, and (c) V6"
Audiometric confirmation in three affected siblings of the Iranian family, which is the severe-to-profound majority pattern in a single pedigree.
Prelingual Onset Hearing Impairment Prelingual sensorineural hearing impairment HP:0000399 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prelingual sensorineural hearing impairment (HP:0000399). HP:0000399 is a phenotype from the Human Phenotype Ontology.
Prelingual onset includes congenital and early-childhood presentations; it does not require neonatal audiometric confirmation.
Show evidence (3 references)
PMID:39261511 SUPPORT DIRECT Human Clinical
"Hearing impairment was congenital or evident at prelingual onset."
The onset description for the Korean proband.
PMID:33269433 SUPPORT DIRECT Human Clinical
"This study determined the genetic causes in five Pakistani DFNB families with prelingual onset."
The ESRRB splice allele c.787+1G>A was found in this prelingual-onset series, which places at least one further DFNB35 family in the prelingual category.
PMID:35101039 SUPPORT DIRECT Human Clinical
"As stated by parents, HL was congenital, and no other abnormality indicated syndromic HL."
Congenital onset in the Iranian family, reported by parental history rather than by newborn screening - which is worth noting, because parental recall is how onset is established in most of these consanguineous pedigrees.
Progressive Hearing Impairment HP:0001730 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive hearing impairment (HP:0001730). HP:0001730 is a phenotype from the Human Phenotype Ontology.
Progression frequency cannot be estimated from this single longitudinal report.
Show evidence (2 references)
PMID:39261511 SUPPORT DIRECT Human Clinical
"Over the course of a 17-year monitoring period, audiograms exhibited a progressive nature of hearing loss in the right ear (Fig. 1b)."
Serial audiometry documented right-ear progression in the reported compound-heterozygous case.
PMID:39261511 SUPPORT DIRECT Human Clinical
"The majority of hearing loss phenotypes exhibited symmetry, prelingual onset, and severe-to-profound SNHL, whereas our proband showed asymmetric hearing loss with a progressive nature."
The authors contrast this case with the predominant symmetric severe-to-profound presentation; that contrast does not establish a numerical progression frequency.
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:18179891 SUPPORT DIRECT Human Clinical
"Transient otoacoustic emission spectra (TEOAEs) were absent in two individuals"
Both tested relatives lacked TEOAEs. The population frequency is unknown.
Vestibular Dysfunction Abnormal vestibular function HP:0001751 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal vestibular function (HP:0001751). HP:0001751 is a phenotype from the Human Phenotype Ontology.
The pediatric study classifies the case as ESRRB-associated; the molecular details require interpretation alongside its supplementary genetic table. No population frequency is assigned.
Show evidence (1 reference)
PMID:34744965 SUPPORT DIRECT Human Clinical
"| ESRRB | 0/1 | | 1/1 | | 1/1 |"
Table 2 reports normal rotary-chair testing (0/1 abnormal), abnormal cVEMP (1/1), and peripheral vestibular loss (1/1) in the sole ESRRB-associated case. VHIT and oVEMP entries are blank. Column assignments were checked against the published PDF; this selected single case does not establish population frequency or laterality.
Head and Neck 1
Increased Dental Caries Experience Carious teeth HP:0000670 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Carious teeth (HP:0000670). HP:0000670 is a phenotype from the Human Phenotype Ontology.
This is a reported association with variable expression, not an established syndromic enamel defect. The selected pedigrees and telephone histories do not provide a population frequency. General-population SNP and enamel-microhardness experiments are distinct from the DFNB35 family observations.
Show evidence (2 references)
PMID:25023176 SUPPORT DIRECT Human Clinical
"the ESRRB mutation (six homo- zygous, four heterozygous) have severe dental caries"
The Turkish family results distinguish six affected homozygotes from four hearing-unaffected heterozygotes; the observation is not limited to biallelic disease.
PMID:25023176 REFUTE DIRECT Human Clinical
"The affected four-year-old child is caries-free in his primary dentition"
The Czech affected child did not have caries at age four. This qualifies the abstract summary of two families and argues against treating caries as obligatory.
🧬

Genetic Associations

1
ESRRB
Gene: ESRRB hgnc:3473 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ESRRB (hgnc:3473). hgnc:3473 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:18179891 SUPPORT DIRECT Human Clinical
"In a large consanguineous family of Turkish origin, genome-wide homozygosity mapping revealed a locus for recessive nonsyndromic hearing impairment on chromosome 14q24.3-q34.12."
The mapping that led to ESRRB, and the chromosomal location.
Variants (10)
c.1018_1024dupGAGTTTG (p.Val342GlyfsTer44)
frameshift variant
Homozygous seven-base-pair exon-8 duplication in Turkish family TR-21, reported relative to NM_004452. The predicted frameshift is p.Val342GlyfsTer44 (original notation p.V342GfsX44). The original study proposed nonsense-mediated decay or a truncated protein lacking an intact ligand-binding domain; it did not distinguish these experimentally.
Show evidence (2 references)
PMID:18179891 SUPPORT DIRECT Human Clinical
"This duplication results in a frame shift and premature stop codon."
The predicted consequence of the founding allele.
PMID:18179891 SUPPORT DIRECT Human Clinical
"Sequence analysis of ESRRB in an affected individual of family TR-21 revealed a 7 bp duplication in exon 8"
The full text assigns c.1018_1024dupGAGTTTG and predicts p.V342GfsX44.
p.A110V, p.L320P, p.V342L, p.L347P
missense variant
The four missense alleles found in the original DFNB35 family and in three DFNB35-linked consanguineous Pakistani families. p.A110V is in the DNA-binding domain; the other three are in the ligand-binding domain.
Show evidence (1 reference)
PMID:18179891 SUPPORT DIRECT Human Clinical
"one of the substitutions (p.A110V) is located in the DNA-binding domain of ESRRB, whereas the other three are substitutions (p.L320P, p.V342L, and p.L347P) located within the ligand-binding domain"
Names the four alleles and their domain assignments, which is the origin of the DBD/LBD split that still describes the spectrum.
p.Arg382Cys (c.1144C>T) Uncertain Significance
missense variant
Recurrent ligand-binding-domain variant classified as uncertain in the 2024 study. The study reported gnomAD v4.1.0 allele frequencies of 0.007065 in East Asians and 0.002095 overall. Protein-stability, reporter and family-cell experiments added PS3-supporting evidence, leading the authors to call it a warm VUS; it was not upgraded to likely pathogenic or pathogenic. A hypomorphic effect in trans with a loss-of-function allele was proposed but not established by an in vivo model.
Show evidence (2 references)
PMID:39261511 SUPPORT DIRECT Human Clinical
"the allele frequency of p.(Arg382Cys) variant is 0.007065 among East Asian while the allele frequency among all ethnicities is 0.002095, according to the Genome Aggregation Database (gnomAD) v.4.1.0"
The population frequency that drove the VUS classification, with the population it applies to stated.
PMID:39261511 SUPPORT DIRECT In Vitro
"we obtained additional evidence of PS3_supporting, permitting the reclassification as a 'warm VUS'"
The authors' own conclusion, which stops short of likely pathogenic - worth recording precisely rather than rounding up to pathogenic.
c.397+2T>G Pathogenic
splice donor variant
Canonical donor splice-site variant found in trans with p.Arg382Cys in a Korean family. A minigene assay showed it skips exon 4, producing a premature stop codon and nonsense-mediated decay, confirmed by cycloheximide stabilisation of the transcript in patient cells.
Show evidence (1 reference)
PMID:39261511 SUPPORT DIRECT In Vitro
"The treatment resulted in the stabilization of ESRRB mRNA, suggesting that the reduction in ESRRB mRNA is dependent on the NMD pathway"
Cycloheximide rescue of the transcript, which is what turns the predicted NMD into a measured one.
p.R291L
missense variant
Homozygous missense allele in a consanguineous Czech family, and one of the two DFNB35 families in which dental caries was assessed.
Show evidence (1 reference)
PMID:22951369 SUPPORT DIRECT Human Clinical
"Mutation p.R291L in a homozygous state was found in the deaf child, the parents were heterozygous."
The allele and its segregation.
p.Y305H
missense variant
Novel missense ligand-binding-domain allele in a Tunisian ARNSHL family.
Show evidence (1 reference)
PMID:21802533 SUPPORT INDIRECT Computational
"Molecular modeling showed that the p.Y305H mutation is likely to alter the conformation of the ligand binding-site by destabilizing the coactivator binding pocket."
The mechanistic argument is modelling rather than assay, so it is graded COMPUTATIONAL and INDIRECT. The clinical evidence for the allele is the family segregation reported alongside it.
p.G167R (c.499G>A) Likely Pathogenic
missense variant
Homozygous c.499G>A (p.Gly167Arg), in the DNA-binding domain, segregated with congenital severe-to-profound hearing loss in an Iranian Azeri Turkish family and was absent from 200 study controls. The paper classified it as likely pathogenic using segregation, rarity and computational evidence; it did not measure a functional consequence.
Show evidence (3 references)
PMID:35101039 SUPPORT DIRECT Human Clinical
"A novel homozygous missense mutation, c.499G>A (p.G167R), was identified in exon 5 of the ESRRB (estrogen-related receptor beta) gene."
The allele, its zygosity and its exon.
PMID:35101039 SUPPORT DIRECT Human Clinical
"Healthy and affected family members confirmed the co-segregation of the variant with ARNSHL."
Segregation, which is the clinical evidence for the allele. The paper's own pathogenicity argument beyond that is in silico, as its title says.
PMID:35101039 SUPPORT DIRECT Human Clinical
"our discovered variant met the pathogenicity criteria and was considered “likely pathogenic”"
The classification in the discussion is likely pathogenic, despite stronger wording elsewhere in the report.
p.Tyr295Cys Likely Pathogenic
missense variant
Homozygous c.884A>G (p.Tyr295Cys) segregated in a Tunisian family with two affected members. Table 3 classifies it as likely pathogenic. Predicted folding and cofactor-binding effects were computational hypotheses, not measured in inner-ear cells.
Show evidence (2 references)
PMID:34194829 SUPPORT DIRECT Human Clinical
"five novel variants including three missense (ESRRB-Tyr295Cys, MYO15A-Phe2089Leu and MYO7A-Tyr560Cys)"
Reports the ESRRB allele among the novel pathogenic variants in this cohort.
PMID:34194829 SUPPORT DIRECT Human Clinical
"| P2 | ESRRB-Tyr295Cys | Yes | – | – | PM2-PP1* | PP3 | – | Likely Pathogenic |"
Table 3 explicitly assigns likely pathogenic using rarity, segregation and computational evidence.
c.787+1G>A
splice donor variant
Novel homozygous splicing donor-site variant in a consanguineous Pakistani family with prelingual nonsyndromic hearing loss.
Show evidence (1 reference)
PMID:33269433 SUPPORT DIRECT Human Clinical
"two splicing donor site mutations of c.787+1G>A in ESRRB (DFNB35) and c.637+1G>T in CABP2 (DFNB93)"
Names the allele and assigns it to DFNB35.
c.733G>C (p.Asp245His)
missense variant
Homozygous ligand-binding-domain variant reported in one Pakistani participant with moderate-to-severe hearing loss. It extends the observed severity range; a modifier mechanism was suggested but not identified.
Show evidence (1 reference)
PMID:32681043 SUPPORT DIRECT Human Clinical
"A variant c.733G > C (p.Asp245His) in ESRRB was identified for moderate to severe hearing loss in one participant of this study."
The specific allele and patient phenotype are stated in the full text; Table 1 gives the homozygous genotype. No functional assay was reported.
💊

Medical Actions

4
Cochlear Implantation
Action: cochlear device implantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cochlear device implantation, annotated with Surgical Procedure (NCIT:C15329), qualified as medical device cochlear implant. NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Device
Two children with biallelic ESRRB variants were among the good-outcome controls in a 2015 cochlear-implant study. Controls were selected for CAP 7 and SIR 5 after more than three years of implant use. These are favorable observations in two selected recipients, not an unbiased DFNB35 success rate; variant interpretation and individual clinical factors remain relevant. A separate pediatric series reports preoperative vestibular testing in one ESRRB-associated child but no individual postoperative auditory outcome.
Mechanism Target:
BYPASSES Bilateral Sensorineural Hearing Impairment — A cochlear implant stimulates auditory nerve fibers and can bypass impaired cochlear sensory function. Rodent ESRRB expression in supporting and neural compartments does not establish either neural preservation or failure in patients. Two selected ESRRB-associated recipients had good outcomes; the mechanism link does not predict benefit for every genotype.
Show evidence (3 references)
PMID:26166082 SUPPORT DIRECT Human Clinical
"2 had bi-allelic mutations in ESRRB"
The full text identifies two ESRRB-associated recipients among the good-outcome controls; the observation is more specific than the six-gene aggregate in the abstract.
PMID:26166082 SUPPORT DIRECT Human Clinical
"Thirty unrelated children with good CI performance (CAP score = 7 and SIR score = 5) were selected"
These outcome criteria apply to the matched-control group containing the two ESRRB-associated children. Outcome-based ascertainment prevents estimating treatment success frequency.
PMID:34744965 SUPPORT INDIRECT Human Clinical
"The most common cause of non-syndromic HL was due to mutations in GJB2 (n = 13) followed by MYO15A (3), MYO6 (2), POU3F4 (2), TMPRSS3 (1), CDH23 (1), TMC1 (1), and ESRRB (1)."
Places one ESRRB child in a cochlear implant candidate cohort, establishing that DFNB35 patients do reach implantation. It reports no outcome for that child.
Hearing Aids and Auditory Rehabilitation
Action: auditory rehabilitation with amplificationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is auditory rehabilitation with amplification, 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
Hearing aids, communication support and auditory or speech-language habilitation are individualized to residual hearing and family needs. General genetic hearing-loss guidance supports amplification for mild-to-severe loss; no ESRRB-specific amplification outcome is established.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/books/NBK1434/ SUPPORT INDIRECT Other
"can be used in individuals with mild-to-severe hearing loss."
The sentence describes hearing aids in general genetic hearing-loss care. It does not establish a DFNB35-specific effect.
Dental caries surveillance and prevention
Action: preventive dental careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is preventive dental care, annotated with Preventive Intervention (NCIT:C15843). NCIT:C15843 is a clinical intervention from the NCI Thesaurus. Ontology label: Preventive Intervention NCIT:C15843
Platform: Behavioral / lifestyle
A plausible, unproven addition to routine care, recorded because the ESRRB caries association was proposed by its authors as an actionable one. The proposal is explicitly conditional in the source, and no DFNB35 preventive study has been done.
Show evidence (1 reference)
PMID:25023176 SUPPORT INDIRECT Human Clinical
"provides options for the development of new caries prevention strategies, if the associated ESRRB genetic variants are correlated with efficacy"
The authors' conditional proposal, quoted with its condition intact. It supports recording surveillance as a consideration, not a recommendation.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Platform: Behavioral / lifestyle
Counseling should use confirmed parental genotypes and the interpretation of each familial ESRRB variant. When both parents carry a pathogenic allele for the same autosomal recessive disorder, each pregnancy has a 25% chance of biallelic disease. A VUS alone does not establish a molecular diagnosis or a predictable severity.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/books/NBK1434/ SUPPORT INDIRECT Other
"has at conception a 25% chance of having hearing loss"
This recurrence statement applies to the parental heterozygote configuration specified in the general GeneReviews overview.
🔬

Diagnosis

2
Genetic testing for biallelic ESRRB variants
Audiological assessment establishes sensorineural hearing loss, while sequencing and segregation analysis evaluate ESRRB as the molecular cause. Normal temporal-bone imaging in reported patients does not exclude DFNB35. Variant interpretation remains essential: homozygosity alone does not establish pathogenicity, and the recurrent p.Arg382Cys allele remained a VUS after functional testing in the 2024 report.
Show evidence (3 references)
PMID:39261511 SUPPORT DIRECT Human Clinical
"Neither temporal bone computed tomography (CT) nor internal acoustic canal magnetic resonance imaging (MRI) revealed any anomalies within the inner ear"
Normal CT and MRI were reported in the Korean proband; this single observation does not establish that every DFNB35 patient has normal imaging.
PMID:39261511 SUPPORT DIRECT Human Clinical
"At this stage, based on the ACMG-AMP guideline, the p.(Arg382Cys) variant was classified as VUS, evidenced by PM3, PP3, and BA1"
The authors explicitly classified p.Arg382Cys as VUS; their subsequent functional work supplied supporting evidence without a likely-pathogenic classification.
PMID:22951369 SUPPORT INDIRECT Human Clinical
"Homozygosity mapping is a powerful method for identification of genes in heterogeneous recessive diseases."
The method by which DFNB35 families have historically been found. Indirect: it describes gene discovery in consanguineous pedigrees rather than diagnostic testing of an individual patient.
Vestibular assessment
Vestibular function should be interpreted by test and genotype. Two adults in Turkish family TR-21 had normal caloric testing. A later pediatric ESRRB-associated case had abnormal cVEMP with a normal rotary-chair result. Normal canal testing does not establish normal otolith function.
Show evidence (2 references)
PMID:18179891 SUPPORT DIRECT Human Clinical
"For these two individuals, computerized tomography of the temporal bone and caloric testing for evaluation of the vestibular function were performed, and no abnormalities were found."
Normal caloric results in two affected Turkish relatives are direct human evidence, with limited sample size and vestibular-organ coverage.
PMID:34744965 SUPPORT DIRECT Human Clinical
"| ESRRB | 0/1 | | 1/1 | | 1/1 |"
Table 2 reports normal rotary-chair testing (0/1 abnormal), abnormal cVEMP (1/1), and peripheral vestibular loss (1/1) in the sole ESRRB-associated case. VHIT and oVEMP entries are blank. Column assignments were checked against the published PDF; this selected single case does not establish population frequency or laterality.
📊

Prevalence

3
Worldwide reported literature
Cases In Literature Unknown
Fewer than twenty families reported as of 2024, carrying twenty-two distinct alleles, with a strong ascertainment bias toward consanguineous Pakistani pedigrees. Recorded as a case count rather than a rate because no population denominator has been published.
Show evidence (3 references)
PMID:39261511 SUPPORT DIRECT Human Clinical
"To date, less than 20 families with SNHL exclusively of Pakistani ethnicity have been diagnosed with ESRRB biallelic variants"
The case count and the ascertainment bias in one sentence. Note the sentence overstates exclusivity - Turkish, Czech, Tunisian and Korean families are also reported, including by this same paper - so it is cited for the order of magnitude.
PMID:39261511 SUPPORT DIRECT Human Clinical
"To date, 25 variant alleles of ESRRB (condensed to 22 when considering the same variants) have been reported to cause ESRRB-associated DFNB35, including variants found in the present study."
The size of the reported allelic spectrum, which is the other measure of how small this disease is.
PMID:35101039 SUPPORT DIRECT Human Clinical
"There are currently more than 13 variants have been found in DFNB35, nearly half of which relates to Pakistani ethnicity"
A more careful statement of the same ascertainment bias than the "exclusively Pakistani" phrasing quoted above: about half, not all. Reported families are also Turkish, Czech, Tunisian, Iranian, Korean and Han Chinese.
Tunisian families with autosomal recessive nonsyndromic hearing loss
Cases In Literature Unknown
One DFNB35 family found; screening 127 further Tunisian ARNSHL families found no additional ESRRB mutations. This is a denominator for how rare DFNB35 is *among hearing-loss families*, not a population prevalence.
Show evidence (1 reference)
PMID:21802533 SUPPORT DIRECT Human Clinical
"Using linkage and DHPLC analysis, no more mutations were detected in the ESRRB gene in other 127 Tunisian families with ARNSHL indicating that DFNB35 is most likely to be a rare type of ARNSHL in the Tunisian population."
Gives an explicit denominator of 127 further families screened without a second hit.
Czech patients with early-onset nonsyndromic hearing loss
Cases In Literature Unknown
One DFNB35 family found; sequencing ESRRB in 39 further Czech patients yielded only two homozygous variants judged to be polymorphisms.
Show evidence (1 reference)
PMID:22951369 SUPPORT DIRECT Human Clinical
"The entire coding region of the ESRRB gene was sequenced in additional 39 patients of Czech origin with early NSHL and only two variants, p.V413I and p.P386S, were found in homozygous state, but are considered to be polymorphisms."
A second screening denominator, and a useful warning that homozygous ESRRB coding variants are not automatically DFNB35 alleles.
📊

Related Datasets

1
Transcriptional regulation by Errb (Nr3b2) in stria vascularis geo:GSE8434
Microarray comparison of microdissected cochlear lateral walls from Errb-mutant mice and wild-type littermate controls, associated with the original strial-development study. Three wild-type and three mutant samples are represented in the linked GDS2955 record.
mouse MICROARRAY n=6 Affymetrix Mouse Genome 430 2.0...
Conditions: Wild-type littermate controls Errb-mutant stria vascularis
PMID:17765677
Tissue-level mouse expression profiles can nominate downstream genes but do not establish direct ESRRB binding or the effects of individual human variants.
🐁

Animal Models

1
Nr3b2 (Esrrb) null mouse, including genetically mosaic animals
The model that established what ERR-beta does in the inner ear. Because germline Nr3b2 loss is not compatible with normal development, the informative experiments are on the inner ear epithelium and on genetically mosaic animals in which null marginal cells sit beside wild-type ones - which is what makes the non-cell-autonomous effects on intermediate cells and capillaries interpretable.
Species
Mouse
Genotype
Nr3b2(-/-); mosaic Nr3b2(-/-) inner ear epithelium
Publication
PMID:17765677
Pathograph links
Failure of the Strial Marginal Cell Secretory Programme recapitulates fidelity: high Null mouse marginal cells fail to express multiple ion-channel and transporter genes. This directly models the secretory gene-expression node.
Limitations: Null animals establish gene function but do not measure the residual activity or phenotype of individual human missense variants. The accessible primary abstract lacks quantitative auditory physiology.
Readouts
Expression of strial marginal cell ion channel and transporter genes
Direction: DECREASED
Interpretation: The secretory gene programme is not switched on, which is the definition of this node.
Show evidence (1 reference)
PMID:17765677 SUPPORT DIRECT Model Organism
"Nr3b2(-/-) strial marginal cells fail to express multiple ion channel and transporter genes"
The direct measurement of the transcriptional readout in null marginal cells.
Show evidence (1 reference)
PMID:17765677 SUPPORT DIRECT Model Organism
"an orphan nuclear receptor, is specifically expressed in and controls the development of the endolymph-producing cells of the inner ear"
Establishes that this model is informative for the marginal cell node by showing the gene acts in exactly those cells.
Impaired Endolymph Homeostasis partially recapitulates fidelity: moderate The 2008 gene-discovery paper summarizes impaired endolymph production and defective hearing and balance in conditional-null Esrrb mice.
Limitations: Physiological consequences are summarized in a later paper; the accessible primary abstract does not provide quantitative endolymph or auditory measurements. Extrapolation to human alleles is limited.
Show evidence (1 reference)
PMID:18179891 SUPPORT INDIRECT Model Organism
"Disturbed endolymph production in these mice results in an aberrant inner-ear fluid homeostasis and as a consequence in defective hearing and balance."
The human gene-discovery paper summarizes earlier conditional mouse experiments; this is indirect evidence for their physiological outcome.
Partial Marginal Cell Fate Transformation recapitulates fidelity: high Nr3b2-null mouse strial marginal cells partially acquire the identity of neighboring Pendrin-expressing epithelial cells. This is a partial fate transformation, not evidence that every marginal cell disappears or becomes an identical mature neighboring cell.
Limitations: Directly observed in the null/mosaic mouse model; corresponding human cochlear histology has not been reported in the cited studies.
Show evidence (1 reference)
PMID:17765677 SUPPORT DIRECT Model Organism
"they show a partial transformation toward the fate of the immediately adjacent Pendrin-expressing epithelial cells"
The authors distinguish a partial identity change from loss of transporter expression.
Secondary Strial Intermediate Cell Expression Changes recapitulates fidelity: high In genetically mosaic mice, Nr3b2-null marginal cells induce secondary changes in gene expression in the underlying intermediate-cell layer. This establishes a local non-cell-autonomous effect, without identifying a specific intercellular signal.
Limitations: Directly observed in the null/mosaic mouse model; corresponding human cochlear histology has not been reported in the cited studies.
Show evidence (1 reference)
PMID:17765677 SUPPORT DIRECT Model Organism
"Nr3b2(-/-) strial marginal cells produce secondary alterations in gene expression in the underlying intermediate cells"
Mosaic analysis links mutant marginal cells to altered expression in the neighboring strial layer.
Local Strial Capillary Loss recapitulates fidelity: high Local loss of strial capillaries accompanies Nr3b2-null marginal-cell regions in mosaic mice. The primary abstract reports the vascular consequence without establishing its temporal order relative to intermediate-cell expression changes or specifying the vascular signaling mechanism.
Limitations: Directly observed in the null/mosaic mouse model; corresponding human cochlear histology has not been reported in the cited studies.
Show evidence (1 reference)
PMID:17765677 SUPPORT DIRECT Model Organism
"In genetically mosaic mice, Nr3b2(-/-) strial marginal cells produce secondary alterations in gene expression in the underlying intermediate cells and a local loss of strial capillaries."
The capillary finding is separated from the intermediate-cell expression phenotype; no serial causal order between them is inferred.
{ }

Source YAML

click to show 
name: Autosomal Recessive Nonsyndromic Hearing Loss 35
category: Mendelian
creation_date: "2026-09-03T00:00:00Z"
synonyms:
- DFNB35
- deafness, autosomal recessive 35
- deafness, autosomal recessive type 35
- autosomal recessive deafness 35
- autosomal recessive nonsyndromic deafness 35
- autosomal recessive nonsyndromic deafness type 35
- ESRRB autosomal recessive nonsyndromic deafness
- autosomal recessive nonsyndromic deafness caused by mutation in ESRRB
description: >-
  DFNB35 is autosomal recessive bilateral sensorineural hearing loss caused by biallelic pathogenic
  variants in ESRRB, encoding the orphan nuclear receptor ERR-beta (NR3B2). Reported families usually
  have prelingual severe-to-profound loss, although moderate severity, asymmetry and progression
  occur. The reported missense predominance does not establish residual function for every allele.
  The recurrent p.Arg382Cys variant impaired protein stability and reporter activity in cultured
  cells but remained a variant of uncertain significance in the 2024 study.

  Mouse loss-of-function experiments implicate defective strial marginal-cell differentiation and
  ion-transporter expression, with secondary intermediate-cell and capillary abnormalities. Developmental
  mouse RNA localization and postnatal rat immunohistochemistry also place ESRRB in nonsensory and
  neural cochlear compartments. Absent otoacoustic emissions in two affected Turkish relatives support
  outer-hair-cell dysfunction; the proposed secondary origin is inferred from rodent expression rather
  than demonstrated in human cochlear tissue.

  Vestibular findings vary across small reports: two Turkish adults had normal caloric testing, whereas
  a pediatric implant-candidate series reported abnormal cervical vestibular evoked myogenic potentials
  in its one ESRRB-associated case. Severe caries was reported in affected and heterozygous members
  of a Turkish family, whereas the affected Czech child was caries-free at age four. Its frequency
  and an ESRRB-specific enamel mechanism remain uncertain.

disease_term:
  preferred_term: autosomal recessive nonsyndromic hearing loss 35
  term:
    id: MONDO:0012060
    label: autosomal recessive nonsyndromic hearing loss 35
parents:
- Autosomal Recessive Nonsyndromic Hearing Loss
inheritance:
- name: Autosomal recessive
  description: >-
    Biallelic ESRRB variants. Most reported pedigrees are consanguineous and homozygous -
    Turkish, Pakistani, Tunisian, Czech - with unaffected heterozygous parents. The
    compound heterozygous configuration is the exception and has been documented in a
    Korean family and a Han Chinese family, both carrying p.Arg382Cys in trans with a
    second allele.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:18179891
    reference_title: "Mutations of ESRRB encoding estrogen-related receptor beta cause autosomal-recessive nonsyndromic hearing impairment DFNB35."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Mutation analysis of ESRRB, a candidate gene in the overlapping region, revealed a homozygous 7 bp duplication in exon 8 in all affected individuals."
    explanation: >-
      Homozygosity in every affected member of the consanguineous Turkish family that
      defined the gene, which is the recessive pattern.
  - reference: PMID:22951369
    reference_title: "DFNB35 due to a novel mutation in the ESRRB gene in a Czech consanguineous family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Mutation p.R291L in a homozygous state was found in the deaf child, the parents were heterozygous."
    explanation: >-
      Segregation in the Czech family: homozygous in the affected child, heterozygous and
      unaffected in both parents.
  - reference: PMID:39261511
    reference_title: "Functional pathogenicity of ESRRB variant of uncertain significance contributes to hearing loss (DFNB35)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Consequently, the majority of reported cases exhibited homozygous zygosity except the p.(Arg382Cys) variant, which presented as a compound heterozygous variant in trans with either c.16A>G in a Han Chinese family or c.397 + 2T>G in a South Korean family."
    explanation: >-
      States the zygosity distribution across the whole reported literature, and names the
      two compound heterozygous exceptions.
pathophysiology:
- name: ESRRB Loss of Function
  biological_scale: MOLECULAR
  role: initiator
  mechanism_confidence: ESTABLISHED
  description: >-
    Biallelic ESRRB variants impair the function of an orphan nuclear-receptor transcription factor.
    Reported alleles include missense substitutions in the DNA-binding and ligand-binding domains,
    frameshift, nonsense, splice and in-frame variants. The founding c.1018_1024dupGAGTTTG allele
    predicts p.Val342GlyfsTer44; nonsense-mediated decay or an abnormal truncated protein were alternative
    hypotheses in the original paper. Exon-4 skipping and transcript stabilization by cycloheximide
    support nonsense-mediated decay for c.397+2T>G. Missense status alone does not establish a hypomorphic
    effect, and residual function has not been measured across the allelic spectrum.
  genes:
  - preferred_term: ESRRB
    term:
      id: hgnc:3473
      label: ESRRB
  molecular_functions:
  - preferred_term: ERR-beta nuclear receptor transcription factor activity
    term:
      id: GO:0004879
      label: nuclear receptor activity
    modifier: DECREASED
  downstream:
  - target: Failure of the Strial Marginal Cell Secretory Programme
    causal_link_type: DIRECT
    description: >-
      ERR-beta is the transcription factor that installs and maintains the endolymph secretory programme
      in strial marginal cells, so reduced ERR-beta activity is read out directly as failure of that
      programme.
  - target: Partial Marginal Cell Fate Transformation
    causal_link_type: DIRECT
    description: >-
      Null marginal cells partially shift epithelial identity in the mouse model.
  - target: Secondary Strial Intermediate Cell Expression Changes
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Loss of Nr3b2 in marginal cells produces a non-cell-autonomous intermediate-cell response in
      mosaic mice.
  - target: Local Strial Capillary Loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Mosaic null marginal-cell regions show local capillary loss; the intervening signal is unresolved.
  - target: Reduced Stability of ESRRB Arg382Cys Protein
    causal_link_type: DIRECT
    description: >-
      The p.Arg382Cys allele specifically reduced protein stability in overexpression assays; this
      consequence is not assigned to all ESRRB variants.
  evidence:
  - reference: PMID:18179891
    reference_title: Mutations of ESRRB encoding estrogen-related receptor beta cause autosomal-recessive nonsyndromic hearing impairment DFNB35.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Sequence analysis of the ESRRB gene in the affected individuals of the original DFNB35 family
      and in three other DFNB35-linked consanguineous families from Pakistan revealed four missense
      mutations.
    explanation: >-
      Establishes that the founding DFNB35 alleles are predominantly missense rather than truncating.
  - reference: PMID:18179891
    reference_title: Mutations of ESRRB encoding estrogen-related receptor beta cause autosomal-recessive nonsyndromic hearing impairment DFNB35.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    directness: INDIRECT
    snippet: >-
      Molecular modeling of this nuclear receptor showed that the missense mutations are likely to
      affect the structure and stability of these domains.
    explanation: >-
      The original mechanistic argument for these missense alleles was structural modelling, not
      an assay - graded COMPUTATIONAL and INDIRECT for that reason.
  - reference: PMID:39261511
    reference_title: Functional pathogenicity of ESRRB variant of uncertain significance contributes to hearing loss (DFNB35).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Of the 19 coding variants, all were located in functional domains except for one variant (c.16A>G:p.Arg6Gly).
      Nine were resided in the LBD while the remaining 9 were positioned in the DNA binding domain
      (DBD).
    explanation: >-
      The domain distribution of the reported coding alleles, which is the basis for describing DFNB35
      as a domain-restricted loss of transcription factor function.
  - reference: PMID:39261511
    reference_title: Functional pathogenicity of ESRRB variant of uncertain significance contributes to hearing loss (DFNB35).
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: >-
      In alignment with bioinformatics analysis, the c.397 + 2T>G splicing event was observed to
      induce exon 4 skipping, leading to formation of a premature stop codon followed by nonsense-mediated
      decay (NMD).
    explanation: >-
      Minigene assay in HEK293T cells showing that the splice allele produces a transcript destined
      for degradation, which is the truncating end of the spectrum.
  notes: >-
    No ESRRB genotype-phenotype correlation has been established: the 2024 review of the full reported
    spectrum found no significant difference in onset, severity or symmetry between DNA-binding-domain
    and ligand-binding-domain alleles.
- name: Reduced Stability of ESRRB Arg382Cys Protein
  biological_scale: MOLECULAR
  role: amplifier
  mechanism_confidence: ESTABLISHED
  description: >-
    Overexpressed ESRRB p.Arg382Cys protein had reduced stability in cycloheximide-chase assays in
    HEI-OC1 and HEK293T cells. Nuclear localization was not significantly altered. These assay findings
    do not establish clinical pathogenicity or a shared effect of every ESRRB allele.
  evidence:
  - reference: PMID:39261511
    reference_title: Functional pathogenicity of ESRRB variant of uncertain significance contributes to hearing loss (DFNB35).
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: >-
      Consistent with molecular modeling and dynamics studies, the stability of the ESRRB p.(Arg382Cys)
      variant was significantly reduced compared to that of the wild-type
    explanation: >-
      Cycloheximide chase showed reduced mutant protein stability in HEI-OC1 and HEK293T cells. Its
      contribution to reduced reporter activity is plausible but was not separated experimentally
      from other functional effects.
  - reference: PMID:39261511
    reference_title: Functional pathogenicity of ESRRB variant of uncertain significance contributes to hearing loss (DFNB35).
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: >-
      However, immunocytochemistry data showed that there was no significant difference in the translocation
      ability of ESRRB into the nucleus between the mutant and the wild type
    explanation: >-
      No significant difference in nuclear localization was detected under the tested overexpression
      conditions; this does not exclude every possible trafficking defect.
  downstream:
  - target: Reduced ERR-beta Transcriptional Output at Target Promoters
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Reduced stability is a proposed contributor to lower reporter output; the experiments did not
      isolate it from other effects of the variant.
- name: Reduced ERR-beta Transcriptional Output at Target Promoters
  biological_scale: MOLECULAR
  role: amplifier
  mechanism_confidence: ESTABLISHED
  description: >-
    ESRRB p.Arg382Cys reduced SMAD7-promoter reporter activation in HEI-OC1 and HEK293T cells. Wild-type
    overexpression produced 2.09-fold and 2.21-fold activity relative to the internal control, whereas
    mutant values of 1.19-fold and 1.24-fold were not significantly different from that control.
    This supports impaired transcriptional output in the assay systems without proving zero residual
    activity or clinical pathogenicity. In family-derived lymphoblastoid cells, ATP1B1 and EGR1 were
    lower in the proband and the unaffected mother than in the father; NRP1, TBX3 and SPARC were
    lower in the proband and father than in the mother. These comparisons do not establish direct
    promoter binding or corresponding changes in the intact inner ear.
  biological_processes:
  - preferred_term: regulation of transcription by ERR-beta at target promoters
    term:
      id: GO:0006355
      label: regulation of DNA-templated transcription
    modifier: DECREASED
  downstream:
  - target: Failure of the Strial Marginal Cell Secretory Programme
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Reduced transcription of the ion channel, transporter and ATPase genes that constitute the marginal cell secretory programme.
    description: >-
      Reduced transcription of ion-handling genes provides a candidate route from ESRRB dysfunction
      to strial failure. The human-variant reporter and lymphoblastoid experiments did not test marginal-cell
      differentiation or secretion.
  evidence:
  - reference: PMID:39261511
    reference_title: Functional pathogenicity of ESRRB variant of uncertain significance contributes to hearing loss (DFNB35).
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: >-
      Transient overexpression of the ESRRB wild-type significantly increased luciferase activity,
      demonstrating a 2.09-fold increase relative to the internal control in HEI-OC1 cells (p < 0.01)
      and 2.21-fold in HEK293T cells (p < 0.01). However, the luciferase activity of ESRRB mutant
      did not exhibit a significant deviation from the internal control
    explanation: >-
      Wild-type overexpression activated the SMAD7 reporter; mutant activity was not significantly
      above the internal control. This is not a measurement of complete loss of endogenous transcription.
  - reference: PMID:39261511
    reference_title: Functional pathogenicity of ESRRB variant of uncertain significance contributes to hearing loss (DFNB35).
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: >-
      we observed marked decreases in mRNA levels of ATP1B1 and EGR1 (decreased 55.1% and 45.4% respectively)
    explanation: >-
      The reductions of ATP1B1 and EGR1 were measured in proband lymphoblastoid cells relative to
      the father; the unaffected mother also showed reductions. They are not measurements in strial
      tissue.
  notes: >-
    Functional findings remain IN_VITRO. The family-derived cells are lymphoblastoid lines, and HEI-OC1
    cells do not reproduce intact strial development. The study retained p.Arg382Cys as a warm VUS,
    with PS3-supporting functional evidence.
- name: Failure of the Strial Marginal Cell Secretory Programme
  biological_scale: CELLULAR
  role: central_effector
  mechanism_confidence: ESTABLISHED
  description: >-
    Loss of Nr3b2/Esrrb in mouse strial marginal cells prevents expression of multiple ion-channel
    and transporter genes required for the endolymph-producing epithelial program. ERR-beta also
    acts in vestibular dark cells. This node describes the gene-expression defect; the partial cell-fate
    change and secondary strial effects are modeled separately.
  cell_types:
  - preferred_term: strial marginal cell
    term:
      id: CL:0002492
      label: strial marginal cell
  - preferred_term: vestibular dark cell
    term:
      id: CL:0000846
      label: vestibular dark cell
  biological_processes:
  - preferred_term: potassium ion transport into endolymph
    term:
      id: GO:0006813
      label: potassium ion transport
    modifier: DECREASED
  locations:
  - preferred_term: stria vascularis of the cochlear duct
    term:
      id: UBERON:0002282
      label: stria vascularis of cochlear duct
  downstream:
  - target: Impaired Endolymph Homeostasis
    causal_link_type: DIRECT
    description: >-
      The marginal cells are the endolymph-producing epithelium; a marginal cell that never acquires
      its transporter repertoire cannot secrete.
  evidence:
  - reference: PMID:17765677
    reference_title: Estrogen-related receptor beta/NR3B2 controls epithelial cell fate and endolymph production by the stria vascularis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      We show here that estrogen-related receptor beta (ERR-beta; NR3B2), an orphan nuclear receptor,
      is specifically expressed in and controls the development of the endolymph-producing cells
      of the inner ear: the strial marginal cells in the cochlea and the vestibular dark cells in
      the ampulla and utricle.
    explanation: >-
      Localises ERR-beta function to exactly these two cell types, which is what puts the DFNB35
      lesion in the lateral wall rather than in the hair cell.
  - reference: PMID:17765677
    reference_title: Estrogen-related receptor beta/NR3B2 controls epithelial cell fate and endolymph production by the stria vascularis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Nr3b2(-/-) strial marginal cells fail to express multiple ion channel and transporter genes
    explanation: >-
      The null marginal cells lose expression of the secretory machinery. This is a mouse result,
      not a direct measurement in human strial tissue.
  notes: >-
    The marginal-cell localization and knockout experiments provide direct model evidence. Collin
    et al. additionally reported a broader distribution in P4 rat cochlea, including supporting and
    neural compartments; different ages, species and antibodies limit direct comparison of localization
    patterns.
- name: Partial Marginal Cell Fate Transformation
  biological_scale: CELLULAR
  role: central_effector
  mechanism_confidence: ESTABLISHED
  description: >-
    Nr3b2-null mouse strial marginal cells partially acquire the identity of neighboring Pendrin-expressing
    epithelial cells. This is a partial fate transformation, not evidence that every marginal cell
    disappears or becomes an identical mature neighboring cell.
  cell_types:
  - preferred_term: strial marginal cell
    term:
      id: CL:0002492
      label: strial marginal cell
  locations:
  - preferred_term: stria vascularis of the cochlear duct
    term:
      id: UBERON:0002282
      label: stria vascularis of cochlear duct
  evidence:
  - reference: PMID:17765677
    reference_title: Estrogen-related receptor beta/NR3B2 controls epithelial cell fate and endolymph production by the stria vascularis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      they show a partial transformation toward the fate of the immediately adjacent Pendrin-expressing
      epithelial cells
    explanation: >-
      The authors distinguish a partial identity change from loss of transporter expression.
- name: Secondary Strial Intermediate Cell Expression Changes
  biological_scale: CELLULAR
  role: amplifier
  mechanism_confidence: ESTABLISHED
  description: >-
    In genetically mosaic mice, Nr3b2-null marginal cells induce secondary changes in gene expression
    in the underlying intermediate-cell layer. This establishes a local non-cell-autonomous effect,
    without identifying a specific intercellular signal.
  cell_types:
  - preferred_term: strial intermediate cell
    term:
      id: CL:0002486
      label: strial intermediate cell
  locations:
  - preferred_term: stria vascularis of the cochlear duct
    term:
      id: UBERON:0002282
      label: stria vascularis of cochlear duct
  evidence:
  - reference: PMID:17765677
    reference_title: Estrogen-related receptor beta/NR3B2 controls epithelial cell fate and endolymph production by the stria vascularis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Nr3b2(-/-) strial marginal cells produce secondary alterations in gene expression in the underlying
      intermediate cells
    explanation: >-
      Mosaic analysis links mutant marginal cells to altered expression in the neighboring strial
      layer.
- name: Local Strial Capillary Loss
  biological_scale: TISSUE
  role: amplifier
  mechanism_confidence: ESTABLISHED
  description: >-
    Local loss of strial capillaries accompanies Nr3b2-null marginal-cell regions in mosaic mice.
    The primary abstract reports the vascular consequence without establishing its temporal order
    relative to intermediate-cell expression changes or specifying the vascular signaling mechanism.
  locations:
  - preferred_term: stria vascularis of the cochlear duct
    term:
      id: UBERON:0002282
      label: stria vascularis of cochlear duct
  evidence:
  - reference: PMID:17765677
    reference_title: Estrogen-related receptor beta/NR3B2 controls epithelial cell fate and endolymph production by the stria vascularis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      In genetically mosaic mice, Nr3b2(-/-) strial marginal cells produce secondary alterations
      in gene expression in the underlying intermediate cells and a local loss of strial capillaries.
    explanation: >-
      The capillary finding is separated from the intermediate-cell expression phenotype; no serial
      causal order between them is inferred.
- name: Impaired Endolymph Homeostasis
  biological_scale: TISSUE
  role: amplifier
  mechanism_confidence: PROVISIONAL
  description: >-
    Defective marginal-cell differentiation and ion-transporter expression are proposed to impair
    cochlear endolymph production and ionic homeostasis. The 2008 gene-discovery paper summarizes
    disturbed endolymph production with defective hearing and balance in conditional-null mice. The
    available cached primary abstract establishes strial cellular abnormalities but supplies no numerical
    endocochlear potential, endolymph potassium or volume measurement. Quantitative extrapolation
    to human variants remains unresolved.
  cell_types:
  - preferred_term: strial marginal cell
    term:
      id: CL:0002492
      label: strial marginal cell
  biological_processes:
  - preferred_term: potassium ion homeostasis of endolymph
    term:
      id: GO:0055075
      label: potassium ion homeostasis
    modifier: DYSREGULATED
  locations:
  - preferred_term: stria vascularis of the cochlear duct
    term:
      id: UBERON:0002282
      label: stria vascularis of cochlear duct
  - preferred_term: endolymph
    term:
      id: UBERON:0001852
      label: endolymph
  downstream:
  - target: Secondary Outer Hair Cell Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Disturbed ionic support is a candidate explanation for secondary sensory dysfunction. The full
      human sequence has not been measured.
  evidence:
  - reference: PMID:18179891
    reference_title: Mutations of ESRRB encoding estrogen-related receptor beta cause autosomal-recessive nonsyndromic hearing impairment DFNB35.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      Disturbed endolymph production in these mice results in an aberrant inner-ear fluid homeostasis
      and as a consequence in defective hearing and balance.
    explanation: >-
      The human gene-discovery paper summarizes earlier conditional mouse experiments; this is indirect
      evidence for their physiological outcome.
  notes: >-
    The sensorineural_hair_cell_loss module bundles ionic disruption with oxidative stress, cell
    death and neural degeneration. These additional processes are not established by the ESRRB evidence,
    so module conformance is not asserted. Tbx1 mutant studies provide related strial-development
    evidence, but their deafness is not a direct ESRRB perturbation.
- name: Secondary Outer Hair Cell Dysfunction
  biological_scale: CELLULAR
  role: central_effector
  mechanism_confidence: PROVISIONAL
  description: >-
    Absent transiently evoked otoacoustic emissions in two affected Turkish relatives indicate outer-hair-cell
    dysfunction. Collin et al. proposed a secondary origin because ESRRB was not detected in rodent
    cochlear sensory hair cells. The upstream cause is inferred from animal localization and human
    audiology; neither hair-cell death nor the precise strial-to-hair-cell mechanism was measured
    in these patients.
  cell_types:
  - preferred_term: cochlear outer hair cell
    term:
      id: CL:0000601
      label: cochlear outer hair cell
  evidence:
  - reference: PMID:18179891
    reference_title: Mutations of ESRRB encoding estrogen-related receptor beta cause autosomal-recessive nonsyndromic hearing impairment DFNB35.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Transient otoacoustic emission spectra (TEOAEs) were absent in two individuals
    explanation: >-
      The two tested Turkish relatives had absent emissions, supporting impaired outer-hair-cell
      function.
  - reference: PMID:18179891
    reference_title: Mutations of ESRRB encoding estrogen-related receptor beta cause autosomal-recessive nonsyndromic hearing impairment DFNB35.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      No ESRRB expression was detected in the sensory cells in the organ of Corti, but only in the
      supporting cells
    explanation: >-
      P4 rat immunohistochemistry supports a nonsensory localization under the tested conditions;
      it does not directly demonstrate the origin of human dysfunction.
  - reference: PMID:18179891
    reference_title: Mutations of ESRRB encoding estrogen-related receptor beta cause autosomal-recessive nonsyndromic hearing impairment DFNB35.
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: >-
      Because ESRRB is not expressed in these cells, the loss of outer hair cell function is probably
      a secondary effect.
    explanation: >-
      The proposed secondary mechanism is the authors' inference combining human audiology with rodent
      localization.
  downstream:
  - target: Absent Otoacoustic Emissions
    causal_link_type: DIRECT
    description: >-
      Loss of measurable outer-hair-cell emissions is the functional readout observed in the Turkish
      relatives.
  - target: Bilateral Sensorineural Hearing Impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Reduced outer-hair-cell function can contribute to cochlear hearing impairment; the proportion
      of DFNB35 severity attributable to this process is not established.
- name: Proposed ESRRB-Related Enamel Susceptibility
  biological_scale: CELLULAR
  role: modifier
  mechanism_confidence: PROVISIONAL
  description: >-
    Mouse Esrrb expression in secretory-stage ameloblasts provides a possible anatomical basis for
    an enamel contribution to caries susceptibility. Human common-variant association and extracted-tooth
    microhardness experiments suggest a locus-level effect, but neither reduced ESRRB activity nor
    abnormal enamel formation was measured in DFNB35 patients. The two reported pedigrees include
    severe caries in Turkish homozygotes and heterozygotes and a caries-free Czech affected child.
  cell_types:
  - preferred_term: ameloblast
    term:
      id: CL:0000059
      label: ameloblast
  biological_processes:
  - preferred_term: amelogenesis
    term:
      id: GO:0097186
      label: amelogenesis
  downstream:
  - target: Increased Dental Caries Experience
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The proposed route is a softer, more acid-soluble enamel surface, but the human data are association
      and family observation rather than a demonstrated causal chain.
  evidence:
  - reference: PMID:25023176
    reference_title: Role of estrogen related receptor beta (ESRRB) in DFN35B hearing impairment and dental decay.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      Esrrb is expressed by mouse ameloblasts, the cells that deposit tooth enamel, during the secretory
      stage of amelogenesis in mice
    explanation: >-
      Expression in normal mouse ameloblasts establishes localization, not reduced activity or a
      dental phenotype in a mutant mouse.
  - reference: PMID:25023176
    reference_title: Role of estrogen related receptor beta (ESRRB) in DFN35B hearing impairment and dental decay.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: >-
      Through experiments that tested the effects of acid dissolution of the enamel surface, we reasoned
      that ESRRB variants contributes to formation of an enamel structure that is more susceptible
      to the acidic effects in- volved in the initiation of dental caries.
    explanation: >-
      The proposed mechanism derives from acid-dissolution experiments on extracted teeth from a
      general orthodontic cohort, not from DFNB35 patient enamel. Reported SNP associations did not
      reach the paper's stated Bonferroni threshold of 0.0004.
  notes: >-
    The enamel microhardness associations had reported p values of 0.0007 and 0.0006, above the stated
    multiple-comparison threshold. They provide tentative support for a hypothesis, not a demonstrated
    mediator of caries in biallelic ESRRB disease.

phenotypes:
- name: Bilateral Sensorineural Hearing Impairment
  category: Auditory
  description: >-
    The defining and, so far, only consistently reported feature. Every DFNB35 patient described
    has sensorineural rather than conductive or mixed loss, which is what the lateral wall localisation
    of the lesion predicts.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Bilateral sensorineural hearing impairment
    term:
      id: HP:0008619
      label: Bilateral sensorineural hearing impairment
  evidence:
  - reference: PMID:39261511
    reference_title: Functional pathogenicity of ESRRB variant of uncertain significance contributes to hearing loss (DFNB35).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      In all affected DFNB35 patients, the type of hearing loss was identified as SNHL.
    explanation: >-
      A statement across the whole reported DFNB35 literature that the loss is sensorineural in every
      case.
  - reference: PMID:35101039
    reference_title: 'A novel missense variant in ESRRB gene causing autosomal recessive non-syndromic hearing loss: in silico analysis of a case.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Our study evaluated the genetic cause of bilateral severe to profound HL in an Iranian family
      with Azeri Turkish ethnicity.
    explanation: >-
      Bilaterality stated for an individual DFNB35 family, which is what the cross-literature sentence
      above does not supply.
  notes: >-
    Bound to the bilateral term because no unilateral DFNB35 case has been reported. The first quoted
    sentence establishes the sensorineural type across the literature but not laterality; laterality
    rests on the individual pedigree audiograms, of which the Iranian family is one.
- name: Severe to Profound Hearing Impairment
  category: Auditory
  description: >-
    Most reported patients fall at the severe-to-profound end. The exception is instructive: the
    Korean proband had moderate loss in one ear and severe-to-profound in the other, and the milder
    ear then deteriorated over seventeen years of follow-up. So severity is not fixed at presentation
    in every patient, and the asymmetric, progressive pattern is documented at least once.
  phenotype_term:
    preferred_term: Severe sensorineural hearing impairment
    term:
      id: HP:0008625
      label: Severe sensorineural hearing impairment
  evidence:
  - reference: PMID:39261511
    reference_title: Functional pathogenicity of ESRRB variant of uncertain significance contributes to hearing loss (DFNB35).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      The majority of hearing loss phenotypes exhibited symmetry, prelingual onset, and severe-to-profound
      SNHL, whereas our proband showed asymmetric hearing loss with a progressive nature.
    explanation: >-
      Describes the majority pattern and the documented exception without supplying a population
      frequency estimate.
  - reference: PMID:32681043
    reference_title: Spectrum of genetic variants in moderate to severe sporadic hearing loss in Pakistan.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      A missense variant in ESRRB was implicated for recessively inherited moderate to severe hearing
      loss.
    explanation: >-
      A sporadic Pakistani case at the moderate-to-severe rather than profound end. Indirect for
      this phenotype because it qualifies the severity range rather than asserting the severe-to-profound
      majority.
  - reference: PMID:35101039
    reference_title: 'A novel missense variant in ESRRB gene causing autosomal recessive non-syndromic hearing loss: in silico analysis of a case.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      The audiograms show bilateral severe to profound hearing loss in (a) V4, (b) V5, and (c) V6
    explanation: >-
      Audiometric confirmation in three affected siblings of the Iranian family, which is the severe-to-profound
      majority pattern in a single pedigree.
  notes: >-
    The node is named "Severe to Profound" but the binding is HP:0008625, *Severe* sensorineural
    hearing impairment, which is the narrower of the two. That direction is deliberate: HPO has no
    combined severe-to-profound term, and binding to the profound term instead would over-state severity
    for the patients at the severe end. The broader range is carried by `preferred_term` and by the
    description, which the term contract permits.
- name: Prelingual Onset Hearing Impairment
  category: Auditory
  description: >-
    Onset is typically before speech acquisition, so DFNB35 usually presents as congenital or early-childhood
    deafness rather than as adult-onset loss. The Korean proband's hearing was described as congenital
    or evident at prelingual onset, and the Pakistani families in which the ESRRB splice allele was
    found were ascertained specifically for prelingual onset.
  phenotype_term:
    preferred_term: Prelingual sensorineural hearing impairment
    term:
      id: HP:0000399
      label: Prelingual sensorineural hearing impairment
  evidence:
  - reference: PMID:39261511
    reference_title: Functional pathogenicity of ESRRB variant of uncertain significance contributes to hearing loss (DFNB35).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Hearing impairment was congenital or evident at prelingual onset.
    explanation: >-
      The onset description for the Korean proband.
  - reference: PMID:33269433
    reference_title: Homozygous mutations in Pakistani consanguineous families with prelingual nonsyndromic hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      This study determined the genetic causes in five Pakistani DFNB families with prelingual onset.
    explanation: >-
      The ESRRB splice allele c.787+1G>A was found in this prelingual-onset series, which places
      at least one further DFNB35 family in the prelingual category.
  - reference: PMID:35101039
    reference_title: 'A novel missense variant in ESRRB gene causing autosomal recessive non-syndromic hearing loss: in silico analysis of a case.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      As stated by parents, HL was congenital, and no other abnormality indicated syndromic HL.
    explanation: >-
      Congenital onset in the Iranian family, reported by parental history rather than by newborn
      screening - which is worth noting, because parental recall is how onset is established in most
      of these consanguineous pedigrees.
  notes: >-
    Prelingual onset includes congenital and early-childhood presentations; it does not require neonatal
    audiometric confirmation.
- name: Progressive Hearing Impairment
  category: Auditory
  description: >-
    A Korean proband with c.397+2T>G in trans with p.Arg382Cys had progressive right-ear hearing
    loss over 17 years. The missense allele remained a VUS after functional testing. This case establishes
    a reported longitudinal observation but does not supply a population frequency or a general prognosis
    for all ESRRB genotypes.
  phenotype_term:
    preferred_term: Progressive hearing impairment
    term:
      id: HP:0001730
      label: Progressive hearing impairment
  evidence:
  - reference: PMID:39261511
    reference_title: Functional pathogenicity of ESRRB variant of uncertain significance contributes to hearing loss (DFNB35).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Over the course of a 17-year monitoring period, audiograms exhibited a progressive nature of
      hearing loss in the right ear (Fig. 1b).
    explanation: >-
      Serial audiometry documented right-ear progression in the reported compound-heterozygous case.
  - reference: PMID:39261511
    reference_title: Functional pathogenicity of ESRRB variant of uncertain significance contributes to hearing loss (DFNB35).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      The majority of hearing loss phenotypes exhibited symmetry, prelingual onset, and severe-to-profound
      SNHL, whereas our proband showed asymmetric hearing loss with a progressive nature.
    explanation: >-
      The authors contrast this case with the predominant symmetric severe-to-profound presentation;
      that contrast does not establish a numerical progression frequency.
  notes: >-
    Progression frequency cannot be estimated from this single longitudinal report.
- name: Increased Dental Caries Experience
  category: Dental
  description: >-
    In Turkish family TR-21, all six homozygous affected relatives and four heterozygous relatives
    with available dental histories were reported to have severe caries; five noncarriers were caries-free
    or had low caries experience. In the Czech p.Arg291Leu family, the affected four-year-old child
    was caries-free in the primary dentition, while the mother and maternal grandfather had high
    caries experience. Histories were collected by telephone, and age, access to dental care and
    other environmental factors limit causal interpretation.
  phenotype_term:
    preferred_term: Carious teeth
    term:
      id: HP:0000670
      label: Carious teeth
  evidence:
  - reference: PMID:25023176
    reference_title: Role of estrogen related receptor beta (ESRRB) in DFN35B hearing impairment and dental decay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      the ESRRB mutation (six homo- zygous, four heterozygous) have severe dental caries
    explanation: >-
      The Turkish family results distinguish six affected homozygotes from four hearing-unaffected
      heterozygotes; the observation is not limited to biallelic disease.
  - reference: PMID:25023176
    reference_title: Role of estrogen related receptor beta (ESRRB) in DFN35B hearing impairment and dental decay.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      The affected four-year-old child is caries-free in his primary dentition
    explanation: >-
      The Czech affected child did not have caries at age four. This qualifies the abstract summary
      of two families and argues against treating caries as obligatory.
  notes: >-
    This is a reported association with variable expression, not an established syndromic enamel
    defect. The selected pedigrees and telephone histories do not provide a population frequency.
    General-population SNP and enamel-microhardness experiments are distinct from the DFNB35 family
    observations.
- name: Absent Otoacoustic Emissions
  category: Auditory
  description: >-
    Transiently evoked otoacoustic emissions were absent in two affected members of Turkish family
    TR-21, tested at ages 48 and 23 years. This supports outer-hair-cell dysfunction without establishing
    hair-cell loss or its cellular cause.
  phenotype_term:
    preferred_term: Absent otoacoustic emissions
    term:
      id: HP:6000182
      label: Absent otoacoustic emissions
  evidence:
  - reference: PMID:18179891
    reference_title: Mutations of ESRRB encoding estrogen-related receptor beta cause autosomal-recessive nonsyndromic hearing impairment DFNB35.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Transient otoacoustic emission spectra (TEOAEs) were absent in two individuals
    explanation: >-
      Both tested relatives lacked TEOAEs. The population frequency is unknown.
- name: Vestibular Dysfunction
  category: Auditory
  description: >-
    Abnormal cVEMP with normal rotary-chair testing was reported in one ESRRB-associated child evaluated
    before cochlear implantation. This supports a possible otolith-pathway deficit despite preserved
    tested canal function. Normal caloric testing in two Turkish adults provides contrasting case-level
    evidence. Frequency, laterality and genotype dependence remain unresolved.
  phenotype_term:
    preferred_term: Abnormal vestibular function
    term:
      id: HP:0001751
      label: Abnormal vestibular function
  evidence:
  - reference: PMID:34744965
    reference_title: Peripheral Vestibular Dysfunction Is a Common Occurrence in Children With Non-syndromic and Syndromic Genetic Hearing Loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      | ESRRB | 0/1 |  | 1/1 |  | 1/1 |
    explanation: >-
      Table 2 reports normal rotary-chair testing (0/1 abnormal), abnormal cVEMP (1/1), and peripheral
      vestibular loss (1/1) in the sole ESRRB-associated case. VHIT and oVEMP entries are blank.
      Column assignments were checked against the published PDF; this selected single case does not
      establish population frequency or laterality.
  notes: >-
    The pediatric study classifies the case as ESRRB-associated; the molecular details require interpretation
    alongside its supplementary genetic table. No population frequency is assigned.

prevalence:
- population: Worldwide reported literature
  measure_type: CASES_IN_LITERATURE
  prevalence_class: UNKNOWN
  notes: >-
    Fewer than twenty families reported as of 2024, carrying twenty-two distinct alleles,
    with a strong ascertainment bias toward consanguineous Pakistani pedigrees. Recorded as
    a case count rather than a rate because no population denominator has been published.
  evidence:
  - reference: PMID:39261511
    reference_title: "Functional pathogenicity of ESRRB variant of uncertain significance contributes to hearing loss (DFNB35)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "To date, less than 20 families with SNHL exclusively of Pakistani ethnicity have been diagnosed with ESRRB biallelic variants"
    explanation: >-
      The case count and the ascertainment bias in one sentence. Note the sentence
      overstates exclusivity - Turkish, Czech, Tunisian and Korean families are also
      reported, including by this same paper - so it is cited for the order of magnitude.
  - reference: PMID:39261511
    reference_title: "Functional pathogenicity of ESRRB variant of uncertain significance contributes to hearing loss (DFNB35)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "To date, 25 variant alleles of ESRRB (condensed to 22 when considering the same variants) have been reported to cause ESRRB-associated DFNB35, including variants found in the present study."
    explanation: The size of the reported allelic spectrum, which is the other measure of how small this disease is.
  - reference: PMID:35101039
    reference_title: "A novel missense variant in ESRRB gene causing autosomal recessive non-syndromic hearing loss: in silico analysis of a case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "There are currently more than 13 variants have been found in DFNB35, nearly half of which relates to Pakistani ethnicity"
    explanation: >-
      A more careful statement of the same ascertainment bias than the "exclusively
      Pakistani" phrasing quoted above: about half, not all. Reported families are also
      Turkish, Czech, Tunisian, Iranian, Korean and Han Chinese.
- population: Tunisian families with autosomal recessive nonsyndromic hearing loss
  measure_type: CASES_IN_LITERATURE
  prevalence_class: UNKNOWN
  notes: >-
    One DFNB35 family found; screening 127 further Tunisian ARNSHL families found no
    additional ESRRB mutations. This is a denominator for how rare DFNB35 is *among
    hearing-loss families*, not a population prevalence.
  evidence:
  - reference: PMID:21802533
    reference_title: "A novel missense mutation in the ESRRB gene causes DFNB35 hearing loss in a Tunisian family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Using linkage and DHPLC analysis, no more mutations were detected in the ESRRB gene in other 127 Tunisian families with ARNSHL indicating that DFNB35 is most likely to be a rare type of ARNSHL in the Tunisian population."
    explanation: >-
      Gives an explicit denominator of 127 further families screened without a second hit.
- population: Czech patients with early-onset nonsyndromic hearing loss
  measure_type: CASES_IN_LITERATURE
  prevalence_class: UNKNOWN
  notes: >-
    One DFNB35 family found; sequencing ESRRB in 39 further Czech patients yielded only two
    homozygous variants judged to be polymorphisms.
  evidence:
  - reference: PMID:22951369
    reference_title: "DFNB35 due to a novel mutation in the ESRRB gene in a Czech consanguineous family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "The entire coding region of the ESRRB gene was sequenced in additional 39 patients of Czech origin with early NSHL and only two variants, p.V413I and p.P386S, were found in homozygous state, but are considered to be polymorphisms."
    explanation: >-
      A second screening denominator, and a useful warning that homozygous ESRRB coding
      variants are not automatically DFNB35 alleles.
genetic:
- name: ESRRB
  notes: >-
    Estrogen-related receptor beta, an orphan nuclear receptor at 14q24.3. Biallelic variants cause
    DFNB35. The reported alleles concentrate in the two functional domains - the DNA-binding domain
    and the ligand-binding domain - and are predominantly missense. The gene has a second, unrelated
    life as a core pluripotency transcription factor in embryonic stem cells, which is why searching
    the gene name returns mostly stem-cell and breast-cancer literature rather than deafness literature.
  gene_term:
    preferred_term: ESRRB
    term:
      id: hgnc:3473
      label: ESRRB
  relationship_type: CAUSATIVE
  variants:
  - name: c.1018_1024dupGAGTTTG (p.Val342GlyfsTer44)
    description: >-
      Homozygous seven-base-pair exon-8 duplication in Turkish family TR-21, reported relative to
      NM_004452. The predicted frameshift is p.Val342GlyfsTer44 (original notation p.V342GfsX44).
      The original study proposed nonsense-mediated decay or a truncated protein lacking an intact
      ligand-binding domain; it did not distinguish these experimentally.
    type: frameshift_variant
    evidence:
    - reference: PMID:18179891
      reference_title: Mutations of ESRRB encoding estrogen-related receptor beta cause autosomal-recessive nonsyndromic hearing impairment DFNB35.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        This duplication results in a frame shift and premature stop codon.
      explanation: >-
        The predicted consequence of the founding allele.
    - reference: PMID:18179891
      reference_title: Mutations of ESRRB encoding estrogen-related receptor beta cause autosomal-recessive nonsyndromic hearing impairment DFNB35.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        Sequence analysis of ESRRB in an affected individual of family TR-21 revealed a 7 bp duplication
        in exon 8
      explanation: >-
        The full text assigns c.1018_1024dupGAGTTTG and predicts p.V342GfsX44.
  - name: p.A110V, p.L320P, p.V342L, p.L347P
    description: >-
      The four missense alleles found in the original DFNB35 family and in three DFNB35-linked consanguineous
      Pakistani families. p.A110V is in the DNA-binding domain; the other three are in the ligand-binding
      domain.
    type: missense_variant
    evidence:
    - reference: PMID:18179891
      reference_title: Mutations of ESRRB encoding estrogen-related receptor beta cause autosomal-recessive nonsyndromic hearing impairment DFNB35.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        one of the substitutions (p.A110V) is located in the DNA-binding domain of ESRRB, whereas
        the other three are substitutions (p.L320P, p.V342L, and p.L347P) located within the ligand-binding
        domain
      explanation: >-
        Names the four alleles and their domain assignments, which is the origin of the DBD/LBD split
        that still describes the spectrum.
  - name: p.Arg382Cys (c.1144C>T)
    description: >-
      Recurrent ligand-binding-domain variant classified as uncertain in the 2024 study. The study
      reported gnomAD v4.1.0 allele frequencies of 0.007065 in East Asians and 0.002095 overall.
      Protein-stability, reporter and family-cell experiments added PS3-supporting evidence, leading
      the authors to call it a warm VUS; it was not upgraded to likely pathogenic or pathogenic.
      A hypomorphic effect in trans with a loss-of-function allele was proposed but not established
      by an in vivo model.
    clinical_significance: UNCERTAIN_SIGNIFICANCE
    type: missense_variant
    evidence:
    - reference: PMID:39261511
      reference_title: Functional pathogenicity of ESRRB variant of uncertain significance contributes to hearing loss (DFNB35).
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        the allele frequency of p.(Arg382Cys) variant is 0.007065 among East Asian while the allele
        frequency among all ethnicities is 0.002095, according to the Genome Aggregation Database
        (gnomAD) v.4.1.0
      explanation: >-
        The population frequency that drove the VUS classification, with the population it applies
        to stated.
    - reference: PMID:39261511
      reference_title: Functional pathogenicity of ESRRB variant of uncertain significance contributes to hearing loss (DFNB35).
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: >-
        we obtained additional evidence of PS3_supporting, permitting the reclassification as a 'warm
        VUS'
      explanation: >-
        The authors' own conclusion, which stops short of likely pathogenic - worth recording precisely
        rather than rounding up to pathogenic.
  - name: c.397+2T>G
    description: >-
      Canonical donor splice-site variant found in trans with p.Arg382Cys in a Korean family. A minigene
      assay showed it skips exon 4, producing a premature stop codon and nonsense-mediated decay,
      confirmed by cycloheximide stabilisation of the transcript in patient cells.
    clinical_significance: PATHOGENIC
    type: splice_donor_variant
    evidence:
    - reference: PMID:39261511
      reference_title: Functional pathogenicity of ESRRB variant of uncertain significance contributes to hearing loss (DFNB35).
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: >-
        The treatment resulted in the stabilization of ESRRB mRNA, suggesting that the reduction
        in ESRRB mRNA is dependent on the NMD pathway
      explanation: >-
        Cycloheximide rescue of the transcript, which is what turns the predicted NMD into a measured
        one.
  - name: p.R291L
    description: >-
      Homozygous missense allele in a consanguineous Czech family, and one of the two DFNB35 families
      in which dental caries was assessed.
    type: missense_variant
    evidence:
    - reference: PMID:22951369
      reference_title: DFNB35 due to a novel mutation in the ESRRB gene in a Czech consanguineous family.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        Mutation p.R291L in a homozygous state was found in the deaf child, the parents were heterozygous.
      explanation: >-
        The allele and its segregation.
  - name: p.Y305H
    description: >-
      Novel missense ligand-binding-domain allele in a Tunisian ARNSHL family.
    type: missense_variant
    evidence:
    - reference: PMID:21802533
      reference_title: A novel missense mutation in the ESRRB gene causes DFNB35 hearing loss in a Tunisian family.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      directness: INDIRECT
      snippet: >-
        Molecular modeling showed that the p.Y305H mutation is likely to alter the conformation of
        the ligand binding-site by destabilizing the coactivator binding pocket.
      explanation: >-
        The mechanistic argument is modelling rather than assay, so it is graded COMPUTATIONAL and
        INDIRECT. The clinical evidence for the allele is the family segregation reported alongside
        it.
  - name: p.G167R (c.499G>A)
    description: >-
      Homozygous c.499G>A (p.Gly167Arg), in the DNA-binding domain, segregated with congenital severe-to-profound
      hearing loss in an Iranian Azeri Turkish family and was absent from 200 study controls. The
      paper classified it as likely pathogenic using segregation, rarity and computational evidence;
      it did not measure a functional consequence.
    clinical_significance: LIKELY_PATHOGENIC
    type: missense_variant
    evidence:
    - reference: PMID:35101039
      reference_title: 'A novel missense variant in ESRRB gene causing autosomal recessive non-syndromic hearing loss: in silico analysis of a case.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        A novel homozygous missense mutation, c.499G>A (p.G167R), was identified in exon 5 of the
        ESRRB (estrogen-related receptor beta) gene.
      explanation: >-
        The allele, its zygosity and its exon.
    - reference: PMID:35101039
      reference_title: 'A novel missense variant in ESRRB gene causing autosomal recessive non-syndromic hearing loss: in silico analysis of a case.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        Healthy and affected family members confirmed the co-segregation of the variant with ARNSHL.
      explanation: >-
        Segregation, which is the clinical evidence for the allele. The paper's own pathogenicity
        argument beyond that is in silico, as its title says.
    - reference: PMID:35101039
      reference_title: 'A novel missense variant in ESRRB gene causing autosomal recessive non-syndromic hearing loss: in silico analysis of a case.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        our discovered variant met the pathogenicity criteria and was considered “likely pathogenic”
      explanation: >-
        The classification in the discussion is likely pathogenic, despite stronger wording elsewhere
        in the report.
  - name: p.Tyr295Cys
    description: >-
      Homozygous c.884A>G (p.Tyr295Cys) segregated in a Tunisian family with two affected members.
      Table 3 classifies it as likely pathogenic. Predicted folding and cofactor-binding effects
      were computational hypotheses, not measured in inner-ear cells.
    clinical_significance: LIKELY_PATHOGENIC
    type: missense_variant
    evidence:
    - reference: PMID:34194829
      reference_title: Novel pathogenic mutations and further evidence for clinical relevance of genes and variants causing hearing impairment in Tunisian population.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        five novel variants including three missense (ESRRB-Tyr295Cys, MYO15A-Phe2089Leu and MYO7A-Tyr560Cys)
      explanation: >-
        Reports the ESRRB allele among the novel pathogenic variants in this cohort.
    - reference: PMID:34194829
      reference_title: Novel pathogenic mutations and further evidence for clinical relevance of genes and variants causing hearing impairment in Tunisian population.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        | P2 | ESRRB-Tyr295Cys | Yes | – | – | PM2-PP1* | PP3 | – | Likely Pathogenic |
      explanation: >-
        Table 3 explicitly assigns likely pathogenic using rarity, segregation and computational
        evidence.
  - name: c.787+1G>A
    description: >-
      Novel homozygous splicing donor-site variant in a consanguineous Pakistani family with prelingual
      nonsyndromic hearing loss.
    type: splice_donor_variant
    evidence:
    - reference: PMID:33269433
      reference_title: Homozygous mutations in Pakistani consanguineous families with prelingual nonsyndromic hearing loss.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        two splicing donor site mutations of c.787+1G>A in ESRRB (DFNB35) and c.637+1G>T in CABP2
        (DFNB93)
      explanation: >-
        Names the allele and assigns it to DFNB35.
  - name: c.733G>C (p.Asp245His)
    type: missense_variant
    description: >-
      Homozygous ligand-binding-domain variant reported in one Pakistani participant with moderate-to-severe
      hearing loss. It extends the observed severity range; a modifier mechanism was suggested but
      not identified.
    evidence:
    - reference: PMID:32681043
      reference_title: Spectrum of genetic variants in moderate to severe sporadic hearing loss in Pakistan.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        A variant c.733G > C (p.Asp245His) in ESRRB was identified for moderate to severe hearing
        loss in one participant of this study.
      explanation: >-
        The specific allele and patient phenotype are stated in the full text; Table 1 gives the
        homozygous genotype. No functional assay was reported.
  evidence:
  - reference: PMID:18179891
    reference_title: Mutations of ESRRB encoding estrogen-related receptor beta cause autosomal-recessive nonsyndromic hearing impairment DFNB35.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      In a large consanguineous family of Turkish origin, genome-wide homozygosity mapping revealed
      a locus for recessive nonsyndromic hearing impairment on chromosome 14q24.3-q34.12.
    explanation: >-
      The mapping that led to ESRRB, and the chromosomal location.

diagnosis:
- name: Genetic testing for biallelic ESRRB variants
  description: >-
    Audiological assessment establishes sensorineural hearing loss, while sequencing and segregation
    analysis evaluate ESRRB as the molecular cause. Normal temporal-bone imaging in reported patients
    does not exclude DFNB35. Variant interpretation remains essential: homozygosity alone does not
    establish pathogenicity, and the recurrent p.Arg382Cys allele remained a VUS after functional
    testing in the 2024 report.
  evidence:
  - reference: PMID:39261511
    reference_title: Functional pathogenicity of ESRRB variant of uncertain significance contributes to hearing loss (DFNB35).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Neither temporal bone computed tomography (CT) nor internal acoustic canal magnetic resonance
      imaging (MRI) revealed any anomalies within the inner ear
    explanation: >-
      Normal CT and MRI were reported in the Korean proband; this single observation does not establish
      that every DFNB35 patient has normal imaging.
  - reference: PMID:39261511
    reference_title: Functional pathogenicity of ESRRB variant of uncertain significance contributes to hearing loss (DFNB35).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      At this stage, based on the ACMG-AMP guideline, the p.(Arg382Cys) variant was classified as
      VUS, evidenced by PM3, PP3, and BA1
    explanation: >-
      The authors explicitly classified p.Arg382Cys as VUS; their subsequent functional work supplied
      supporting evidence without a likely-pathogenic classification.
  - reference: PMID:22951369
    reference_title: DFNB35 due to a novel mutation in the ESRRB gene in a Czech consanguineous family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      Homozygosity mapping is a powerful method for identification of genes in heterogeneous recessive
      diseases.
    explanation: >-
      The method by which DFNB35 families have historically been found. Indirect: it describes gene
      discovery in consanguineous pedigrees rather than diagnostic testing of an individual patient.
- name: Vestibular assessment
  description: >-
    Vestibular function should be interpreted by test and genotype. Two adults in Turkish family
    TR-21 had normal caloric testing. A later pediatric ESRRB-associated case had abnormal cVEMP
    with a normal rotary-chair result. Normal canal testing does not establish normal otolith function.
  evidence:
  - reference: PMID:18179891
    reference_title: Mutations of ESRRB encoding estrogen-related receptor beta cause autosomal-recessive nonsyndromic hearing impairment DFNB35.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      For these two individuals, computerized tomography of the temporal bone and caloric testing
      for evaluation of the vestibular function were performed, and no abnormalities were found.
    explanation: >-
      Normal caloric results in two affected Turkish relatives are direct human evidence, with limited
      sample size and vestibular-organ coverage.
  - reference: PMID:34744965
    reference_title: Peripheral Vestibular Dysfunction Is a Common Occurrence in Children With Non-syndromic and Syndromic Genetic Hearing Loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      | ESRRB | 0/1 |  | 1/1 |  | 1/1 |
    explanation: >-
      Table 2 reports normal rotary-chair testing (0/1 abnormal), abnormal cVEMP (1/1), and peripheral
      vestibular loss (1/1) in the sole ESRRB-associated case. VHIT and oVEMP entries are blank.
      Column assignments were checked against the published PDF; this selected single case does not
      establish population frequency or laterality.

treatments:
- name: Cochlear Implantation
  description: >-
    Two children with biallelic ESRRB variants were among the good-outcome controls in a 2015 cochlear-implant
    study. Controls were selected for CAP 7 and SIR 5 after more than three years of implant use.
    These are favorable observations in two selected recipients, not an unbiased DFNB35 success rate;
    variant interpretation and individual clinical factors remain relevant. A separate pediatric
    series reports preoperative vestibular testing in one ESRRB-associated child but no individual
    postoperative auditory outcome.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: cochlear device implantation
    term:
      id: NCIT:C15329
      label: Surgical Procedure
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: cochlear implant
        term:
          id: NCIT:C157820
          label: Cochlear Implant
  target_mechanisms:
  - target: Bilateral Sensorineural Hearing Impairment
    treatment_effect: BYPASSES
    description: >-
      A cochlear implant stimulates auditory nerve fibers and can bypass impaired cochlear sensory
      function. Rodent ESRRB expression in supporting and neural compartments does not establish
      either neural preservation or failure in patients. Two selected ESRRB-associated recipients
      had good outcomes; the mechanism link does not predict benefit for every genotype.
  evidence:
  - reference: PMID:26166082
    reference_title: Identifying Children With Poor Cochlear Implantation Outcomes Using Massively Parallel Sequencing.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      2 had bi-allelic mutations in ESRRB
    explanation: >-
      The full text identifies two ESRRB-associated recipients among the good-outcome controls; the
      observation is more specific than the six-gene aggregate in the abstract.
  - reference: PMID:26166082
    reference_title: Identifying Children With Poor Cochlear Implantation Outcomes Using Massively Parallel Sequencing.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Thirty unrelated children with good CI performance (CAP score = 7 and SIR score = 5) were selected
    explanation: >-
      These outcome criteria apply to the matched-control group containing the two ESRRB-associated
      children. Outcome-based ascertainment prevents estimating treatment success frequency.
  - reference: PMID:34744965
    reference_title: Peripheral Vestibular Dysfunction Is a Common Occurrence in Children With Non-syndromic and Syndromic Genetic Hearing Loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      The most common cause of non-syndromic HL was due to mutations in GJB2 (n = 13) followed by
      MYO15A (3), MYO6 (2), POU3F4 (2), TMPRSS3 (1), CDH23 (1), TMC1 (1), and ESRRB (1).
    explanation: >-
      Places one ESRRB child in a cochlear implant candidate cohort, establishing that DFNB35 patients
      do reach implantation. It reports no outcome for that child.
  notes: >-
    The 2015 study provides favorable outcome observations but no unselected ESRRB cohort, causal
    treatment comparison or variant-independent prognosis. Neural ESRRB expression alone does not
    predict implantation outcome.
- name: Hearing Aids and Auditory Rehabilitation
  description: >-
    Hearing aids, communication support and auditory or speech-language habilitation are individualized
    to residual hearing and family needs. General genetic hearing-loss guidance supports amplification
    for mild-to-severe loss; no ESRRB-specific amplification outcome is established.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: auditory rehabilitation with amplification
    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
  notes: >-
    General care guidance; the treatment term describes rehabilitation and the qualifier identifies
    the hearing-aid device.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1434/
    reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: >-
      can be used in individuals with mild-to-severe hearing loss.
    explanation: >-
      The sentence describes hearing aids in general genetic hearing-loss care. It does not establish
      a DFNB35-specific effect.
- name: Dental caries surveillance and prevention
  description: >-
    A plausible, unproven addition to routine care, recorded because the ESRRB caries association
    was proposed by its authors as an actionable one. The proposal is explicitly conditional in the
    source, and no DFNB35 preventive study has been done.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: preventive dental care
    term:
      id: NCIT:C15843
      label: Preventive Intervention
  evidence:
  - reference: PMID:25023176
    reference_title: Role of estrogen related receptor beta (ESRRB) in DFN35B hearing impairment and dental decay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      provides options for the development of new caries prevention strategies, if the associated
      ESRRB genetic variants are correlated with efficacy
    explanation: >-
      The authors' conditional proposal, quoted with its condition intact. It supports recording
      surveillance as a consideration, not a recommendation.
  notes: >-
    No treatment_effect and no target_mechanisms link: nothing has been shown to modify the enamel
    or caries phenotype in DFNB35, so asserting a mechanism target would claim more than the evidence
    carries.
- name: Genetic Counseling
  therapeutic_modality: BEHAVIORAL
  description: >-
    Counseling should use confirmed parental genotypes and the interpretation of each familial ESRRB
    variant. When both parents carry a pathogenic allele for the same autosomal recessive disorder,
    each pregnancy has a 25% chance of biallelic disease. A VUS alone does not establish a molecular
    diagnosis or a predictable severity.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1434/
    reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: >-
      has at conception a 25% chance of having hearing loss
    explanation: >-
      This recurrence statement applies to the parental heterozygote configuration specified in the
      general GeneReviews overview.

animal_models:
- name: Nr3b2 (Esrrb) null mouse, including genetically mosaic animals
  species: Mouse
  genotype: Nr3b2(-/-); mosaic Nr3b2(-/-) inner ear epithelium
  publication: PMID:17765677
  description: >-
    The model that established what ERR-beta does in the inner ear. Because germline Nr3b2 loss is
    not compatible with normal development, the informative experiments are on the inner ear epithelium
    and on genetically mosaic animals in which null marginal cells sit beside wild-type ones - which
    is what makes the non-cell-autonomous effects on intermediate cells and capillaries interpretable.
  modeled_mechanisms:
  - target: Failure of the Strial Marginal Cell Secretory Programme
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Null mouse marginal cells fail to express multiple ion-channel and transporter genes. This
      directly models the secretory gene-expression node.
    limitations: >-
      Null animals establish gene function but do not measure the residual activity or phenotype
      of individual human missense variants. The accessible primary abstract lacks quantitative auditory
      physiology.
    readouts:
    - name: Expression of strial marginal cell ion channel and transporter genes
      target: Failure of the Strial Marginal Cell Secretory Programme
      direction: DECREASED
      interpretation: The secretory gene programme is not switched on, which is the definition of this node.
      evidence:
      - reference: PMID:17765677
        reference_title: Estrogen-related receptor beta/NR3B2 controls epithelial cell fate and endolymph production by the stria vascularis.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        directness: DIRECT
        snippet: >-
          Nr3b2(-/-) strial marginal cells fail to express multiple ion channel and transporter genes
        explanation: >-
          The direct measurement of the transcriptional readout in null marginal cells.
    evidence:
    - reference: PMID:17765677
      reference_title: Estrogen-related receptor beta/NR3B2 controls epithelial cell fate and endolymph production by the stria vascularis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        an orphan nuclear receptor, is specifically expressed in and controls the development of
        the endolymph-producing cells of the inner ear
      explanation: >-
        Establishes that this model is informative for the marginal cell node by showing the gene
        acts in exactly those cells.
  - target: Impaired Endolymph Homeostasis
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      The 2008 gene-discovery paper summarizes impaired endolymph production and defective hearing
      and balance in conditional-null Esrrb mice.
    limitations: >-
      Physiological consequences are summarized in a later paper; the accessible primary abstract
      does not provide quantitative endolymph or auditory measurements. Extrapolation to human alleles
      is limited.
    evidence:
    - reference: PMID:18179891
      reference_title: Mutations of ESRRB encoding estrogen-related receptor beta cause autosomal-recessive nonsyndromic hearing impairment DFNB35.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: >-
        Disturbed endolymph production in these mice results in an aberrant inner-ear fluid homeostasis
        and as a consequence in defective hearing and balance.
      explanation: >-
        The human gene-discovery paper summarizes earlier conditional mouse experiments; this is
        indirect evidence for their physiological outcome.
  - target: Partial Marginal Cell Fate Transformation
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Nr3b2-null mouse strial marginal cells partially acquire the identity of neighboring Pendrin-expressing
      epithelial cells. This is a partial fate transformation, not evidence that every marginal cell
      disappears or becomes an identical mature neighboring cell.
    limitations: >-
      Directly observed in the null/mosaic mouse model; corresponding human cochlear histology has
      not been reported in the cited studies.
    evidence:
    - reference: PMID:17765677
      reference_title: Estrogen-related receptor beta/NR3B2 controls epithelial cell fate and endolymph production by the stria vascularis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        they show a partial transformation toward the fate of the immediately adjacent Pendrin-expressing
        epithelial cells
      explanation: >-
        The authors distinguish a partial identity change from loss of transporter expression.
  - target: Secondary Strial Intermediate Cell Expression Changes
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      In genetically mosaic mice, Nr3b2-null marginal cells induce secondary changes in gene expression
      in the underlying intermediate-cell layer. This establishes a local non-cell-autonomous effect,
      without identifying a specific intercellular signal.
    limitations: >-
      Directly observed in the null/mosaic mouse model; corresponding human cochlear histology has
      not been reported in the cited studies.
    evidence:
    - reference: PMID:17765677
      reference_title: Estrogen-related receptor beta/NR3B2 controls epithelial cell fate and endolymph production by the stria vascularis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        Nr3b2(-/-) strial marginal cells produce secondary alterations in gene expression in the
        underlying intermediate cells
      explanation: >-
        Mosaic analysis links mutant marginal cells to altered expression in the neighboring strial
        layer.
  - target: Local Strial Capillary Loss
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Local loss of strial capillaries accompanies Nr3b2-null marginal-cell regions in mosaic mice.
      The primary abstract reports the vascular consequence without establishing its temporal order
      relative to intermediate-cell expression changes or specifying the vascular signaling mechanism.
    limitations: >-
      Directly observed in the null/mosaic mouse model; corresponding human cochlear histology has
      not been reported in the cited studies.
    evidence:
    - reference: PMID:17765677
      reference_title: Estrogen-related receptor beta/NR3B2 controls epithelial cell fate and endolymph production by the stria vascularis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        In genetically mosaic mice, Nr3b2(-/-) strial marginal cells produce secondary alterations
        in gene expression in the underlying intermediate cells and a local loss of strial capillaries.
      explanation: >-
        The capillary finding is separated from the intermediate-cell expression phenotype; no serial
        causal order between them is inferred.

discussions:
- discussion_id: dfnb35_strial_failure_to_threshold
  kind: HUMAN_MODEL_MISMATCH
  attaches_to:
  - pathophysiology#Impaired Endolymph Homeostasis
  prompt: >-
    Does loss of ERR-beta actually raise hearing thresholds in a mouse, and by how much?
  rationale: >-
    Mouse loss-of-function evidence supports defective strial development, and the 2008 gene-discovery
    paper summarizes defective hearing, balance and endolymph production in rescued or conditional-null
    mice. The available records do not provide a verified quantitative genotype-dependent ABR, DPOAE
    or endocochlear-potential comparison. Human missense alleles should not be assumed to retain
    function without assay evidence. Comparing null and defined missense alleles would clarify dose
    dependence; human vestibular results include both normal caloric testing and a single abnormal
    cVEMP report.
  proposed_experiments:
  - experiment_id: dfnb35_exp_abr_ep_conditional_ko
    name: Auditory brainstem response and endocochlear potential in a conditional Esrrb inner-ear knockout
    description: >-
      Measure longitudinal ABR, DPOAE, endocochlear potential and vestibular responses in conditional-null
      animals and a defined human-variant knock-in such as p.Arg382Cys, including the variant in
      trans with a null allele. This tests the proposed hypomorphic mechanism without assuming it.
    would_support:
    - pathophysiology#Impaired Endolymph Homeostasis
    supporting_outcome:
    - Elevated ABR thresholds together with a reduced endocochlear potential and reduced endolymphatic potassium, with the missense knock-in showing an intermediate deficit.
    would_refute:
    - pathophysiology#Impaired Endolymph Homeostasis
    refuting_outcome:
    - Normal endocochlear potential and normal ABR thresholds despite the documented marginal cell fate defect, which would mean the fate conversion is compensated and the deafness arises somewhere else.
- discussion_id: dfnb35_is_it_really_nonsyndromic
  kind: KNOWLEDGE_GAP
  attaches_to:
  - phenotypes#Increased Dental Caries Experience
  prompt: >-
    Does ESRRB dysfunction increase caries susceptibility beyond age, dental care and environmental
    influences?
  rationale: >-
    The Turkish pedigree had severe caries in six affected homozygotes and four heterozygotes, while
    the Czech affected child was caries-free at four years. Telephone histories and unequal dental-care
    access limit interpretation. Normal mouse ameloblast expression and common-SNP associations do
    not establish a DFNB35-specific enamel defect. Standardized dental examination across genotypes
    is needed to assess this association.
  proposed_experiments:
  - experiment_id: dfnb35_exp_dmft_pedigrees
    name: DMFT scoring in reported DFNB35 pedigrees
    description: >-
      Score decayed, missing and filled teeth in affected homozygotes, heterozygous relatives and
      unaffected relatives across the reported DFNB35 families, controlling for age and access to
      dental care, which is the obvious confounder in consanguineous cohorts from different countries.
    would_support:
    - phenotypes#Increased Dental Caries Experience
    supporting_outcome:
    - Higher DMFT in biallelic carriers than in their unaffected relatives across multiple independent pedigrees.
    would_refute:
    - phenotypes#Increased Dental Caries Experience
    refuting_outcome:
    - No DMFT difference between biallelic carriers and relatives once age and dental access are matched, which would make the two-family observation a confound of socioeconomic ascertainment.
- discussion_id: dfnb35_absent_vestibular_phenotype
  kind: KNOWLEDGE_GAP
  attaches_to:
  - phenotypes#
  prompt: >-
    How often is vestibular function affected in ESRRB-related hearing loss, and does it depend on
    genotype or the vestibular test used?
  rationale: >-
    Vestibular function is not uniformly unexamined or uniformly abnormal. Collin et al. reported
    normal caloric testing in two Turkish adults; Wang et al. reported abnormal cVEMP but normal
    rotary-chair testing in one pediatric ESRRB-associated case. The latter finding is tabulated
    rather than individually discussed in the narrative. Different tests sample different vestibular
    end organs, and these small reports cannot define penetrance or establish a simple species discordance
    with null mice.
  proposed_experiments:
  - experiment_id: dfnb35_exp_vestibular_testing
    name: Vestibular testing in molecularly confirmed DFNB35 patients
    description: >-
      Video head impulse testing, cervical and ocular VEMPs and caloric testing in biallelic ESRRB
      patients, who are largely already in contact with cochlear implant programmes where such testing
      is routine.
    would_support:
    - pathophysiology#Failure of the Strial Marginal Cell Secretory Programme
    supporting_outcome:
    - Reduced VEMP responses or caloric hypofunction in a substantial fraction of DFNB35 patients, which would extend the dark cell arm of the mechanism into the clinic.
    would_refute:
    - pathophysiology#Failure of the Strial Marginal Cell Secretory Programme
    refuting_outcome:
    - Consistently normal results across canal and otolith tests in a larger genotype-defined series would argue against a common vestibular deficit, while not negating the existing single-case result.

notes: >-
  DFNB35 is a single-gene recessive hearing-loss disorder. Mouse loss-of-function evidence supports
  a strial marginal-cell mechanism. The broader supporting-cell and neural localization reported
  by Collin et al. was established by developmental mouse in situ hybridization and postnatal-day-4
  rat immunohistochemistry. Expression alone does not demonstrate a separate neuronal disease mechanism
  or preservation of the neural target for cochlear implantation.

  The original Turkish pedigree had absent otoacoustic emissions and normal caloric testing in the
  two extensively evaluated adults. A later pediatric series reported an ESRRB-associated vestibular
  deficit by cVEMP with normal rotary-chair testing. These findings should be interpreted by age,
  genotype and test, without inferring a frequency from a single case or declaring all human vestibular
  function normal.

  The 2008 gene-discovery study reports a frameshift and four missense alleles, not an additional
  in-frame deletion. Its p.Pro386Ser variant was also homozygous in two controls and considered polymorphic;
  a heterozygous p.Thr389Met lacked an identified second allele and remained uncertain. The 2024
  literature synthesis reports 22 distinct variants, including an in-frame allele from other literature,
  and retains p.Arg382Cys as a VUS despite functional evidence. Missense predominance does not establish
  that all human alleles are hypomorphic. No ESRRB-specific GeneReviews chapter is identified in
  the baseline check; the general Genetic Hearing Loss Overview supports management and counseling.
  ClinicalTrials.gov returned no studies for ESRRB or DFNB35 on 2026-09-27.

references:
- reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1434/
  title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
  tags:
  - GeneReviews

datasets:
- accession: geo:GSE8434
  title: Transcriptional regulation by Errb (Nr3b2) in stria vascularis
  description: >-
    Microarray comparison of microdissected cochlear lateral walls from Errb-mutant mice
    and wild-type littermate controls, associated with the original strial-development study.
    Three wild-type and three mutant samples are represented in the linked GDS2955 record.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: MICROARRAY
  sample_count: 6
  conditions:
  - Wild-type littermate controls
  - Errb-mutant stria vascularis
  platform: Affymetrix Mouse Genome 430 2.0 Array (GPL1261)
  publication: PMID:17765677
  notes: >-
    Tissue-level mouse expression profiles can nominate downstream genes but do not establish
    direct ESRRB binding or the effects of individual human variants.
📚

References & Deep Research

References

1
url:https://www.ncbi.nlm.nih.gov/books/NBK1434/
Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
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: Autosomal Recessive Nonsyndromic Hearing Loss 35 (DFNB35, ESRRB) · 2026-09-03T20:32:52Z · View source

New Disease entry for MONDO:0012060 (DFNB35, biallelic ESRRB). entry_type decision: DISEASE - a single-gene recessive disorder with one conserved pathograph (ESRRB loss of function -> reduced ERR-beta transcriptional output -> failure of the strial marginal cell secretory programme -> cochlear lateral wall failure -> bilateral sensorineural hearing loss), mechanistically distinct from the hair-cell and stereocilium lesions of the other DFNB entries, so not folded in as a subtype. Stub deleted. Mechanism anchored on Chen and Nathans (PMID:17765677), which places ERR-beta in strial marginal cells and vestibular dark cells and reports the Nr3b2-null cell-fate defect, plus the 2024 Korean functional study (PMID:39261511), which supplies the only measurements made in human material (minigene exon-4 skipping with NMD, cycloheximide-chase protein destabilisation, abolished SMAD7 reporter activity, and reduced ATP1B1/EGR1/NRP1/TBX3/SPARC transcripts in patient lymphoblastoid cells). Discipline applied to the inferred step: no ESRRB mouse with an audiometric readout was found, so the step from failed strial secretion to an elevated threshold is left explicitly inferred - the tissue node is mechanism_confidence PROVISIONAL, the animal-model link for it is PARTIALLY_RECAPITULATES with the missing endolymph/EP/ABR measurements named in limitations, and a HUMAN_MODEL_MISMATCH discussion records the gap. The corroborating Tbx1 stria-vascularis deafness result (PMID:31550482) is carried on the edge with directness INDIRECT and an explanation stating it is a different gene. Also curated: the dental-caries finding (PMID:25023176) as an OCCASIONAL phenotype plus a modifier ameloblast node, with a KNOWLEDGE_GAP discussion arguing that nonsyndromic may be resting on nomenclature rather than data, since only two DFNB35 families have ever been examined for teeth. Deliberately not curated: progression, differential_diagnoses, any vestibular phenotype (a third discussion records that absence as untested), and datasets/clinical_trials/environmental. Deep research: falcon provider, preflight-dr PASS against MONDO:0012060 (ESRRB mentioned 51 times, top gene). The report contributed one reference not found by direct PubMed search (PMID:35101039, Iranian Azeri Turkish family, p.G167R), which was added. Validation: just validate, validate-terms, count-verified-snippets 58/58, validate-disorders, check-duplicate-keys, check-entity-refs, check-causal-targets, check-snippet-length, check-title-snippets, check-snippet-grading, check-environmental-evidence, check-folded-hyphens, check-stubs - all exit 0.

Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 21 citations 2026-09-03T13:17:46.096427

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

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

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

Disease Characteristics Research Template

Target Disease

  • Disease Name: Autosomal Recessive Nonsyndromic Hearing Loss 35 (DFNB35, ESRRB-related)
  • MONDO ID: MONDO:0012060 (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Autosomal Recessive Nonsyndromic Hearing Loss 35 (DFNB35, ESRRB-related) covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

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

1. Disease Information

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

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

2. Etiology

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

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

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

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

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

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

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

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

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

4. Genetic/Molecular Information

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

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

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

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

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

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

5. Environmental Information

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

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

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

    Search first: CDC databases, WHO, PubMed, NHANES

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

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

6. Mechanism / Pathophysiology

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

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

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

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

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

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

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

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

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

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

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

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

    Search first: PubMed, Gene Ontology, Reactome

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

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

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

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

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

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

7. Anatomical Structures Affected

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

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

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

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

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

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

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

8. Temporal Development

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

    Search first: OMIM, Orphanet, HPO, PubMed

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

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

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

9. Inheritance and Population

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

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

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

10. Diagnostics

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

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

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

11. Outcome/Prognosis

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

12. Treatment

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

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

13. Prevention

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

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

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

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

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

    Search first: NSGC resources, ACMG guidelines, GeneReviews

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

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

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

    Search first: VBO (Vertebrate Breed Ontology)

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

    Search first: NCBI Gene

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

15. Model Organisms

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

Citation Requirements

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

Output Format

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

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

Autosomal Recessive Nonsyndromic Hearing Loss 35 (DFNB35; ESRRB-related)

Executive summary

DFNB35 is an exceptionally rare Mendelian sensorineural hearing-loss disorder caused by biallelic germline variants in ESRRB, which encodes estrogen-related receptor β (ERRβ), an orphan nuclear-receptor transcription factor. The usual presentation is congenital or prelingual, bilateral, approximately symmetric severe-to-profound sensorineural hearing loss (SNHL), although moderate disease and asymmetric progressive loss are now documented. Before the first South Korean case in 2024, fewer than 20 affected families had been reported, with strong ascertainment in consanguineous Pakistani and Turkish pedigrees. Consequently, prevalence, penetrance, carrier frequency, natural history, treatment outcomes, and genotype–phenotype relationships remain poorly quantified. (choi2024functionalpathogenicityof pages 1-2, choi2024functionalpathogenicityof pages 7-8)

The principal 2024 advance was functional characterization of ESRRB c.397+2T>G and c.1144C>T, p.(Arg382Cys). The splice variant caused exon-4 skipping, premature termination, and nonsense-mediated decay (NMD). p.Arg382Cys destabilized ERRβ, reduced transcriptional activity, and altered inner-ear-relevant downstream genes. Nevertheless, because p.Arg382Cys is relatively frequent in East Asians, its authors assigned only ACMG/AMP PS3-supporting evidence and called it a “warm VUS,” not definitively pathogenic. (choi2024functionalpathogenicityof pages 3-4, choi2024functionalpathogenicityof pages 5-7, choi2024functionalpathogenicityof pages 8-9)

Domain Best-supported finding Evidence type/strength Key source/date
Disease identity and inheritance DFNB35 is autosomal-recessive nonsyndromic sensorineural hearing loss caused by biallelic germline ESRRB variants; locus 14q24.3. Strong: linkage, segregation, multiple independent families, and functional evidence. Collin et al., Jan 2008, DOI (collin2008mutationsofesrrb pages 1-2, collin2008mutationsofesrrb pages 5-6); Choi et al., Sep 2024, DOI (choi2024functionalpathogenicityof pages 1-2)
Core phenotype Usually congenital/prelingual, bilateral, approximately symmetric severe-to-profound SNHL; moderate-to-severe and asymmetric progressive disease also occur. Vestibular dysfunction was absent in the original families. Moderate: consistent case-series evidence, but few patients and incomplete longitudinal characterization. Collin et al., Jan 2008 (collin2008mutationsofesrrb pages 5-6, collin2008mutationsofesrrb pages 11-12); Choi et al., Sep 2024 (choi2024functionalpathogenicityof pages 3-4, choi2024functionalpathogenicityof pages 7-8)
Rarity and populations Fewer than 20 affected families had been reported before the 2024 Korean case; many early families were consanguineous and Pakistani or Turkish. Disease-specific prevalence, incidence, and carrier frequency are unknown. Moderate for extreme rarity; limited for population estimates: ascertainment is strongly family- and ancestry-biased. Choi et al., Sep 2024 (choi2024functionalpathogenicityof pages 1-2); Collin et al., Jan 2008 (collin2008mutationsofesrrb pages 1-2, collin2008mutationsofesrrb pages 5-6)
Causal gene and protein ESRRB encodes estrogen-related receptor β (ERRβ), an orphan nuclear-receptor transcription factor with a C4 zinc-finger DNA-binding domain and a C-terminal ligand-binding domain. Strong: established molecular genetics and protein-domain biology. Collin et al., Jan 2008, DOI (collin2008mutationsofesrrb pages 5-6); Choi et al., Sep 2024 (choi2024functionalpathogenicityof pages 1-2)
Variant spectrum A 2024 synthesis identified 25 reported alleles representing 22 unique variants: 90.9% SNVs; 72.7% missense, 4.5% nonsense, 9.1% frameshift, 9.1% splice, and 4.5% in-frame. Nine coding variants mapped to each of the DNA- and ligand-binding domains. Moderate-to-strong: literature synthesis backed by reported pedigrees; classifications may change with new population or functional evidence. Choi et al., Sep 2024 (choi2024functionalpathogenicityof pages 5-7)
Exemplar pathogenic variants Segregating examples include c.1018_1024dupGAGTTTG (p.Val342GlyfsTer44), p.Ala110Val, p.Leu320Pro, p.Val342Leu, p.Leu347Pro, c.397+2T>G, and p.Arg382Cys in trans with a loss-of-function allele. p.Pro386Ser was found in controls and treated as polymorphic; p.Thr389Met remained uncertain. Strong for segregating loss-of-function/domain variants; variable for missense variants. Collin et al., Jan 2008 (collin2008mutationsofesrrb pages 5-6); Choi et al., Sep 2024 (choi2024functionalpathogenicityof pages 2-3, choi2024functionalpathogenicityof pages 8-9)
2024 functional advance c.397+2T>G caused exon-4 skipping, premature termination, and nonsense-mediated decay. p.Arg382Cys destabilized ERRβ and abolished/reduced transcriptional activity; authors assigned PS3-supporting but retained a “warm VUS” rather than pathogenic classification. Its gnomAD v4.1 East-Asian frequency was 0.007065, versus 0.002095 overall. Strong functional evidence for splicing; moderate supporting evidence for p.Arg382Cys: patient cells, minigene, reporter, protein, and computational assays, but one family and no knock-in animal. Choi et al., Sep 2024, DOI (choi2024functionalpathogenicityof pages 3-4, choi2024functionalpathogenicityof pages 5-7, choi2024functionalpathogenicityof pages 8-9)
Molecular mechanism Biallelic loss or hypomorphic dysfunction reduces ERRβ-dependent transcription. In patient cells, ATP1B1 and EGR1 decreased 55.1% and 45.4% versus the father; splice-allele-associated targets NRP1, TBX3, and SPARC fell approximately 48–53%. Disruption of cochlear ion/fluid homeostasis is plausible, but the complete human causal pathway remains partly inferred. Moderate: direct cellular transcriptional evidence plus animal/anatomical support; downstream electrophysiology has not been demonstrated in affected humans. Choi et al., Sep 2024 (choi2024functionalpathogenicityof pages 5-7); Collin et al., Jan 2008 (collin2008mutationsofesrrb pages 11-12)
Anatomy and cell types ESRRB localizes to cochlear supporting and nonsensory tissues, stria vascularis/spiral ligament, nerve fibers, and spiral-ganglion cells; it was not detected in inner or outer hair cells. Absent otoacoustic emissions therefore likely reflect secondary outer-hair-cell dysfunction. Moderate: developmental mouse RNA localization and postnatal rat immunohistochemistry, supported by human audiology; direct human cochlear tissue evidence is lacking. Collin et al., Jan 2008 (collin2008mutationsofesrrb pages 11-12, collin2008mutationsofesrrb pages 9-11)
Model-organism evidence Complete Esrrb loss is embryonically lethal; rescued or conditional-null mice show impaired hearing and balance, circling/head tossing, and defective stria-vascularis development. Moderate-to-strong mechanistic support: mammalian loss-of-function phenotype, although it does not precisely model every human allele or the nonsyndromic presentation. Collin et al., Jan 2008 (collin2008mutationsofesrrb pages 11-12)
Diagnosis Confirm SNHL audiologically, exclude acquired causes and structural anomalies as indicated, then use a comprehensive hearing-loss panel or exome/genome sequencing with CNV analysis. Establish biallelic variants in trans, perform segregation testing, and use RNA/minigene or other functional assays for splice variants and unresolved VUSs. Strong for molecular approach; disease-specific evidence derives mainly from targeted sequencing/WES and functional follow-up. Ghasemnejad et al., Feb 2022, DOI (ghasemnejad2022anovelmissense pages 2-4); Choi et al., Sep 2024 (choi2024functionalpathogenicityof pages 2-3)
Treatment and trials No disease-modifying or ESRRB-specific therapy is established. Current care is individualized hearing aids, cochlear-implant evaluation for severe-to-profound loss, speech/language and auditory rehabilitation, educational support, and serial audiometry. Searches identified no ESRRB/DFNB35-specific interventional trial. General standard-of-care evidence; very limited DFNB35-specific outcome evidence. Absence of a retrieved trial is search-limited, not proof that none exists. Choi et al., Sep 2024 (choi2024functionalpathogenicityof pages 1-2, choi2024functionalpathogenicityof pages 11-12)
Major evidence gaps No reliable prevalence, penetrance, carrier-frequency, sex-ratio, natural-history, cochlear-implant outcome, modifier-gene, gene–environment, protective-factor, biomarker, epigenomic, metabolomic, or human single-cell dataset is available specifically for DFNB35. Dental-decay association and variant-specific genotype–phenotype correlations remain insufficiently established. Evidence insufficient: conclusions should not be extrapolated from general SNHL without qualification. Variant and family limitations summarized by Choi et al., Sep 2024 (choi2024functionalpathogenicityof pages 7-8, choi2024functionalpathogenicityof pages 1-2, choi2024functionalpathogenicityof pages 8-9)

Table: Compact evidence-grade synthesis of the disease identity, phenotype, genetics, mechanism, clinical implementation, and principal knowledge gaps in ESRRB-related DFNB35.

Evidence scope and limitations

This synthesis prioritizes the original gene-discovery study and the 2024 functional study. Evidence labels used below are human clinical/genetic, animal, in vitro, or computational/inferred. The retrieved primary-text excerpts did not provide verified PMID metadata; therefore, PMIDs are not guessed. DOI links and publication dates are supplied instead. Database identifiers should be revalidated against the live database before production ingestion, particularly because ontology releases and ClinVar assertions change.

1. Disease information

Definition

DFNB35 is an autosomal-recessive nonsyndromic hearing impairment in which two disease-relevant ESRRB alleles impair cochlear auditory function without a consistently established extra-auditory syndrome. The locus maps to 14q24.3. The original report established causality through linkage/homozygosity mapping, segregation of biallelic variants in multiple pedigrees, absence from matched controls, protein-domain modeling, and inner-ear expression studies. (collin2008mutationsofesrrb pages 1-2, collin2008mutationsofesrrb pages 5-6)

Identifiers and synonyms

  • Preferred name: autosomal recessive nonsyndromic hearing loss 35.
  • Synonyms: DFNB35; deafness, autosomal recessive 35; ESRRB-related nonsyndromic hearing loss; ESRRB-related autosomal-recessive nonsyndromic hearing impairment.
  • MONDO: MONDO:0012060, as supplied in the request; confirm against the current MONDO release.
  • Gene/locus: ESRRB, chromosome 14q24.3; transcript used in the 2024 study: NM_004452.4. (choi2024functionalpathogenicityof pages 1-2)
  • OMIM: commonly represented as the DFNB35/deafness phenotype and ESRRB gene entries, but exact accession numbers were not verified in the retrieved evidence and should not be populated without direct OMIM validation.
  • Orphanet: no disease-specific identifier was verified.
  • ICD-10/ICD-11: no genotype-specific code exists in the evidence reviewed. Code under congenital/bilateral sensorineural hearing loss according to the documented phenotype and local coding rules.
  • MeSH: use Hearing Loss, Sensorineural and Hearing Loss, Genetic; no DFNB35-specific MeSH heading was identified.

The disease description is based on aggregated family-level literature and disease resources, not individual EHR-derived population surveillance. The 2024 report does include one deeply phenotyped clinical proband. (choi2024functionalpathogenicityof pages 2-3, choi2024functionalpathogenicityof pages 1-2)

2. Etiology, risk, protection, and gene–environment interaction

Primary cause

The demonstrated cause is biallelic germline ESRRB variation, usually homozygous in consanguineous families but also compound heterozygous. Pathogenic mechanisms include frameshift/truncation, canonical-splice disruption with NMD, and damaging missense changes in the DNA-binding or ligand-binding domains. (collin2008mutationsofesrrb pages 5-6, choi2024functionalpathogenicityof pages 5-7)

Genetic risk factors

  • Having two pathogenic or functionally damaging alleles in trans is the principal risk factor.
  • Parental consanguinity increases the probability of homozygosity for rare recessive alleles; many discovery pedigrees were consanguineous.
  • Family history may be absent in a recessive condition, especially in a small family.
  • p.Arg382Cys may be an East-Asian-enriched hypomorphic risk allele that manifests when paired with a severe loss-of-function allele, but this remains a hypothesis rather than a settled classification. Its reported gnomAD v4.1 allele frequency was 0.007065 in East Asians and 0.002095 overall. (choi2024functionalpathogenicityof pages 3-4, choi2024functionalpathogenicityof pages 8-9)

No validated modifier gene, susceptibility locus outside ESRRB, or protective ESRRB allele has been established specifically for DFNB35.

Environmental and lifestyle factors

Noise, ototoxic drugs, congenital infection, and other exposures can independently worsen hearing, but they are not demonstrated causes of DFNB35. In the 2022 Iranian family, no relevant environmental or ototoxic exposure was reported; in the Korean proband, congenital CMV testing was negative. (ghasemnejad2022anovelmissense pages 2-4, choi2024functionalpathogenicityof pages 2-3)

No disease-specific association with smoking, alcohol, diet, exercise, occupation, radiation, toxins, or infectious agents is established. Avoidance of excessive noise and ototoxic exposure is prudent hearing conservation, not proven prevention of the inherited lesion.

Protective factors and gene–environment interaction

No genetic, nutritional, pharmacological, or behavioral factor has been shown to prevent ESRRB-related disease. A formal ESRRB genotype-by-noise, infection, age, sex, hormone, or drug interaction has not been demonstrated. Because ERRβ is a transcriptional regulator and the Korean ear showed longitudinal progression, environmental modifiers are biologically possible but presently speculative.

3. Phenotypes

Core auditory phenotype

  1. Sensorineural hearing loss — clinical sign/functional abnormality; suggested HPO: HP:0000407.
  2. Congenital hearing impairment — onset descriptor; suggested HPO: HP:0008527.
  3. Prelingual hearing loss — suggested HPO: HP:0012715.
  4. Bilateral hearing impairment — suggested HPO: HP:0008619.
  5. Severe or profound hearing impairment — use the current HPO severity terms after release validation.
  6. Progressive hearing impairment, where documented — HP:0001730.
  7. Asymmetric hearing loss, documented in the 2024 proband — use an HPO asymmetry/laterality annotation if supported in the target HPO release.

Most reported patients had symmetric, prelingual, severe-to-profound SNHL. The Korean proband had moderate right-ear and severe-to-profound left-ear SNHL, with right-ear progression over 17 years. The Iranian p.Gly167Arg family had congenital bilateral severe-to-profound loss. (ghasemnejad2022anovelmissense pages 2-4, choi2024functionalpathogenicityof pages 3-4, choi2024functionalpathogenicityof pages 7-8)

Transient-evoked otoacoustic emissions were absent in affected members of the original TR-21 pedigree, indicating outer-hair-cell system dysfunction. Because ESRRB was not detected in hair cells, the authors interpreted this as a likely secondary physiological consequence. (collin2008mutationsofesrrb pages 11-12)

Vestibular and extra-auditory features

The original human families had no reported vestibular dysfunction, despite vestibular expression and balance abnormalities in knockout animals. Normal vestibular function should therefore be regarded as typical but not proven universal. (collin2008mutationsofesrrb pages 11-12)

No reproducible endocrine, neurological, renal, ocular, cardiac, immune, or metabolic syndrome is established. One affected male reproduced, arguing against obligatory male infertility. (collin2008mutationsofesrrb pages 9-11)

A proposed association between ESRRB/DFNB35 and dental decay has appeared in the literature, but the retrieved evidence did not establish penetrance, causality, or a consistent syndromic dental phenotype. Dental caries should not presently be treated as a defining DFNB35 manifestation.

Quality-of-life effects

No DFNB35-specific EQ-5D, SF-36, PROMIS, language, educational, or participation dataset exists. By clinical inference from congenital severe-to-profound SNHL, untreated disease can impair spoken-language acquisition, communication, education, social participation, and employment. These are general consequences of early severe hearing loss, not quantified DFNB35-specific outcomes.

4. Genetic and molecular information

Gene and protein

ESRRB encodes ERRβ, a nuclear-receptor-family transcription factor. It contains an N-terminal C4 zinc-finger DNA-binding domain and a C-terminal ligand-binding domain. ERRβ is considered an orphan receptor; no disease-correcting endogenous ligand is established. (ghasemnejad2022anovelmissense pages 2-4, collin2008mutationsofesrrb pages 5-6)

Suggested annotations:

  • HGNC symbol: ESRRB; HGNC identifier should be verified directly before ingestion.
  • GO molecular function: DNA-binding transcription-factor activity; sequence-specific DNA binding; nuclear-receptor activity; transcription coregulator binding.
  • GO cellular component: nucleus, nucleoplasm, transcription regulator complex.
  • GO biological process: regulation of transcription by RNA polymerase II; inner-ear development; sensory perception of sound; epithelial/ion-homeostasis regulation. The last two should be annotated with evidence qualifiers reflecting model/inference.

Variant spectrum

The 2024 synthesis counted 25 reported alleles representing 22 unique variants. Of these, 90.9% were SNVs, 4.5% indels, and 4.5% duplications; 72.7% were missense, 4.5% nonsense, 9.1% frameshift, 9.1% splice, and 4.5% in-frame. Nine coding variants localized to the DNA-binding domain and nine to the ligand-binding domain. No significant phenotype difference by domain was demonstrated. (choi2024functionalpathogenicityof pages 5-7)

Representative variants include:

  • c.1018_1024dupGAGTTTG, p.Val342GlyfsTer44 — homozygous frameshift/truncating allele in TR-21.
  • c.329C>T, p.Ala110Val — DNA-binding-domain missense.
  • c.959T>C, p.Leu320Pro, c.1024G>T, p.Val342Leu, and c.1040C>T, p.Leu347Pro — ligand-binding-domain missense variants.
  • c.1018_1020delGAG, p.Glu340del — in-frame ligand-binding-domain deletion, segregating in a Pakistani pedigree and absent from 500 control chromosomes.
  • c.499G>A, p.Gly167Arg — homozygous missense variant in an Iranian Azeri Turkish family, absent from 200 controls and public frequency data available to that study.
  • c.397+2T>G — canonical splice-region variant causing exon-4 skipping and NMD.
  • c.1144C>T, p.Arg382Cys — recurrent ligand-binding-domain missense VUS with supporting functional evidence. (choi2024functionalpathogenicityof pages 2-3, ghasemnejad2022anovelmissense pages 2-4, collin2008mutationsofesrrb pages 5-6, choi2024functionalpathogenicityof pages 3-4)

Important counterexamples are p.Pro386Ser, seen in 9/100 Pakistani controls including two homozygotes and interpreted as polymorphic, and heterozygous p.Thr389Met, for which no second allele was found and pathogenicity remained uncertain. These illustrate why domain location and in-silico prediction alone are insufficient. (collin2008mutationsofesrrb pages 5-6)

All established disease alleles are germline. Somatic ESRRB alterations are not relevant to the inherited DFNB35 mechanism.

Functional consequences

  • c.397+2T>G: mutant minigene product was 260 bp versus 670 bp for wild type; sequencing confirmed exon-4 skipping. Premature termination and cycloheximide rescue of transcript levels supported NMD. (choi2024functionalpathogenicityof pages 3-4, choi2024functionalpathogenicityof pages 5-7)
  • p.Arg382Cys: lost modeled interactions with Lys335, Glu337, and Glu385; molecular dynamics showed increased structural fluctuation and solvent exposure. Protein and reporter studies demonstrated instability and markedly impaired transcriptional activity. (choi2024functionalpathogenicityof pages 3-4)
  • Patient-cell expression changes included ATP1B1 −55.1% and EGR1 −45.4% versus the father; NRP1, TBX3, and SPARC were reduced by approximately 48–53% in comparisons informative for the splice allele. (choi2024functionalpathogenicityof pages 5-7)

Modifiers, epigenetics, and chromosomal abnormalities

No validated modifier gene or disease-specific methylation, histone, chromatin, or noncoding-regulatory signature is known. DFNB35 is not classically a chromosomal-abnormality disorder. CNV analysis remains appropriate diagnostically, but no recurrent large ESRRB deletion/duplication syndrome was established in the reviewed evidence.

5. Environmental information

No toxin, pollutant, radiation source, lifestyle exposure, or pathogen is necessary or sufficient to cause DFNB35. Congenital CMV and structural abnormalities should be excluded when clinically appropriate because they can phenocopy congenital SNHL; the Korean proband had negative CMV testing and normal CT/MRI. (choi2024functionalpathogenicityof pages 2-3)

Recommended knowledge-base representation is therefore:

  • genetic causal factor: present/established;
  • environmental causal factor: none established;
  • infectious trigger: none established;
  • lifestyle factor: none established;
  • general aggravators such as noise/ototoxic drugs: plausible but not DFNB35-specific.

6. Mechanism and pathophysiology

Ordered causal chain

  1. Biallelic ESRRB variants lead to absent, unstable, structurally altered, or hypomorphic ERRβ protein.
  2. Defective ERRβ results in reduced nuclear transcriptional activity at ERRβ-regulated genes; exon-skipping alleles additionally lead to NMD and reduced transcript abundance.
  3. Altered ERRβ transcription leads to dysregulation of inner-ear-relevant genes, including ATP1B1, EGR1, NRP1, TBX3, and SPARC in the 2024 cellular system. (Demonstrated in patient-derived or transfected cells.)
  4. This transcriptional disturbance is inferred to impair development or maintenance of cochlear nonsensory/supporting, strial, ligament, neural, and fluid-homeostatic compartments.
  5. Stria-vascularis branch: defective marginal-cell/strial development or function is inferred to disturb endolymph production, ionic homeostasis, and the endocochlear electrochemical environment required for mechanotransduction.
  6. Supporting/neural branch: dysfunction in organ-of-Corti supporting cells, nerve fibers, and spiral-ganglion cells may lead to impaired sensory support and auditory signal transmission.
  7. These changes result in cochlear dysfunction, secondary outer-hair-cell physiological failure, elevated auditory thresholds, and congenital/prelingual SNHL; in some genotypes the residual activity may permit moderate or progressive disease rather than congenital profound deafness. (choi2024functionalpathogenicityof pages 7-8, collin2008mutationsofesrrb pages 11-12, choi2024functionalpathogenicityof pages 5-7, collin2008mutationsofesrrb pages 9-11)

Upstream versus downstream mechanisms

The upstream lesion is ESRRB loss or hypomorphic function. Intermediate events are altered transcription and impaired cochlear development/homeostasis. Downstream events are disturbed sensory transduction/neural signaling, absent otoacoustic emissions, and hearing loss. Direct endocochlear-potential measurements have not been reported in affected humans, so the human ion-homeostasis link remains mechanistically well motivated but partly inferred.

Pathways and cellular processes

This is principally a transcriptional-regulatory/nuclear-receptor disorder, not a proven Wnt, MAPK, PI3K–AKT, mTOR, inflammatory, autophagic, or primary metabolic-storage disease. ATP1B1 dysregulation provides a plausible connection to Na+/K+-ATPase-dependent ion gradients. No primary immune mechanism, metabolite accumulation, fibrosis, ischemia, or apoptotic cascade has been established.

Suggested GO biological-process terms include regulation of transcription by RNA polymerase II; inner-ear morphogenesis; cochlear development; auditory receptor-cell support; potassium-ion homeostasis; sensory perception of sound; and auditory-system development. Ion-homeostasis annotations should carry an inferred/model-supported qualifier.

Suggested Cell Ontology targets, subject to exact ID validation, include marginal cell of stria vascularis, epithelial supporting cell, spiral-ganglion neuron, Schwann/glial cell, fibrocyte, and sensory epithelial supporting cell. Hair cells should not be annotated as the principal ESRRB-expressing target on current evidence. (collin2008mutationsofesrrb pages 11-12, collin2008mutationsofesrrb pages 9-11)

Molecular profiling and advanced technologies

The strongest disease-specific molecular profiling is targeted transcript quantification in the 2024 family/cell experiments. No validated DFNB35-specific bulk transcriptomic, proteomic, metabolomic, lipidomic, spatial-transcriptomic, or integrated multi-omic signature is available. No ESRRB patient-derived inner-ear organoid, iPSC auditory model, or CRISPR functional screen was identified.

7. Anatomical structures affected

Organ and tissue levels

The primary organ is the inner ear, specifically the cochlea. Suggested anatomy annotations are cochlea, cochlear duct, organ of Corti, stria vascularis, spiral ligament, spiral limbus, basilar membrane, and spiral ganglion. Exact UBERON identifiers should be programmatically validated against the target release.

Developmental mouse RNA and postnatal rat immunohistochemistry localized Esrrb/ERRβ to cochlear turns, stria vascularis, vestibular structures, vestibular ganglion, spiral-limbus and basilar-membrane mesothelial cells, organ-of-Corti supporting cells, parts of the spiral ligament, nerve fibers, and spiral-ganglion cells. It was absent from inner and outer hair cells. (collin2008mutationsofesrrb pages 11-12, collin2008mutationsofesrrb pages 9-11)

Subcellular level

ERRβ acts principally in the nucleus/nucleoplasm, where its DNA-binding domain recognizes regulatory sequences and its ligand-binding domain supports receptor conformation and transcriptional regulation. p.Arg382Cys primarily affects protein stability and transcriptional competence rather than a demonstrated mitochondrial, lysosomal, ER, or ciliary process.

Localization and laterality

Human disease is usually bilateral. Symmetry is common, but the 2024 case establishes that marked asymmetry can occur. Normal temporal-bone CT and internal-auditory-canal MRI in that patient indicate that gross malformation is not required. (choi2024functionalpathogenicityof pages 2-3)

8. Temporal development

Typical onset is congenital or recognized before language acquisition. The course is chronic and lifelong. Most early reports described severe-to-profound impairment without adequate longitudinal data to distinguish stable from progressive disease. The Korean case demonstrated progression in the better ear over 17 years, expanding the natural history. (choi2024functionalpathogenicityof pages 3-4, choi2024functionalpathogenicityof pages 7-8)

No formal stages, remission pattern, spontaneous recovery, or disease-specific progression rate has been defined. The critical clinical period is early infancy and childhood, when auditory access is required for language development. Newborn hearing screening, prompt confirmation, amplification or implant evaluation, and early communication intervention are therefore essential, although not ESRRB-specific.

9. Inheritance and population

Inheritance

Inheritance is autosomal recessive. For two confirmed heterozygous carrier parents, each pregnancy has an expected 25% probability of an affected child, 50% probability of an unaffected carrier, and 25% probability of inheriting neither familial allele, assuming conventional Mendelian segregation.

Available pedigrees are compatible with high penetrance for severe biallelic alleles, but a numerical penetrance estimate is unavailable. Expressivity is variable in severity, symmetry, and progression. There is no evidence of anticipation. Germline mosaicism has not been specifically reported but cannot be reduced to zero in counseling.

Epidemiology and demographics

No incidence or prevalence per 100,000 is available. Fewer than 20 families were known before the 2024 report; thus DFNB35 accounts for only a very small fraction of genetic hearing loss. (choi2024functionalpathogenicityof pages 1-2)

Early reports were enriched for Pakistani and Turkish consanguineous families, with additional Iranian, Tunisian, Czech, Egyptian, and Korean observations in the wider literature. This distribution reflects ascertainment and founder structure as well as possible allele enrichment; it does not imply restriction to those ancestries. No reliable male:female ratio, age distribution, carrier frequency, or global geographic prevalence is known.

The relatively high East-Asian frequency of p.Arg382Cys demands caution: functional impairment does not by itself prove that homozygosity causes fully penetrant DFNB35. Its proposed role as a hypomorphic allele in trans with loss of function needs replication. (choi2024functionalpathogenicityof pages 3-4, choi2024functionalpathogenicityof pages 8-9)

10. Diagnostics

Clinical evaluation

  1. Newborn or childhood hearing screening.
  2. Diagnostic age-appropriate audiology: auditory brainstem response, otoacoustic emissions, tympanometry, behavioral pure-tone audiometry, and speech testing where developmentally appropriate.
  3. Confirm sensorineural rather than conductive loss and document laterality, configuration, severity, and progression.
  4. Assess vestibular symptoms and perform targeted examination.
  5. Review prenatal/perinatal history, congenital infection, noise, trauma, and ototoxic exposure.
  6. CT or MRI is not required to diagnose DFNB35 but may exclude structural or neural causes, particularly with asymmetry or implant planning. The Korean patient had normal CT/MRI. (choi2024functionalpathogenicityof pages 2-3)

There is no blood chemistry, urine test, enzyme assay, biopsy, histopathology, circulating protein, metabolite, or imaging biomarker specific to DFNB35.

Genetic testing strategy

A comprehensive hearing-loss multigene panel including ESRRB is usually more efficient than initial ESRRB-only testing because congenital SNHL is highly heterogeneous. WES is appropriate when panel testing is negative or broad phenotyping is required; WGS can detect cryptic splice, regulatory, and structural variants missed by WES. In the reported families, successful methods included linkage/homozygosity mapping, targeted capture, WES, PCR/Sanger confirmation, segregation analysis, and functional RNA/minigene assays. (ghasemnejad2022anovelmissense pages 2-4, collin2008mutationsofesrrb pages 1-2, choi2024functionalpathogenicityof pages 2-3)

Required interpretation steps are:

  • identify two relevant ESRRB alleles;
  • demonstrate that they are in trans;
  • apply hearing-loss-specific ACMG/AMP criteria;
  • inspect population frequencies by ancestry;
  • evaluate splice effects experimentally when feasible;
  • avoid upgrading missense variants solely from in-silico prediction;
  • test relatives for segregation.

CMA or genome-based CNV analysis may detect large deletions but is not a first-line standalone test for this sequence-variant-predominant disorder. Conventional karyotyping, FISH, mitochondrial testing, and repeat-expansion testing do not directly interrogate the usual DFNB35 mechanism; use them only when the broader differential indicates.

Differential diagnosis

The differential includes GJB2/GJB6-related deafness, SLC26A4-related disease/Pendred syndrome, OTOF-related auditory neuropathy, STRC deletions, congenital CMV, inner-ear malformations, mitochondrial hearing loss, syndromic deafness, and environmental/ototoxic injury. Distinguishing evidence includes molecular diagnosis, vestibular/thyroid/ocular/renal findings, imaging, CMV testing, auditory-neuropathy physiology, and exposure history.

11. Outcome and prognosis

DFNB35 is not known to shorten life expectancy or cause disease-specific mortality. Survival statistics are therefore not applicable. Morbidity is auditory and communication-related. Untreated congenital severe-to-profound loss can produce lifelong language, educational, and social disability; timely rehabilitation can substantially reduce functional consequences, although DFNB35-specific outcome rates are unavailable.

Spontaneous biological recovery is not reported. Hearing aids or cochlear implants improve access to sound but do not correct ESRRB dysfunction. No disease-specific prognostic biomarker exists. Residual hearing, age at intervention, duration of auditory deprivation, communication support, and neural integrity are clinically relevant general predictors, but they have not been validated specifically in DFNB35.

12. Treatment

Current clinical management

There is no approved ESRRB-directed drug or disease-modifying therapy. Management is phenotype based:

  • conventional hearing aids for aidable residual hearing;
  • cochlear-implant assessment for severe-to-profound loss or inadequate aided speech access;
  • auditory-verbal, speech-language, sign-language, or bilingual communication support according to family preference and clinical context;
  • educational accommodations and assistive listening systems;
  • serial audiometry, especially because progression and asymmetry can occur;
  • psychosocial and family support.

Suggested NCIt concepts include Hearing Aid, Cochlear Implantation, Auditory Rehabilitation, Speech Therapy, Genetic Counseling, and Audiologic Examination; exact NCIt codes should be validated before ingestion.

No DFNB35-specific hearing-aid response percentage, cochlear-implant speech score, adverse-event rate, or comparative treatment trial was identified. Preservation of spiral-ganglion function may influence implant performance, but ESRRB expression in ganglion cells makes genotype-specific prediction uncertain. Counseling should not promise a particular implant outcome.

Advanced and experimental therapy

As of the search performed for this report, no ESRRB/DFNB35-specific interventional clinical trial, AAV replacement study, gene-editing program, RNA therapy, cell therapy, or pharmacological rescue was identified. This is a search-limited negative result, not proof that no newly registered study exists.

Inner-ear gene therapy advanced rapidly in 2023–2024, particularly for OTOF/DFNB9, but this cannot be extrapolated directly to ESRRB. ERRβ is expressed in several nonsensory and neural cochlear cell populations, so successful therapy would require appropriate vector tropism, developmental timing, dosage control, and safety for a transcription factor. The authors of the 2024 study specifically identified a knock-in model as a needed next step. (choi2024functionalpathogenicityof pages 8-9, choi2024functionalpathogenicityof pages 11-12)

No ESRRB-specific pharmacogenomic recommendation exists.

13. Prevention

Primary prevention

The genotype cannot be prevented by lifestyle modification after conception. Reproductive options following identification of familial variants include genetic counseling, partner testing, cascade carrier testing, preimplantation genetic testing for monogenic disease, prenatal diagnosis, donor gametes, and informed natural conception. These are options, not directives.

Secondary prevention

Universal newborn hearing screening, rapid diagnostic audiology, molecular testing, and cascade testing permit early intervention and identification of at-risk relatives. For siblings with the familial genotype, audiological surveillance should begin immediately even if initial screening is reassuring.

Tertiary prevention

Early amplification/implant evaluation, communication access, speech-language services, educational support, and avoidance of preventable cochlear injury reduce secondary disability. Routine vaccination prevents infectious causes of hearing loss but does not prevent ESRRB-related DFNB35. No medication or prophylactic procedure prevents the molecular disease.

14. Other species and natural disease

Comparative biology

Orthologous Esrrb is present in laboratory mouse (Mus musculus, NCBI Taxonomy 10090) and rat (Rattus norvegicus, Taxonomy 10116). Developmental expression is evolutionarily consistent with an inner-ear role. No naturally occurring companion-animal breed disorder confidently equivalent to human DFNB35 was identified, and no VBO breed annotation is warranted.

DFNB35 is neither infectious nor zoonotic; transmission is genetic. Cross-species susceptibility refers to conserved loss-of-function biology, not contagious transmission.

15. Model organisms

Mouse models

Complete Esrrb-null mice die embryonically, limiting direct postnatal auditory analysis. Rescued or conditional-null animals show defective hearing and balance, walking abnormalities, circling/head tossing, and impaired stria-vascularis development. These findings support the proposed developmental and fluid-homeostatic mechanism. (collin2008mutationsofesrrb pages 11-12)

Strengths: mammalian cochlear architecture; recapitulation of hearing/balance dysfunction; capacity to study strial development and auditory physiology.

Limitations: embryonic lethality of complete loss; balance disease is more prominent than in reported humans; null alleles may not model human hypomorphic missense variants; no p.Arg382Cys knock-in model was available in the 2024 report. (choi2024functionalpathogenicityof pages 8-9)

Rat and cellular systems

Postnatal rat inner-ear immunohistochemistry has been useful for mapping ERRβ to supporting, strial, ligament, neural, and ganglion compartments. (collin2008mutationsofesrrb pages 9-11)

Cell models used in 2024 included patient-derived lymphoblastoid cells, minigene splice assays, HEK293T reporter assays, protein-stability assays, and computational molecular dynamics. These directly test splicing and transcription but cannot reproduce cochlear biomechanics, endocochlear potential, or developmental cell interactions. (choi2024functionalpathogenicityof pages 5-7, choi2024functionalpathogenicityof pages 3-4, choi2024functionalpathogenicityof pages 11-12)

Useful resources for future model curation include MGI, IMPC, IMSR/MMRRC, and Alliance of Genome Resources. A priority model is an ESRRB p.Arg382Cys knock-in, alone and in trans with a null allele, with longitudinal ABR, DPOAE, endocochlear-potential, vestibular, histological, and single-cell profiling.

Recent developments and authoritative interpretation

The most important recent disease-specific publication is Choi et al., Scientific Reports, published September 2024, DOI: https://doi.org/10.1038/s41598-024-70795-8. Its abstract states: “The splicing variant … caused exon 4 skipping, leading to premature stop codon formation and nonsense-mediated decay,” and reports that p.Arg382Cys “reduced transcriptional activity and altered expression of downstream target genes essential for inner ear function.” This is the strongest functional evidence yet for reinterpretation of an ESRRB VUS, but the authors appropriately stopped short of a definitive pathogenic classification. (choi2024functionalpathogenicityof pages 2-3, choi2024functionalpathogenicityof pages 8-9)

The landmark gene-discovery paper is Collin et al., American Journal of Human Genetics, published January 2008, DOI: https://doi.org/10.1016/j.ajhg.2007.09.008. It established ESRRB as the DFNB35 gene through multiple linked consanguineous pedigrees and connected human disease to cochlear and strial expression. (collin2008mutationsofesrrb pages 1-2, collin2008mutationsofesrrb pages 5-6, collin2008mutationsofesrrb pages 11-12)

Ghasemnejad et al., BMC Medical Genomics, published February 2022, DOI: https://doi.org/10.1186/s12920-022-01165-4, described homozygous p.Gly167Arg in a consanguineous Iranian Azeri Turkish family. Its abstract reports that the variant co-segregated with ARNSHL and emphasizes targeted genomic capture for genetically heterogeneous hearing loss. The pathogenic interpretation relied heavily on segregation and computational evidence and is consequently less functionally resolved than the 2024 alleles. (ghasemnejad2022anovelmissense pages 2-4)

Priority knowledge gaps

  1. A curated, transcript-consistent ClinVar/LOVD inventory of every ESRRB allele with current ACMG classifications and ancestry-specific frequencies.
  2. Prospective natural-history data with standardized audiograms, vestibular testing, speech outcomes, and treatment history.
  3. Replication and segregation studies for p.Arg382Cys, especially homozygotes and loss-of-function compound heterozygotes.
  4. Human inner-ear or iPSC-derived cell models and allele-specific knock-in mice.
  5. Direct measurements of endocochlear potential, ion transport, and strial physiology.
  6. DFNB35-specific hearing-aid and cochlear-implant outcomes.
  7. Rigorous assessment of proposed dental involvement, modifier genes, environmental interactions, and sex effects.
  8. Cell-type-resolved transcriptomics/spatial profiling and evaluation of therapeutic vector tropism.

Knowledge-base conclusion

The highest-confidence entry is: biallelic germline ESRRB loss-of-function or damaging hypomorphic variants cause a very rare autosomal-recessive, usually congenital/prelingual bilateral SNHL through impaired ERRβ transcriptional regulation in cochlear nonsensory, strial, supporting, and neural compartments. Disturbed stria-vascularis/endolymph ion homeostasis is strongly supported by expression and animal data but remains partly inferred in humans. Phenotypic breadth now includes moderate, asymmetric, and progressive hearing loss. No syndrome-defining extra-auditory feature, prevalence estimate, biomarker, disease-modifying therapy, or ESRRB-specific clinical trial is established. (collin2008mutationsofesrrb pages 11-12, choi2024functionalpathogenicityof pages 7-8, choi2024functionalpathogenicityof pages 5-7)

References

  1. (choi2024functionalpathogenicityof pages 1-2): Won Hoon Choi, Yeijean Cho, Ju Hyuen Cha, Dae Hee Lee, Jong Gwan Jeong, Sung Ho Jung, Jae-Jin Song, Jun Ho Lee, and Sang-Yeon Lee. Functional pathogenicity of esrrb variant of uncertain significance contributes to hearing loss (dfnb35). Scientific Reports, Sep 2024. URL: https://doi.org/10.1038/s41598-024-70795-8, doi:10.1038/s41598-024-70795-8. This article has 3 citations and is from a peer-reviewed journal.

  2. (choi2024functionalpathogenicityof pages 7-8): Won Hoon Choi, Yeijean Cho, Ju Hyuen Cha, Dae Hee Lee, Jong Gwan Jeong, Sung Ho Jung, Jae-Jin Song, Jun Ho Lee, and Sang-Yeon Lee. Functional pathogenicity of esrrb variant of uncertain significance contributes to hearing loss (dfnb35). Scientific Reports, Sep 2024. URL: https://doi.org/10.1038/s41598-024-70795-8, doi:10.1038/s41598-024-70795-8. This article has 3 citations and is from a peer-reviewed journal.

  3. (choi2024functionalpathogenicityof pages 3-4): Won Hoon Choi, Yeijean Cho, Ju Hyuen Cha, Dae Hee Lee, Jong Gwan Jeong, Sung Ho Jung, Jae-Jin Song, Jun Ho Lee, and Sang-Yeon Lee. Functional pathogenicity of esrrb variant of uncertain significance contributes to hearing loss (dfnb35). Scientific Reports, Sep 2024. URL: https://doi.org/10.1038/s41598-024-70795-8, doi:10.1038/s41598-024-70795-8. This article has 3 citations and is from a peer-reviewed journal.

  4. (choi2024functionalpathogenicityof pages 5-7): Won Hoon Choi, Yeijean Cho, Ju Hyuen Cha, Dae Hee Lee, Jong Gwan Jeong, Sung Ho Jung, Jae-Jin Song, Jun Ho Lee, and Sang-Yeon Lee. Functional pathogenicity of esrrb variant of uncertain significance contributes to hearing loss (dfnb35). Scientific Reports, Sep 2024. URL: https://doi.org/10.1038/s41598-024-70795-8, doi:10.1038/s41598-024-70795-8. This article has 3 citations and is from a peer-reviewed journal.

  5. (choi2024functionalpathogenicityof pages 8-9): Won Hoon Choi, Yeijean Cho, Ju Hyuen Cha, Dae Hee Lee, Jong Gwan Jeong, Sung Ho Jung, Jae-Jin Song, Jun Ho Lee, and Sang-Yeon Lee. Functional pathogenicity of esrrb variant of uncertain significance contributes to hearing loss (dfnb35). Scientific Reports, Sep 2024. URL: https://doi.org/10.1038/s41598-024-70795-8, doi:10.1038/s41598-024-70795-8. This article has 3 citations and is from a peer-reviewed journal.

  6. (collin2008mutationsofesrrb pages 1-2): Rob W.J. Collin, Ersan Kalay, Muhammad Tariq, Theo Peters, Bert van der Zwaag, Hanka Venselaar, Jaap Oostrik, Kwanghyuk Lee, Zubair M. Ahmed, Refik Çaylan, Yun Li, Henk A. Spierenburg, Erol Eyupoglu, Angelien Heister, Saima Riazuddin, Elif Bahat, Muhammad Ansar, Selcuk Arslan, Bernd Wollnik, Han G. Brunner, Cor W.R.J. Cremers, Ahmet Karaguzel, Wasim Ahmad, Frans P.M. Cremers, Gert Vriend, Thomas B. Friedman, Sheikh Riazuddin, Suzanne M. Leal, and Hannie Kremer. Mutations of esrrb encoding estrogen-related receptor beta cause autosomal-recessive nonsyndromic hearing impairment dfnb35. American journal of human genetics, 82 1:125-38, Jan 2008. URL: https://doi.org/10.1016/j.ajhg.2007.09.008, doi:10.1016/j.ajhg.2007.09.008. This article has 146 citations and is from a highest quality peer-reviewed journal.

  7. (collin2008mutationsofesrrb pages 5-6): Rob W.J. Collin, Ersan Kalay, Muhammad Tariq, Theo Peters, Bert van der Zwaag, Hanka Venselaar, Jaap Oostrik, Kwanghyuk Lee, Zubair M. Ahmed, Refik Çaylan, Yun Li, Henk A. Spierenburg, Erol Eyupoglu, Angelien Heister, Saima Riazuddin, Elif Bahat, Muhammad Ansar, Selcuk Arslan, Bernd Wollnik, Han G. Brunner, Cor W.R.J. Cremers, Ahmet Karaguzel, Wasim Ahmad, Frans P.M. Cremers, Gert Vriend, Thomas B. Friedman, Sheikh Riazuddin, Suzanne M. Leal, and Hannie Kremer. Mutations of esrrb encoding estrogen-related receptor beta cause autosomal-recessive nonsyndromic hearing impairment dfnb35. American journal of human genetics, 82 1:125-38, Jan 2008. URL: https://doi.org/10.1016/j.ajhg.2007.09.008, doi:10.1016/j.ajhg.2007.09.008. This article has 146 citations and is from a highest quality peer-reviewed journal.

  8. (collin2008mutationsofesrrb pages 11-12): Rob W.J. Collin, Ersan Kalay, Muhammad Tariq, Theo Peters, Bert van der Zwaag, Hanka Venselaar, Jaap Oostrik, Kwanghyuk Lee, Zubair M. Ahmed, Refik Çaylan, Yun Li, Henk A. Spierenburg, Erol Eyupoglu, Angelien Heister, Saima Riazuddin, Elif Bahat, Muhammad Ansar, Selcuk Arslan, Bernd Wollnik, Han G. Brunner, Cor W.R.J. Cremers, Ahmet Karaguzel, Wasim Ahmad, Frans P.M. Cremers, Gert Vriend, Thomas B. Friedman, Sheikh Riazuddin, Suzanne M. Leal, and Hannie Kremer. Mutations of esrrb encoding estrogen-related receptor beta cause autosomal-recessive nonsyndromic hearing impairment dfnb35. American journal of human genetics, 82 1:125-38, Jan 2008. URL: https://doi.org/10.1016/j.ajhg.2007.09.008, doi:10.1016/j.ajhg.2007.09.008. This article has 146 citations and is from a highest quality peer-reviewed journal.

  9. (choi2024functionalpathogenicityof pages 2-3): Won Hoon Choi, Yeijean Cho, Ju Hyuen Cha, Dae Hee Lee, Jong Gwan Jeong, Sung Ho Jung, Jae-Jin Song, Jun Ho Lee, and Sang-Yeon Lee. Functional pathogenicity of esrrb variant of uncertain significance contributes to hearing loss (dfnb35). Scientific Reports, Sep 2024. URL: https://doi.org/10.1038/s41598-024-70795-8, doi:10.1038/s41598-024-70795-8. This article has 3 citations and is from a peer-reviewed journal.

  10. (collin2008mutationsofesrrb pages 9-11): Rob W.J. Collin, Ersan Kalay, Muhammad Tariq, Theo Peters, Bert van der Zwaag, Hanka Venselaar, Jaap Oostrik, Kwanghyuk Lee, Zubair M. Ahmed, Refik Çaylan, Yun Li, Henk A. Spierenburg, Erol Eyupoglu, Angelien Heister, Saima Riazuddin, Elif Bahat, Muhammad Ansar, Selcuk Arslan, Bernd Wollnik, Han G. Brunner, Cor W.R.J. Cremers, Ahmet Karaguzel, Wasim Ahmad, Frans P.M. Cremers, Gert Vriend, Thomas B. Friedman, Sheikh Riazuddin, Suzanne M. Leal, and Hannie Kremer. Mutations of esrrb encoding estrogen-related receptor beta cause autosomal-recessive nonsyndromic hearing impairment dfnb35. American journal of human genetics, 82 1:125-38, Jan 2008. URL: https://doi.org/10.1016/j.ajhg.2007.09.008, doi:10.1016/j.ajhg.2007.09.008. This article has 146 citations and is from a highest quality peer-reviewed journal.

  11. (ghasemnejad2022anovelmissense pages 2-4): Tohid Ghasemnejad, Mahmoud Shekari Khaniani, Jafar Nouri Nojadeh, and Sima Mansoori Derakhshan. A novel missense variant in esrrb gene causing autosomal recessive non-syndromic hearing loss: in silico analysis of a case. BMC Medical Genomics, Feb 2022. URL: https://doi.org/10.1186/s12920-022-01165-4, doi:10.1186/s12920-022-01165-4. This article has 4 citations and is from a peer-reviewed journal.

  12. (choi2024functionalpathogenicityof pages 11-12): Won Hoon Choi, Yeijean Cho, Ju Hyuen Cha, Dae Hee Lee, Jong Gwan Jeong, Sung Ho Jung, Jae-Jin Song, Jun Ho Lee, and Sang-Yeon Lee. Functional pathogenicity of esrrb variant of uncertain significance contributes to hearing loss (dfnb35). Scientific Reports, Sep 2024. URL: https://doi.org/10.1038/s41598-024-70795-8, doi:10.1038/s41598-024-70795-8. This article has 3 citations and is from a peer-reviewed journal.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 3
Resolved 3
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 3
On topic 1
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 6
Resolved 6
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0
Terms whose name was checked 1
Terms named correctly 0
Terms named as a different term 1

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:

  • MONDO:0012060 (2 mentions) - the report calls it "if available"; MONDO calls it autosomal recessive nonsyndromic hearing loss 35