Autosomal Recessive Nonsyndromic Hearing Loss 98

Mendelian MONDO:0013929 Pathograph 6 Show in embeddings browser Autosomal Recessive Nonsyndromic Hearing Loss Hereditary Hearing Loss

DFNB98 is the proposition that biallelic TSPEAR variants cause isolated congenital sensorineural deafness. It was named in 2012 from one consanguineous Iranian family, and it is the weakest-supported of the DFNB loci curated here: the ClinGen Hearing Loss Gene Curation Expert Panel classifies TSPEAR-nonsyndromic hearing loss as Disputed, and reaffirmed that classification on review in 2024. The dispute is not a matter of thin evidence. It is that the evidence points somewhere else. TSPEAR unambiguously causes autosomal recessive ectodermal dysplasia 14, a predominantly dental disease; that relationship is replicated across cohorts and supported by functional work in enamel-knot biology. A 2021 cohort of thirteen individuals with biallelic TSPEAR variants found hearing loss in three, and every one of the three also carried variants in TMPRSS3, GJB2 or GJB6 - genes that are themselves ordinary causes of the phenotype. A 2026 cohort of eleven patients from seven families found tooth abnormalities in all of them and hearing loss in none, and states flatly that hearing loss is not a feature of the disease. A CRISPR mouse carrying a TSPEAR frameshift has normal stereocilia and normal auditory function. What survives is a small set of isolated-deafness cases, including a 2026 Iranian child with profound bilateral loss and explicitly normal teeth, skin, hair and nails, and the original family's finding that TSPEAR protein sits at the surface of the hair bundle. That is enough to keep the entity in view and not enough to call it established. This entry is curated as a disease whose causal claim is contested, not as a disease with a settled mechanism. The pathophysiology chain below is grouped under a named mechanistic hypothesis rather than asserted as canonical, the gene carries relationship_type DISPUTED, the refuting evidence is cited in the same sections as the supporting evidence, and the mouse is recorded as FAILS_TO_RECAPITULATE.

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1
Inheritance
4
Pathophys.
3
Phenotypes
1
Hypotheses
2
Gaps
6
Pathograph
1
Genes
2
Differentials
1
Models
9
References
1
Deep Research
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Inheritance

1
Autosomal recessive HP:0000007
Where the phenotype has been reported it is in homozygous probands from consanguineous families, or in one compound heterozygote. The mode of inheritance is not the contested part of DFNB98; whether the genotype causes the phenotype is. One published proband did not segregate: a homozygous nonsense variant was heterozygous in an affected sibling and in the unaffected mother. That single observation does more damage to the causal claim than the family count does good.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:22678063 SUPPORT Human Clinical
"We report a consanguineous Iranian family affected by congenital profound sensorineural deafness segregating in an autosomal recessive mode."
Recessive segregation in the founding family.
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Mechanistic Hypotheses

1
Loss of secreted TSPEAR from the hair bundle surface causes isolated sensorineural deafness
tspear_hair_bundle_deafness ALTERNATIVE
Evidence balance 1 support 2 refute
The proposed mechanism of DFNB98, and the reason it is a hypothesis group rather than the entry's canonical model. TSPEAR is a secreted protein built from a thrombospondin-type laminin G domain followed by seven epilepsy-associated repeats that fold into a beta-propeller. In the founding study the transcript was found in mouse cochlea and the protein was localised by immunofluorescence to the surface of the hair bundles of sensory cells, while the human truncating allele blocked secretion of the protein from transfected cells. From those two observations the argument runs: no secretion, no TSPEAR at the bundle surface, no functioning bundle, deafness. Every causal edge in the pathophysiology section below opts into this group, because every one of them is part of that argument rather than an independently established step. Nothing has connected the missing protein to a measured auditory deficit in any organism. The one animal that has been made and tested - a mouse carrying a TSPEAR frameshift - hears normally and has normal stereocilia.
Pathograph links
Biallelic TSPEAR Loss-of-Function Variant -> Failure of TSPEAR Secretion DIRECT The truncating allele prevents the protein leaving the cell. This is the one step of the chain with a direct measurement behind it.
Failure of TSPEAR Secretion -> Loss of TSPEAR from the Hair Bundle Surface INDIRECT KNOWN INTERMEDIATES A protein that is not secreted cannot reach the extracellular surface where it was localised. The inference is reasonable and it is an inference; nobody has shown absence of TSPEAR from the bundle in a patient or in a model carrying the human allele.
Loss of TSPEAR from the Hair Bundle Surface -> Impaired Cochlear Sound Transduction INDIRECT UNKNOWN INTERMEDIATES The step with no measurement behind it in any species. It is the gap the mouse was built to close, and the mouse came back negative.
Impaired Cochlear Sound Transduction -> Congenital Profound Sensorineural Hearing Loss DIRECT The edge from mechanism to clinical phenotype, and it is the disputed claim itself rather than a step within the argument - which is why it opts into the hypothesis group like every other edge here rather than being asserted outright.
Show evidence (3 references)
PMID:22678063 SUPPORT Model Organism
"Only the larger Tspear transcript was found in the cochlea, and the protein was detected by immunofluorescence at the surface of the hair bundles of sensory cells."
The expression and localisation observation the hypothesis is built on. Mouse tissue, hence MODEL_ORGANISM.
PMID:40716589 REFUTE Model Organism
"Intriguingly, stereociliary morphology and auditory function remain unaffected in TSPEAR S475TfsX79 mutant mice."
The direct test of the hypothesis, in the organism where the localisation was established, with a negative result at both the structural and functional level.
PMID:41195743 REFUTE Human Clinical
"However, the role of TSPEAR in auditory processes is unclear."
The 2026 cohort's own framing of the auditory question before it went looking, which is the state of the hypothesis this group is named for.
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Discussions and Knowledge Gaps

2
Do biallelic TSPEAR variants cause isolated hearing loss at all, or is DFNB98 a misattribution of deafness that other genes explain?
KNOWLEDGE GAP OPEN gap_tspear_hearing_gene_validity
Attached to
genetic#TSPEAR mechanistic_hypotheses#tspear_hair_bundle_deafness
This is the entity's central open question, not a detail within it. The founding family remains unexplained by anything else. Two later isolated-deafness reports exist, one with teeth, skin, hair and nails specifically examined and normal. Against that: a thirteen-person biallelic cohort in which every deaf individual had a competing variant in TMPRSS3, GJB2 or GJB6; a non-segregating nonsense allele; a TSPEAR variant classified as a VUS rather than causal in a mid-frequency hearing-loss series; and a ClinGen re-review in 2024 that saw the newer cases and left the classification at Disputed. Two readings fit all of that. Either TSPEAR causes hearing loss with low penetrance or only for particular alleles, and the cohort study's competing variants are coincidental in a genetically noisy phenotype; or TSPEAR does not cause hearing loss and the reported cases are unexplained deafness in people who happen to carry a common ectodermal-dysplasia allele - which at a carrier rate near 1 in 140 will happen by chance reasonably often. The second study has now partly been done - the 2026 cohort was ascertained on the dental phenotype and reports hearing status - and it came back negative. What is still missing is a comprehensive hearing-loss panel sequenced in every reported isolated-deafness TSPEAR case, which is the half that would say whether the positive reports have competing explanations too.
Proposed experiments
Audiometry in an unselected biallelic-TSPEAR series ascertained on dental phenotype
tspear_unselected_hearing_ascertainment
Recruit individuals with biallelic TSPEAR variants ascertained through ectodermal dysplasia 14 rather than through deafness, and measure hearing formally in all of them with pure-tone audiometry, otoacoustic emissions and auditory brainstem responses. Sequence a comprehensive hearing-loss panel in anyone found to be affected.
Would support
genetic#TSPEAR
Supporting outcome
  • Hearing loss occurs in the dental-ascertained series above population rate and without competing variants in established hearing-loss genes, which would establish a real if incompletely penetrant TSPEAR auditory phenotype and would move the gene from DISPUTED.
Refuting outcome
  • Hearing is normal across the dental-ascertained series, or the affected minority all carry competing variants, which would confirm DFNB98 as a misattribution and make the right curation outcome retirement of the entity rather than this contested entry.
Why does a mouse carrying a TSPEAR frameshift hear normally and have normal stereocilia, when TSPEAR protein was localised to the hair bundle surface in that same species?
HUMAN MODEL MISMATCH OPEN mismatch_tspear_mouse_hears_normally
Attached to
animal_models#Tspear S475TfsX79 CRISPR mouse pathophysiology#Loss of TSPEAR from the Hair Bundle Surface
This is a mismatch rather than a gap: the model exists, the measurements were made, and they disagree with the human claim. Both observations come from mouse cochlea, so this is not even a species argument in the usual sense - the localisation that motivates the mechanism and the negative functional test are in the same animal. Three readings are live and the published work does not choose between them. The mouse allele is a different frameshift from the human founding allele and may retain function the human allele does not. Mouse may compensate through one of the other five mammalian EAR-domain proteins in a way human cochlea does not. Or TSPEAR is genuinely not required for hearing and the localisation, while real, is not load-bearing - which is also what the human cohort data suggest. The stake is that the localisation result is the whole mechanistic content of DFNB98. If it does not survive, the entity has a genotype and a phenotype and nothing joining them.
Proposed experiments
Knock-in of the human p.V576LfsX37 allele with EAR-paralogue compensation testing
tspear_human_allele_knockin_mouse
Generate a mouse carrying the exact founding human TSPEAR allele rather than a different frameshift, phenotype hearing and stereocilia, and in parallel measure expression of the other mammalian EAR-domain proteins in mouse and human cochlea to test whether paralogue compensation could mask a phenotype in mouse.
Would support
pathophysiology#Loss of TSPEAR from the Hair Bundle Surface
Supporting outcome
  • The human allele produces hearing loss in mouse where S475TfsX79 does not, which would make the negative result allele-specific and restore the hair-bundle mechanism.
Refuting outcome
  • The human allele also leaves hearing intact, and paralogue expression is comparable across species, which would leave no mechanistic account of DFNB98 standing and would substantially strengthen the case for retiring the entity.
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Pathophysiology

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Biallelic TSPEAR Loss-of-Function Variant
The founding allele is a homozygous frameshift, c.1726G>T+c.1728delC, predicting p.V576LfsX37, found in three affected siblings of a consanguineous Iranian family with congenital profound deafness. TSPEAR is alternatively spliced into 522- and 669-residue isoforms and the frameshift affects both. Later isolated-deafness reports carry different alleles: a homozygous missense c.668C>T p.Ser223Leu in a 2026 Iranian case, and compound heterozygous variants in a 2024 Chinese family. Nothing links the allele class to whether hearing loss appears, which is part of why the relationship remains contested.
Loss of secreted TSPEAR from the hair bundle surface causes isolated sensorineural deafness
Genetic context TSPEAR hgnc:1268 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns TSPEAR (hgnc:1268). hgnc:1268 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Homozygous in the founding family and in the isolated-deafness case reports, all of which are consanguineous. Typed LOSS_OF_FUNCTION for the frameshift alleles on the strength of the measured secretion failure; the missense alleles are not functionally characterised.
Downstream
Failure of TSPEAR Secretion The truncating allele prevents the protein leaving the cell. This is the one step of the chain with a direct measurement behind it. Loss of secreted TSPEAR from the hair bundle surface causes isolated sensorineural deafness
Show evidence (3 references)
PMID:22678063 SUPPORT Human Clinical
"Whole exome sequencing allowed us to identify a homozygous frame-shifting mutation (c.1726G>T+c.1728delC) in the gene TSPEAR (thrombospondin-type laminin G domain and EAR repeats)."
The founding allele and the family it was found in.
PMID:41486137 SUPPORT Human Clinical
"In this study, a novel homozygous pathogenic variant in thrombospondin type laminin G domain and epilepsy associated repeats was identified (NM_144991.3: c.668C"
A second, independent isolated-deafness allele. The quote stops mid-variant because the source contains a thin space inside the nucleotide change.
PMID:34795337 SUPPORT Human Clinical
"In eight additional probands, eight candidate VUS variants were detected in five genes (DIAPH1, MYO7A, TECTA, TMC1, TSPEAR)."
A TSPEAR variant found in a hearing-loss cohort and classified as a variant of uncertain significance rather than as the cause. Graded PARTIAL because it puts a TSPEAR variant in a deaf proband while declining to call it causal.
Failure of TSPEAR Secretion
TSPEAR is a secreted extracellular-matrix protein, so where it acts depends on it getting out of the cell. Cells transfected with the mutated gene did not secrete the encoded protein. This is an in vitro result in a heterologous cell line, not a measurement in hair cells, and the entry does not claim more than that.
Loss of secreted TSPEAR from the hair bundle surface causes isolated sensorineural deafness
secretion of TSPEAR into the extracellular matrix GO:0009306 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased secretion of TSPEAR into the extracellular matrix, annotated with protein secretion (GO:0009306). GO:0009306 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Loss of TSPEAR from the Hair Bundle Surface A protein that is not secreted cannot reach the extracellular surface where it was localised. The inference is reasonable and it is an inference; nobody has shown absence of TSPEAR from the bundle in a patient or in a model carrying the human allele. Loss of secreted TSPEAR from the hair bundle surface causes isolated sensorineural deafness
Show evidence (1 reference)
PMID:22678063 SUPPORT In Vitro
"This truncating mutation (p.V576LfsX37) impeded the secretion of the encoded protein by cells transfected with the mutated gene."
The secretion assay. Graded IN_VITRO because it is a transfected-cell experiment, even though it is reported in a clinical genetics paper.
Loss of TSPEAR from the Hair Bundle Surface
The proposed site of action. In mouse cochlea the protein was detected at the surface of the hair bundles of sensory cells, and TSPEAR belongs to a protein family - the EAR repeat proteins, which also includes LGI1, LGI2 and VLGR1 - whose other members are implicated in auditory and audiogenic phenotypes. The family argument is suggestive context; it is not evidence about TSPEAR.
Loss of secreted TSPEAR from the hair bundle surface causes isolated sensorineural deafness
cochlear inner hair cell CL:0000589 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlear inner hair cell (CL:0000589). CL:0000589 is a cell type from the Cell Ontology.
Animal models
Tspear S475TfsX79 CRISPR mouse Mouse fails to recapitulate A mouse carrying a TSPEAR frameshift has normal stereocilia and normal hearing. The proposed hair-bundle mechanism of DFNB98 predicts neither.
Downstream
Impaired Cochlear Sound Transduction The step with no measurement behind it in any species. It is the gap the mouse was built to close, and the mouse came back negative. Loss of secreted TSPEAR from the hair bundle surface causes isolated sensorineural deafness
Show evidence (3 references)
PMID:22678063 SUPPORT Model Organism
"Only the larger Tspear transcript was found in the cochlea, and the protein was detected by immunofluorescence at the surface of the hair bundles of sensory cells."
The localisation on which the site of action rests.
PMID:22678063 SUPPORT Human Clinical
"These observations demonstrate that EAR-containing proteins are essential for the development and function of the auditory system."
The protein-family argument, graded PARTIAL because it is a statement about a family of four proteins and not a demonstration about TSPEAR itself.
PMID:40716589 REFUTE Model Organism
"Intriguingly, stereociliary morphology and auditory function remain unaffected in TSPEAR S475TfsX79 mutant mice."
Stereociliary morphology is normal in a mouse carrying a TSPEAR frameshift, which argues directly against a hair-bundle structural role.
Impaired Cochlear Sound Transduction
The clinical endpoint. In the founding family auditory testing implicated at least a cochlear defect, and in the 2026 case there was no auditory brainstem response at all with a flat pure-tone audiogram. Whether TSPEAR loss is what produced it is the disputed question, not a step that can be inferred from the nodes above.
Loss of secreted TSPEAR from the hair bundle surface causes isolated sensorineural deafness
sensory perception of sound GO:0007605 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased sensory perception of sound (GO:0007605). GO:0007605 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Congenital Profound Sensorineural Hearing Loss The edge from mechanism to clinical phenotype, and it is the disputed claim itself rather than a step within the argument - which is why it opts into the hypothesis group like every other edge here rather than being asserted outright. Loss of secreted TSPEAR from the hair bundle surface causes isolated sensorineural deafness
Show evidence (3 references)
PMID:22678063 SUPPORT Human Clinical
"Auditory tests implicated at least a cochlear defect in these patients."
Locates the lesion in the cochlea in the founding family.
PMID:34042254 REFUTE Human Clinical
"Of the individuals displaying hearing loss, all have additional variants in other hearing-loss-associated genes, specifically TMPRSS3, GJB2, and GJB6, that present competing candidates for their hearing loss phenotype."
The central refuting observation from the 2021 cohort: every biallelic-TSPEAR individual with hearing loss had an ordinary alternative explanation for it.
PMID:41195743 REFUTE Human Clinical
"None of the individuals had hearing loss."
A second, independent cohort in which nobody with biallelic TSPEAR variants was deaf. This is the strongest single observation against the endpoint node, because it is an absence of the phenotype rather than a competing explanation for it.
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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 98 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 1
Congenital Profound Sensorineural Hearing Loss FREQUENT Profound sensorineural hearing impairment HP:0011476 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Profound sensorineural hearing impairment (HP:0011476). HP:0011476 is a phenotype from the Human Phenotype Ontology.
Show evidence (4 references)
PMID:22678063 SUPPORT Human Clinical
"We report a consanguineous Iranian family affected by congenital profound sensorineural deafness segregating in an autosomal recessive mode."
The founding phenotype description.
PMID:41486137 SUPPORT Human Clinical
"Herein we report a patient presenting with bilateral profound sensorineural hearing loss."
An independent case with the same severity.
PMID:34042254 REFUTE Human Clinical
"Nearly all of these newly reported individuals (11/13) have phenotypes that include tooth agenesis or ectodermal dysplasia, while three newly reported individuals have hearing loss."
The denominator that makes this phenotype FREQUENT rather than obligate: most people with biallelic TSPEAR variants do not have hearing loss.
+ 1 more reference
Other 2
Absent Auditory Brainstem Response OCCASIONAL Abnormal auditory evoked potentials HP:0006958 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal auditory evoked potentials (HP:0006958). HP:0006958 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41486137 SUPPORT Human Clinical
"The patient was a 6-year-old Iranian girl of Fars ethnicity, born to a consanguineous marriage, who had flat audiogram in pure tone audiometry obtained from both ears and absence of any response in auditory brain response."
The audiological findings in the one case where they are reported in detail.
Dental and Oral Findings in Some Reported Hearing-Loss Cases OCCASIONAL Ankyloglossia HP:0010296 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ankyloglossia (HP:0010296). HP:0010296 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39720278 SUPPORT Human Clinical
"After three corrective surgeries, her tongue was still difficult to stick out and her speech was still compromised."
The tongue-tethering finding and its clinical course in the one hearing-loss proband reported with oral features. Bound to Ankyloglossia because that is the specific finding the source names; the caries and heart-shaped tongue in the same case are not separately curated.
🧬

Genetic Associations

1
TSPEAR
Gene: TSPEAR hgnc:1268 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TSPEAR (hgnc:1268). hgnc:1268 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: DISPUTED
Show evidence (6 references)
CGGV:assertion_f0928b06-d3bb-41fe-8222-d7f0e6c0a25a-2024-10-31T160000.000Z REFUTE Other
"More evidence is needed to either support or refute the role TSPEAR plays in this disease."
The expert panel's statement of what the classification means, which is what DISPUTED encodes here.
CGGV:assertion_f0928b06-d3bb-41fe-8222-d7f0e6c0a25a-2024-10-31T160000.000Z REFUTE Other
"Another nonsense variant that was observed as a homozygous variant in a proband was found to be heterozygous in the proband’s affected sibling and unaffected mother"
A non-segregation observation, which is one of the two strongest case-level arguments against the relationship.
CGGV:assertion_f0928b06-d3bb-41fe-8222-d7f0e6c0a25a-2024-10-31T160000.000Z REFUTE Other
"A frameshift variant that was reported in 2 probands and segregated in 2 additional family members (PMID: 22678063, 37561809) has also been reported in 2 families with ectodermal dysplasia and normal hearing (PMID: 27736875)."
The other one, and arguably the sharper of the two: the frameshift allele carrying most of the DFNB98 case-level evidence has also been found in two families who have the ectodermal phenotype and hear normally. The same allele therefore does not track with deafness.
+ 3 more references
🗃️

External Assertions

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ClinGen TSPEAR-nonsyndromic hearing loss gene-disease validity assertion
ClinGen gene disease validity CGGV:assertion_f0928b06-d3bb-41fe-8222-d7f0e6c0a25a-2024-10-31T160000.000Z
The ClinGen Hearing Loss Gene Curation Expert Panel classifies the autosomal recessive TSPEAR-nonsyndromic hearing loss relationship as Disputed. The pair was first evaluated in 2017 and re-evaluated on 2024-10-31 under SOP v11, taking in the newer case-level reports; the classification did not change. This is the single most consequential fact about DFNB98 and it is recorded structurally rather than as prose.
The same expert panel separately classifies GJB3-nonsyndromic hearing loss as Disputed and MET-nonsyndromic hearing loss as Limited, and CABP2-nonsyndromic hearing loss as Definitive. The DFNB numbering carries no information about validity.
Show evidence (3 references)
CGGV:assertion_f0928b06-d3bb-41fe-8222-d7f0e6c0a25a-2024-10-31T160000.000Z REFUTE Other
"TSPEAR | HGNC:1268 | nonsyndromic genetic hearing loss | MONDO:0019497 | AR | Disputed"
The expert-panel classification row. Graded REFUTE because the assertion argues against the gene-disease relationship this entry is named for.
CGGV:assertion_f0928b06-d3bb-41fe-8222-d7f0e6c0a25a-2024-10-31T160000.000Z REFUTE Other
"In summary, the relationship between TSPEAR and autosomal recessive nonsyndromic hearing loss has been disputed."
The panel's own summary sentence, which is the conclusion of a scored review.
CGGV:assertion_f0928b06-d3bb-41fe-8222-d7f0e6c0a25a-2024-10-31T160000.000Z REFUTE Other
"New case level evidence has been reviewed, but the classification did not change"
Establishes that the 2024 re-review saw the later case reports and was unpersuaded, which is why those reports do not settle the question.
🔬

Diagnosis

2
Genetic testing, interpreted against the disputed gene-disease relationship
There is no clinical or audiological finding that identifies DFNB98; the label follows from a genotype. The consequence of the Disputed classification is that finding biallelic TSPEAR variants in a deaf patient is the beginning of the analysis rather than the end of it. Two things follow concretely. Established hearing-loss genes must be excluded before the TSPEAR finding is accepted, because the cohort that tested this found competing variants in TMPRSS3, GJB2 and GJB6 in every deaf biallelic-TSPEAR individual. And the patient should be examined for dental and ectodermal features, because the established TSPEAR disease is a dental one and its recognition changes the counselling.
Show evidence (1 reference)
PMID:34042254 SUPPORT Human Clinical
"Of the individuals displaying hearing loss, all have additional variants in other hearing-loss-associated genes, specifically TMPRSS3, GJB2, and GJB6, that present competing candidates for their hearing loss phenotype."
Names the specific competing genes that this recommendation exists to exclude.
Examination for dental and ectodermal features
Absence of ectodermal findings is what makes a case a DFNB98 case rather than an ectodermal dysplasia 14 case with deafness alongside, so it has to be looked for deliberately rather than assumed from a referral for hearing loss. In the 2026 report the teeth, skin, hair and nails were each examined and found normal, and the authors note that a purely auditory presentation is uncommon among published TSPEAR cases. The schema has no way to record an examined-and-absent phenotype, so this is curated here as the examination it is rather than as an absent phenotype in the phenotype list.
Show evidence (2 references)
PMID:41486137 SUPPORT Human Clinical
"We examined the patient for any form of ectodermal dysplasia or malformation in teeth, skin, hair, and nail and they were in normal figuration."
A deliberate examination for ectodermal features that found none, which is what qualifies the case as nonsyndromic.
PMID:41486137 SUPPORT Human Clinical
"mutation presenting solely with hearing issues and lack of any ectodermal dysplasia was rare based on the review of previously reported cases."
Qualifies the finding by stating that the isolated presentation is uncommon in the published series.
📊

Prevalence

1
Worldwide
Cases In Literature Not yet documented
No prevalence estimate exists and none can be constructed, because the numerator is exactly the set of cases whose causal attribution is in dispute. Five unique variants in four probands across four publications were counted by the ClinGen review, of which the isolated-deafness cases are a subset. Carrier rates for TSPEAR loss-of-function alleles have been published - roughly 1 in 140 in non-Finnish Europeans - but those are ectodermal dysplasia 14 carrier rates and must not be read across to DFNB98. They are recorded in the differential diagnosis section where they belong.
Show evidence (1 reference)
CGGV:assertion_f0928b06-d3bb-41fe-8222-d7f0e6c0a25a-2024-10-31T160000.000Z SUPPORT Other
"At least 5 unique variants (3 frameshift, 1 nonsense, 1 silent variant in splice consensus sequence) have been reported in at least 4 probands in 4 publications"
The published case count assembled by the expert panel, which is the whole numerator available.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Autosomal Recessive Nonsyndromic Hearing Loss 98:

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Animal Models

1
Tspear S475TfsX79 CRISPR mouse
The only mouse model of a TSPEAR frameshift, and the experiment that was needed. It is negative on every axis TSPEAR has been claimed to matter for: stereociliary morphology, auditory function, tooth morphology and hair development are all normal. It is not entirely a null result. The mutation does perturb Notch and Wnt signalling - Notch1 and downstream targets are down, Heyl is up in skin, and Wnt4 is elevated in both skin and inner ear - so TSPEAR is doing something molecularly in the ear without that something producing a hearing phenotype in this animal.
Species
Mouse
Genotype
Tspear S475TfsX79 frameshift, generated by CRISPR/Cas9 genome editing
Publication
PMID:40716589
Pathograph links
Loss of TSPEAR from the Hair Bundle Surface fails to recapitulate fidelity: moderate A mouse carrying a TSPEAR frameshift has normal stereocilia and normal hearing. The proposed hair-bundle mechanism of DFNB98 predicts neither.
Limitations: The mouse allele S475TfsX79 is not the human founding allele p.V576LfsX37; both are frameshifts but they truncate at different points, so a residual-function argument for the mouse allele has not been formally excluded. The founding human variant has never been knocked in. Mouse and human cochleae also differ, and a family of six EAR-domain proteins offers scope for compensation that has not been tested. Fidelity is therefore MODERATE rather than HIGH: the negative result is real and directly relevant, and it is not the same allele in the same species as the patients.
Readouts
Stereociliary morphology
Direction: UNCHANGED
Interpretation: Hair bundle structure is normal in the absence of functional TSPEAR, which is the opposite of what a surface-of-the-bundle structural role predicts. A deliberate negative result, not a missing measurement.
Show evidence (1 reference)
PMID:40716589 REFUTE Model Organism
"Intriguingly, stereociliary morphology and auditory function remain unaffected in TSPEAR S475TfsX79 mutant mice."
The morphological measurement behind this readout.
Auditory function
Direction: UNCHANGED
Interpretation: Hearing is normal. This is the measurement DFNB98 most needed and it came back against the hypothesis.
Show evidence (1 reference)
PMID:40716589 REFUTE Model Organism
"In conclusion, our data demonstrate that TSPEAR S475TfsX79 mutation does not compromise auditory function, tooth morphology, or hair development in mice, but TSPEAR may modulate both Notch and Wnt signaling pathways in the mouse."
The paper's own conclusion on auditory function.
Notch and Wnt pathway signalling in skin and inner ear
Direction: ALTERED
Interpretation: Pathway signalling is perturbed even though the organ phenotypes are not, so the protein is functional in the ear without being required for hearing in this animal.
Show evidence (1 reference)
PMID:40716589 SUPPORT Model Organism
"Nevertheless, the S475TfsX79 mutation appears to perturb both Notch and Wnt signaling pathways."
The molecular readout that keeps this from being a pure null result.
Show evidence (1 reference)
PMID:40716589 REFUTE Model Organism
"Although tooth abnormalities and a reduced capacity for caudal fin regeneration were observed in the Tspeara-/-;Tspearb-/- knockout zebrafish model, there have been no reports of the Tspear knockout mouse model to date, which hampers further investigation of its physiological role."
Establishes that this is the first mouse to test the question, and notes that the pre-existing zebrafish model produced a dental rather than an auditory phenotype - which is the ectodermal dysplasia entity, not this one.
{ }

Source YAML

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name: Autosomal Recessive Nonsyndromic Hearing Loss 98
creation_date: "2026-08-28T20:00:00Z"
category: Mendelian
disease_term:
  preferred_term: autosomal recessive nonsyndromic hearing loss 98
  term:
    id: MONDO:0013929
    label: autosomal recessive nonsyndromic hearing loss 98
synonyms:
- DFNB98
- deafness, autosomal recessive 98
- TSPEAR-related autosomal recessive nonsyndromic hearing loss
- autosomal recessive nonsyndromic deafness 98
description: >-
  DFNB98 is the proposition that biallelic TSPEAR variants cause isolated congenital
  sensorineural deafness. It was named in 2012 from one consanguineous Iranian family, and it
  is the weakest-supported of the DFNB loci curated here: the ClinGen Hearing Loss Gene
  Curation Expert Panel classifies TSPEAR-nonsyndromic hearing loss as Disputed, and
  reaffirmed that classification on review in 2024.

  The dispute is not a matter of thin evidence. It is that the evidence points somewhere
  else. TSPEAR unambiguously causes autosomal recessive ectodermal dysplasia 14, a
  predominantly dental disease; that relationship is replicated across cohorts and supported
  by functional work in enamel-knot biology. A 2021 cohort of thirteen individuals with
  biallelic TSPEAR variants found hearing loss in three, and every one of the three also
  carried variants in TMPRSS3, GJB2 or GJB6 - genes that are themselves ordinary causes of
  the phenotype. A 2026 cohort of eleven patients from seven families found tooth
  abnormalities in all of them and hearing loss in none, and states flatly that hearing loss
  is not a feature of the disease. A CRISPR mouse carrying a TSPEAR frameshift has normal
  stereocilia and normal auditory function.

  What survives is a small set of isolated-deafness cases, including a 2026 Iranian child
  with profound bilateral loss and explicitly normal teeth, skin, hair and nails, and the
  original family's finding that TSPEAR protein sits at the surface of the hair bundle. That
  is enough to keep the entity in view and not enough to call it established.

  This entry is curated as a disease whose causal claim is contested, not as a disease with
  a settled mechanism. The pathophysiology chain below is grouped under a named mechanistic
  hypothesis rather than asserted as canonical, the gene carries relationship_type DISPUTED,
  the refuting evidence is cited in the same sections as the supporting evidence, and the
  mouse is recorded as FAILS_TO_RECAPITULATE.

parents:
- Autosomal Recessive Nonsyndromic Hearing Loss
- Hereditary Hearing Loss

external_assertions:
- name: ClinGen TSPEAR-nonsyndromic hearing loss gene-disease validity assertion
  source: ClinGen
  assertion_type: gene_disease_validity
  external_id: CGGV:assertion_f0928b06-d3bb-41fe-8222-d7f0e6c0a25a-2024-10-31T160000.000Z
  url: https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f0928b06-d3bb-41fe-8222-d7f0e6c0a25a-2024-10-31T160000.000Z
  description: >-
    The ClinGen Hearing Loss Gene Curation Expert Panel classifies the autosomal recessive
    TSPEAR-nonsyndromic hearing loss relationship as Disputed. The pair was first evaluated
    in 2017 and re-evaluated on 2024-10-31 under SOP v11, taking in the newer case-level
    reports; the classification did not change. This is the single most consequential fact
    about DFNB98 and it is recorded structurally rather than as prose.
  evidence:
  - reference: CGGV:assertion_f0928b06-d3bb-41fe-8222-d7f0e6c0a25a-2024-10-31T160000.000Z
    reference_title: TSPEAR / nonsyndromic genetic hearing loss (Disputed)
    supports: REFUTE
    evidence_source: OTHER
    snippet: "TSPEAR | HGNC:1268 | nonsyndromic genetic hearing loss | MONDO:0019497 | AR | Disputed"
    explanation: >-
      The expert-panel classification row. Graded REFUTE because the assertion argues against
      the gene-disease relationship this entry is named for.
  - reference: CGGV:assertion_f0928b06-d3bb-41fe-8222-d7f0e6c0a25a-2024-10-31T160000.000Z
    reference_title: TSPEAR / nonsyndromic genetic hearing loss (Disputed)
    supports: REFUTE
    evidence_source: OTHER
    snippet: >-
      In summary, the relationship between TSPEAR and autosomal recessive nonsyndromic
      hearing loss has been disputed.
    explanation: >-
      The panel's own summary sentence, which is the conclusion of a scored review.
  - reference: CGGV:assertion_f0928b06-d3bb-41fe-8222-d7f0e6c0a25a-2024-10-31T160000.000Z
    reference_title: TSPEAR / nonsyndromic genetic hearing loss (Disputed)
    supports: REFUTE
    evidence_source: OTHER
    snippet: >-
      New case level evidence has been reviewed, but the classification did not change
    explanation: >-
      Establishes that the 2024 re-review saw the later case reports and was unpersuaded,
      which is why those reports do not settle the question.
  notes: >-
    The same expert panel separately classifies GJB3-nonsyndromic hearing loss as Disputed
    and MET-nonsyndromic hearing loss as Limited, and CABP2-nonsyndromic hearing loss as
    Definitive. The DFNB numbering carries no information about validity.

prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    No prevalence estimate exists and none can be constructed, because the numerator is
    exactly the set of cases whose causal attribution is in dispute. Five unique variants in
    four probands across four publications were counted by the ClinGen review, of which the
    isolated-deafness cases are a subset.

    Carrier rates for TSPEAR loss-of-function alleles have been published - roughly 1 in 140
    in non-Finnish Europeans - but those are ectodermal dysplasia 14 carrier rates and must
    not be read across to DFNB98. They are recorded in the differential diagnosis section
    where they belong.
  evidence:
  - reference: CGGV:assertion_f0928b06-d3bb-41fe-8222-d7f0e6c0a25a-2024-10-31T160000.000Z
    reference_title: TSPEAR / nonsyndromic genetic hearing loss (Disputed)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      At least 5 unique variants (3 frameshift, 1 nonsense, 1 silent variant in splice
      consensus sequence) have been reported in at least 4 probands in 4 publications
    explanation: >-
      The published case count assembled by the expert panel, which is the whole numerator
      available.

mechanistic_hypotheses:
- hypothesis_group_id: tspear_hair_bundle_deafness
  hypothesis_label: >-
    Loss of secreted TSPEAR from the hair bundle surface causes isolated sensorineural
    deafness
  status: ALTERNATIVE
  description: >-
    The proposed mechanism of DFNB98, and the reason it is a hypothesis group rather than the
    entry's canonical model. TSPEAR is a secreted protein built from a thrombospondin-type
    laminin G domain followed by seven epilepsy-associated repeats that fold into a
    beta-propeller. In the founding study the transcript was found in mouse cochlea and the
    protein was localised by immunofluorescence to the surface of the hair bundles of sensory
    cells, while the human truncating allele blocked secretion of the protein from
    transfected cells. From those two observations the argument runs: no secretion, no
    TSPEAR at the bundle surface, no functioning bundle, deafness.

    Every causal edge in the pathophysiology section below opts into this group, because
    every one of them is part of that argument rather than an independently established step.
    Nothing has connected the missing protein to a measured auditory deficit in any organism.
    The one animal that has been made and tested - a mouse carrying a TSPEAR frameshift -
    hears normally and has normal stereocilia.
  evidence:
  - reference: PMID:22678063
    reference_title: Defect in the gene encoding the EAR/EPTP domain-containing protein TSPEAR causes DFNB98 profound deafness.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Only the larger Tspear transcript was found in the cochlea, and the protein was
      detected by immunofluorescence at the surface of the hair bundles of sensory cells.
    explanation: >-
      The expression and localisation observation the hypothesis is built on. Mouse tissue,
      hence MODEL_ORGANISM.
  - reference: PMID:40716589
    reference_title: TSPEAR S475TfsX79 mutation does not affect auditory function, tooth morphology or hair development in mice.
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Intriguingly, stereociliary morphology and auditory function remain unaffected in
      TSPEAR S475TfsX79 mutant mice.
    explanation: >-
      The direct test of the hypothesis, in the organism where the localisation was
      established, with a negative result at both the structural and functional level.
  - reference: PMID:41195743
    reference_title: "Genotypes and Phenotypes of Patients With TSPEAR-Related Disorder: Evidence of a Predominant Dental Phenotype."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, the role of TSPEAR in auditory processes is unclear.
    explanation: >-
      The 2026 cohort's own framing of the auditory question before it went looking, which is
      the state of the hypothesis this group is named for.

pathophysiology:

- name: Biallelic TSPEAR Loss-of-Function Variant
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    The founding allele is a homozygous frameshift, c.1726G>T+c.1728delC, predicting
    p.V576LfsX37, found in three affected siblings of a consanguineous Iranian family with
    congenital profound deafness. TSPEAR is alternatively spliced into 522- and
    669-residue isoforms and the frameshift affects both.

    Later isolated-deafness reports carry different alleles: a homozygous missense
    c.668C>T p.Ser223Leu in a 2026 Iranian case, and compound heterozygous variants in a 2024
    Chinese family. Nothing links the allele class to whether hearing loss appears, which is
    part of why the relationship remains contested.
  genetic_context:
    gene:
      preferred_term: TSPEAR
      term:
        id: hgnc:1268
        label: TSPEAR
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Homozygous in the founding family and in the isolated-deafness case reports, all of
      which are consanguineous. Typed LOSS_OF_FUNCTION for the frameshift alleles on the
      strength of the measured secretion failure; the missense alleles are not
      functionally characterised.
  downstream:
  - target: Failure of TSPEAR Secretion
    causal_link_type: DIRECT
    hypothesis_groups:
    - tspear_hair_bundle_deafness
    description: >-
      The truncating allele prevents the protein leaving the cell. This is the one step of
      the chain with a direct measurement behind it.
  evidence:
  - reference: PMID:22678063
    reference_title: Defect in the gene encoding the EAR/EPTP domain-containing protein TSPEAR causes DFNB98 profound deafness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole exome sequencing allowed us to identify a homozygous frame-shifting mutation
      (c.1726G>T+c.1728delC) in the gene TSPEAR (thrombospondin-type laminin G domain and EAR
      repeats).
    explanation: >-
      The founding allele and the family it was found in.
  - reference: PMID:41486137
    reference_title: "A novel pathogenic mutation in TSPEAR associated with sensorineural hearing loss: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this study, a novel homozygous pathogenic variant in thrombospondin type laminin G
      domain and epilepsy associated repeats was identified (NM_144991.3: c.668C
    explanation: >-
      A second, independent isolated-deafness allele. The quote stops mid-variant because the
      source contains a thin space inside the nucleotide change.
  - reference: PMID:34795337
    reference_title: Comprehensive molecular-genetic analysis of mid-frequency sensorineural hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In eight additional probands, eight candidate VUS variants were detected in five genes
      (DIAPH1, MYO7A, TECTA, TMC1, TSPEAR).
    explanation: >-
      A TSPEAR variant found in a hearing-loss cohort and classified as a variant of
      uncertain significance rather than as the cause. Graded PARTIAL because it puts a
      TSPEAR variant in a deaf proband while declining to call it causal.

- name: Failure of TSPEAR Secretion
  role: central_effector
  biological_scale: MOLECULAR
  description: >-
    TSPEAR is a secreted extracellular-matrix protein, so where it acts depends on it getting
    out of the cell. Cells transfected with the mutated gene did not secrete the encoded
    protein. This is an in vitro result in a heterologous cell line, not a measurement in
    hair cells, and the entry does not claim more than that.
  biological_processes:
  - preferred_term: secretion of TSPEAR into the extracellular matrix
    term:
      id: GO:0009306
      label: protein secretion
    modifier: DECREASED
  downstream:
  - target: Loss of TSPEAR from the Hair Bundle Surface
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - tspear_hair_bundle_deafness
    description: >-
      A protein that is not secreted cannot reach the extracellular surface where it was
      localised. The inference is reasonable and it is an inference; nobody has shown absence
      of TSPEAR from the bundle in a patient or in a model carrying the human allele.
  evidence:
  - reference: PMID:22678063
    reference_title: Defect in the gene encoding the EAR/EPTP domain-containing protein TSPEAR causes DFNB98 profound deafness.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This truncating mutation (p.V576LfsX37) impeded the secretion of the encoded protein by
      cells transfected with the mutated gene.
    explanation: >-
      The secretion assay. Graded IN_VITRO because it is a transfected-cell experiment, even
      though it is reported in a clinical genetics paper.

- name: Loss of TSPEAR from the Hair Bundle Surface
  role: central_effector
  biological_scale: CELLULAR
  description: >-
    The proposed site of action. In mouse cochlea the protein was detected at the surface of
    the hair bundles of sensory cells, and TSPEAR belongs to a protein family - the EAR
    repeat proteins, which also includes LGI1, LGI2 and VLGR1 - whose other members are
    implicated in auditory and audiogenic phenotypes. The family argument is suggestive
    context; it is not evidence about TSPEAR.
  cell_types:
  - preferred_term: cochlear inner hair cell
    term:
      id: CL:0000589
      label: cochlear inner hair cell
  downstream:
  - target: Impaired Cochlear Sound Transduction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - tspear_hair_bundle_deafness
    description: >-
      The step with no measurement behind it in any species. It is the gap the mouse was
      built to close, and the mouse came back negative.
  evidence:
  - reference: PMID:22678063
    reference_title: Defect in the gene encoding the EAR/EPTP domain-containing protein TSPEAR causes DFNB98 profound deafness.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Only the larger Tspear transcript was found in the cochlea, and the protein was
      detected by immunofluorescence at the surface of the hair bundles of sensory cells.
    explanation: >-
      The localisation on which the site of action rests.
  - reference: PMID:22678063
    reference_title: Defect in the gene encoding the EAR/EPTP domain-containing protein TSPEAR causes DFNB98 profound deafness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These observations demonstrate that EAR-containing proteins are essential for the
      development and function of the auditory system.
    explanation: >-
      The protein-family argument, graded PARTIAL because it is a statement about a family of
      four proteins and not a demonstration about TSPEAR itself.
  - reference: PMID:40716589
    reference_title: TSPEAR S475TfsX79 mutation does not affect auditory function, tooth morphology or hair development in mice.
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Intriguingly, stereociliary morphology and auditory function remain unaffected in
      TSPEAR S475TfsX79 mutant mice.
    explanation: >-
      Stereociliary morphology is normal in a mouse carrying a TSPEAR frameshift, which
      argues directly against a hair-bundle structural role.

- name: Impaired Cochlear Sound Transduction
  role: consequence
  biological_scale: ORGANISM
  description: >-
    The clinical endpoint. In the founding family auditory testing implicated at least a
    cochlear defect, and in the 2026 case there was no auditory brainstem response at all
    with a flat pure-tone audiogram. Whether TSPEAR loss is what produced it is the disputed
    question, not a step that can be inferred from the nodes above.
  biological_processes:
  - preferred_term: sensory perception of sound
    term:
      id: GO:0007605
      label: sensory perception of sound
    modifier: DECREASED
  downstream:
  - target: Congenital Profound Sensorineural Hearing Loss
    causal_link_type: DIRECT
    hypothesis_groups:
    - tspear_hair_bundle_deafness
    description: >-
      The edge from mechanism to clinical phenotype, and it is the disputed claim itself
      rather than a step within the argument - which is why it opts into the hypothesis group
      like every other edge here rather than being asserted outright.
  evidence:
  - reference: PMID:22678063
    reference_title: Defect in the gene encoding the EAR/EPTP domain-containing protein TSPEAR causes DFNB98 profound deafness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Auditory tests implicated at least a cochlear defect in these patients.
    explanation: >-
      Locates the lesion in the cochlea in the founding family.
  - reference: PMID:34042254
    reference_title: "TSPEAR variants are primarily associated with ectodermal dysplasia and tooth agenesis but not hearing loss: A novel cohort study."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of the individuals displaying hearing loss, all have additional variants in other
      hearing-loss-associated genes, specifically TMPRSS3, GJB2, and GJB6, that present
      competing candidates for their hearing loss phenotype.
    explanation: >-
      The central refuting observation from the 2021 cohort: every biallelic-TSPEAR
      individual with hearing loss had an ordinary alternative explanation for it.
  - reference: PMID:41195743
    reference_title: "Genotypes and Phenotypes of Patients With TSPEAR-Related Disorder: Evidence of a Predominant Dental Phenotype."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      None of the individuals had hearing loss.
    explanation: >-
      A second, independent cohort in which nobody with biallelic TSPEAR variants was deaf.
      This is the strongest single observation against the endpoint node, because it is an
      absence of the phenotype rather than a competing explanation for it.

phenotypes:

- category: Otologic
  name: Congenital Profound Sensorineural Hearing Loss
  frequency: FREQUENT
  severity: SEVERE
  description: >-
    Bilateral, congenital and profound in the reported isolated-deafness cases. The 2026
    Iranian child had a flat audiogram in both ears and no auditory brainstem response.

    Frequency is FREQUENT rather than OBLIGATE deliberately. In a biallelic-TSPEAR cohort
    assembled without ascertaining on deafness, hearing loss was present in three of thirteen
    individuals and was attributable to another gene in all three. This phenotype is the
    defining feature of the ascertained cases and is not a feature of biallelic TSPEAR
    genotypes generally.
  phenotype_term:
    preferred_term: Profound sensorineural hearing impairment
    term:
      id: HP:0011476
      label: Profound sensorineural hearing impairment
  evidence:
  - reference: PMID:22678063
    reference_title: Defect in the gene encoding the EAR/EPTP domain-containing protein TSPEAR causes DFNB98 profound deafness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a consanguineous Iranian family affected by congenital profound sensorineural
      deafness segregating in an autosomal recessive mode.
    explanation: >-
      The founding phenotype description.
  - reference: PMID:41486137
    reference_title: "A novel pathogenic mutation in TSPEAR associated with sensorineural hearing loss: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Herein we report a patient presenting with bilateral profound sensorineural hearing
      loss.
    explanation: >-
      An independent case with the same severity.
  - reference: PMID:34042254
    reference_title: "TSPEAR variants are primarily associated with ectodermal dysplasia and tooth agenesis but not hearing loss: A novel cohort study."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nearly all of these newly reported individuals (11/13) have phenotypes that include
      tooth agenesis or ectodermal dysplasia, while three newly reported individuals have
      hearing loss.
    explanation: >-
      The denominator that makes this phenotype FREQUENT rather than obligate: most people
      with biallelic TSPEAR variants do not have hearing loss.
  - reference: PMID:41195743
    reference_title: "Genotypes and Phenotypes of Patients With TSPEAR-Related Disorder: Evidence of a Predominant Dental Phenotype."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our results demonstrate that individuals with biallelic variants in TSPEAR show
      complete penetrance for dental manifestations, but not for other ectodermal
      abnormalities.
    explanation: >-
      The 2026 cohort's penetrance finding. Eleven biallelic individuals across seven
      families were fully penetrant for teeth and none was deaf, which roughly doubles the
      published denominator against which this phenotype's frequency has to be read.

- category: Otologic
  name: Absent Auditory Brainstem Response
  frequency: OCCASIONAL
  description: >-
    Recorded in the 2026 case, where the pure-tone audiogram was flat and there was no
    response on auditory brainstem testing. One case, so occasional rather than a
    characteristic finding.
  phenotype_term:
    preferred_term: Abnormal auditory evoked potentials
    term:
      id: HP:0006958
      label: Abnormal auditory evoked potentials
  evidence:
  - reference: PMID:41486137
    reference_title: "A novel pathogenic mutation in TSPEAR associated with sensorineural hearing loss: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient was a 6-year-old Iranian girl of Fars ethnicity, born to a consanguineous
      marriage, who had flat audiogram in pure tone audiometry obtained from both ears and
      absence of any response in auditory brain response.
    explanation: >-
      The audiological findings in the one case where they are reported in detail.

- category: Dental
  name: Dental and Oral Findings in Some Reported Hearing-Loss Cases
  frequency: OCCASIONAL
  description: >-
    Not every case reported under the DFNB98 heading is genuinely nonsyndromic. The 2024
    Chinese proband with compound heterozygous TSPEAR variants and congenital sensorineural
    hearing loss also had dental caries, ankyloglossia and a heart-shaped tongue.

    This is recorded rather than filtered out, because it is precisely the observation that
    keeps the two TSPEAR entities entangled: a case with both hearing loss and oral findings
    can be read as DFNB98 with incidental dental disease or as ectodermal dysplasia 14 with
    hearing loss, and the published report does not settle which.
  phenotype_term:
    preferred_term: Ankyloglossia
    term:
      id: HP:0010296
      label: Ankyloglossia
  evidence:
  - reference: PMID:39720278
    reference_title: Novel compound heterozygous variants in the TSPEAR gene causing autosomal recessive hearing loss in a Chinese family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After three corrective surgeries, her tongue was still difficult to stick out and her
      speech was still compromised.
    explanation: >-
      The tongue-tethering finding and its clinical course in the one hearing-loss proband
      reported with oral features. Bound to Ankyloglossia because that is the specific
      finding the source names; the caries and heart-shaped tongue in the same case are not
      separately curated.

genetic:

- name: TSPEAR
  gene_term:
    preferred_term: TSPEAR
    term:
      id: hgnc:1268
      label: TSPEAR
  relationship_type: DISPUTED
  notes: >-
    Typed DISPUTED rather than CAUSATIVE, matching the ClinGen Hearing Loss Gene Curation
    Expert Panel's own classification. This is the deliberate content of the entry: a reader
    or a downstream query that treats a biallelic TSPEAR finding as a molecular diagnosis of
    deafness would be going beyond what the field currently supports.

    TSPEAR encodes a secreted protein of the extracellular matrix - a thrombospondin-type
    laminin G domain followed by seven epilepsy-associated repeats forming a beta-propeller -
    and is one of six mammalian EAR-domain proteins. Its established disease association is
    ectodermal dysplasia 14, which is a different entity and is not curated here.
  evidence:
  - reference: CGGV:assertion_f0928b06-d3bb-41fe-8222-d7f0e6c0a25a-2024-10-31T160000.000Z
    reference_title: TSPEAR / nonsyndromic genetic hearing loss (Disputed)
    supports: REFUTE
    evidence_source: OTHER
    snippet: >-
      More evidence is needed to either support or refute the role TSPEAR plays in this
      disease.
    explanation: >-
      The expert panel's statement of what the classification means, which is what DISPUTED
      encodes here.
  - reference: CGGV:assertion_f0928b06-d3bb-41fe-8222-d7f0e6c0a25a-2024-10-31T160000.000Z
    reference_title: TSPEAR / nonsyndromic genetic hearing loss (Disputed)
    supports: REFUTE
    evidence_source: OTHER
    snippet: >-
      Another nonsense variant that was observed as a homozygous variant in a proband was
      found to be heterozygous in the proband’s affected sibling and unaffected mother
    explanation: >-
      A non-segregation observation, which is one of the two strongest case-level arguments
      against the relationship.
  - reference: CGGV:assertion_f0928b06-d3bb-41fe-8222-d7f0e6c0a25a-2024-10-31T160000.000Z
    reference_title: TSPEAR / nonsyndromic genetic hearing loss (Disputed)
    supports: REFUTE
    evidence_source: OTHER
    snippet: >-
      A frameshift variant that was reported in 2 probands and segregated in 2 additional
      family members (PMID: 22678063, 37561809) has also been reported in 2 families with
      ectodermal dysplasia and normal hearing (PMID: 27736875).
    explanation: >-
      The other one, and arguably the sharper of the two: the frameshift allele carrying most
      of the DFNB98 case-level evidence has also been found in two families who have the
      ectodermal phenotype and hear normally. The same allele therefore does not track with
      deafness.
  - reference: PMID:34042254
    reference_title: "TSPEAR variants are primarily associated with ectodermal dysplasia and tooth agenesis but not hearing loss: A novel cohort study."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      When presented alongside previous reports, the overall evidence supports the
      association of TSPEAR variants with ectodermal dysplasia and tooth agenesis features
      but creates significant doubt as to whether TSPEAR variants are a monogenic cause of
      hearing loss.
    explanation: >-
      The 2021 cohort study's own conclusion, stated in terms of monogenic causation, which
      is exactly the claim DFNB98 makes.
  - reference: PMID:41195743
    reference_title: "Genotypes and Phenotypes of Patients With TSPEAR-Related Disorder: Evidence of a Predominant Dental Phenotype."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TSPEAR-related disorder is more common than previously thought, while hearing loss is
      not a feature of the disease.
    explanation: >-
      The most recent and most direct statement against the relationship, from a cohort in
      which every affected individual had dental findings and none had hearing loss. It
      postdates the 2024 ClinGen re-review.
  - reference: PMID:22678063
    reference_title: Defect in the gene encoding the EAR/EPTP domain-containing protein TSPEAR causes DFNB98 profound deafness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole exome sequencing allowed us to identify a homozygous frame-shifting mutation
      (c.1726G>T+c.1728delC) in the gene TSPEAR (thrombospondin-type laminin G domain and EAR
      repeats).
    explanation: >-
      The founding association, kept alongside the refuting items rather than displaced by
      them.

inheritance:

- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Where the phenotype has been reported it is in homozygous probands from consanguineous
    families, or in one compound heterozygote. The mode of inheritance is not the contested
    part of DFNB98; whether the genotype causes the phenotype is.

    One published proband did not segregate: a homozygous nonsense variant was heterozygous
    in an affected sibling and in the unaffected mother. That single observation does more
    damage to the causal claim than the family count does good.
  evidence:
  - reference: PMID:22678063
    reference_title: Defect in the gene encoding the EAR/EPTP domain-containing protein TSPEAR causes DFNB98 profound deafness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a consanguineous Iranian family affected by congenital profound sensorineural
      deafness segregating in an autosomal recessive mode.
    explanation: >-
      Recessive segregation in the founding family.

animal_models:

- name: Tspear S475TfsX79 CRISPR mouse
  species: Mouse
  genotype: Tspear S475TfsX79 frameshift, generated by CRISPR/Cas9 genome editing
  publication: PMID:40716589
  description: >-
    The only mouse model of a TSPEAR frameshift, and the experiment that was needed. It is
    negative on every axis TSPEAR has been claimed to matter for: stereociliary morphology,
    auditory function, tooth morphology and hair development are all normal.

    It is not entirely a null result. The mutation does perturb Notch and Wnt signalling -
    Notch1 and downstream targets are down, Heyl is up in skin, and Wnt4 is elevated in both
    skin and inner ear - so TSPEAR is doing something molecularly in the ear without that
    something producing a hearing phenotype in this animal.
  modeled_mechanisms:
  - target: Loss of TSPEAR from the Hair Bundle Surface
    relationship: FAILS_TO_RECAPITULATE
    fidelity: MODERATE
    description: >-
      A mouse carrying a TSPEAR frameshift has normal stereocilia and normal hearing. The
      proposed hair-bundle mechanism of DFNB98 predicts neither.
    limitations: >-
      The mouse allele S475TfsX79 is not the human founding allele p.V576LfsX37; both are
      frameshifts but they truncate at different points, so a residual-function argument for
      the mouse allele has not been formally excluded. The founding human variant has never
      been knocked in. Mouse and human cochleae also differ, and a family of six EAR-domain
      proteins offers scope for compensation that has not been tested. Fidelity is therefore
      MODERATE rather than HIGH: the negative result is real and directly relevant, and it is
      not the same allele in the same species as the patients.
    readouts:
    - name: Stereociliary morphology
      target: Loss of TSPEAR from the Hair Bundle Surface
      direction: UNCHANGED
      interpretation: >-
        Hair bundle structure is normal in the absence of functional TSPEAR, which is the
        opposite of what a surface-of-the-bundle structural role predicts. A deliberate
        negative result, not a missing measurement.
      evidence:
      - reference: PMID:40716589
        reference_title: TSPEAR S475TfsX79 mutation does not affect auditory function, tooth morphology or hair development in mice.
        supports: REFUTE
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Intriguingly, stereociliary morphology and auditory function remain unaffected in
          TSPEAR S475TfsX79 mutant mice.
        explanation: >-
          The morphological measurement behind this readout.
    - name: Auditory function
      target: Loss of TSPEAR from the Hair Bundle Surface
      direction: UNCHANGED
      interpretation: >-
        Hearing is normal. This is the measurement DFNB98 most needed and it came back
        against the hypothesis.
      evidence:
      - reference: PMID:40716589
        reference_title: TSPEAR S475TfsX79 mutation does not affect auditory function, tooth morphology or hair development in mice.
        supports: REFUTE
        evidence_source: MODEL_ORGANISM
        snippet: >-
          In conclusion, our data demonstrate that TSPEAR S475TfsX79 mutation does not
          compromise auditory function, tooth morphology, or hair development in mice, but
          TSPEAR may modulate both Notch and Wnt signaling pathways in the mouse.
        explanation: >-
          The paper's own conclusion on auditory function.
    - name: Notch and Wnt pathway signalling in skin and inner ear
      target: Loss of TSPEAR from the Hair Bundle Surface
      direction: ALTERED
      interpretation: >-
        Pathway signalling is perturbed even though the organ phenotypes are not, so the
        protein is functional in the ear without being required for hearing in this animal.
      evidence:
      - reference: PMID:40716589
        reference_title: TSPEAR S475TfsX79 mutation does not affect auditory function, tooth morphology or hair development in mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Nevertheless, the S475TfsX79 mutation appears to perturb both Notch and Wnt
          signaling pathways.
        explanation: >-
          The molecular readout that keeps this from being a pure null result.
    evidence:
    - reference: PMID:40716589
      reference_title: TSPEAR S475TfsX79 mutation does not affect auditory function, tooth morphology or hair development in mice.
      supports: REFUTE
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Although tooth abnormalities and a reduced capacity for caudal fin regeneration were
        observed in the Tspeara-/-;Tspearb-/- knockout zebrafish model, there have been no
        reports of the Tspear knockout mouse model to date, which hampers further
        investigation of its physiological role.
      explanation: >-
        Establishes that this is the first mouse to test the question, and notes that the
        pre-existing zebrafish model produced a dental rather than an auditory phenotype -
        which is the ectodermal dysplasia entity, not this one.

diagnosis:
- name: Genetic testing, interpreted against the disputed gene-disease relationship
  description: >-
    There is no clinical or audiological finding that identifies DFNB98; the label follows
    from a genotype. The consequence of the Disputed classification is that finding biallelic
    TSPEAR variants in a deaf patient is the beginning of the analysis rather than the end of
    it.

    Two things follow concretely. Established hearing-loss genes must be excluded before the
    TSPEAR finding is accepted, because the cohort that tested this found competing variants
    in TMPRSS3, GJB2 and GJB6 in every deaf biallelic-TSPEAR individual. And the patient
    should be examined for dental and ectodermal features, because the established TSPEAR
    disease is a dental one and its recognition changes the counselling.
  evidence:
  - reference: PMID:34042254
    reference_title: "TSPEAR variants are primarily associated with ectodermal dysplasia and tooth agenesis but not hearing loss: A novel cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of the individuals displaying hearing loss, all have additional variants in other
      hearing-loss-associated genes, specifically TMPRSS3, GJB2, and GJB6, that present
      competing candidates for their hearing loss phenotype.
    explanation: >-
      Names the specific competing genes that this recommendation exists to exclude.

- name: Examination for dental and ectodermal features
  description: >-
    Absence of ectodermal findings is what makes a case a DFNB98 case rather than an
    ectodermal dysplasia 14 case with deafness alongside, so it has to be looked for
    deliberately rather than assumed from a referral for hearing loss. In the 2026 report the
    teeth, skin, hair and nails were each examined and found normal, and the authors note
    that a purely auditory presentation is uncommon among published TSPEAR cases.

    The schema has no way to record an examined-and-absent phenotype, so this is curated here
    as the examination it is rather than as an absent phenotype in the phenotype list.
  evidence:
  - reference: PMID:41486137
    reference_title: "A novel pathogenic mutation in TSPEAR associated with sensorineural hearing loss: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We examined the patient for any form of ectodermal dysplasia or malformation in teeth,
      skin, hair, and nail and they were in normal figuration.
    explanation: >-
      A deliberate examination for ectodermal features that found none, which is what
      qualifies the case as nonsyndromic.
  - reference: PMID:41486137
    reference_title: "A novel pathogenic mutation in TSPEAR associated with sensorineural hearing loss: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mutation presenting solely with hearing issues and lack of any ectodermal dysplasia was
      rare based on the review of previously reported cases.
    explanation: >-
      Qualifies the finding by stating that the isolated presentation is uncommon in the
      published series.

differential_diagnoses:
- name: TSPEAR-related autosomal recessive ectodermal dysplasia 14 (ARED14/ECTD14)
  description: >-
    The established TSPEAR disease, and the entity a biallelic TSPEAR result most likely
    belongs to. It is primarily dental - conical tooth cusps and hypodontia - and it is
    supported by replicated cohorts, founder-variant epidemiology, and functional work
    placing Tspear expression in the enamel knot with a zebrafish double knockout that
    reproduces the dental phenotype.

    It is also common. The non-Finnish European carrier rate for TSPEAR loss-of-function
    alleles is about 1 in 140, which makes ARED14 one of the commonest autosomal recessive
    ectodermal dysplasias. That number belongs to this entity and not to DFNB98; it is quoted
    here so it is not mistaken for a DFNB98 prevalence.

    This is a differential rather than a subtype relationship. ECTD14 has its own OMIM entry
    and its own MONDO term, and dismech does not currently curate it.
  evidence:
  - reference: PMID:37009414
    reference_title: "Clinical, genetic, epidemiologic, evolutionary, and functional delineation of TSPEAR-related autosomal recessive ectodermal dysplasia 14."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Combining data from new and previously published individuals established that ARED14 is
      primarily characterized by dental anomalies such as conical tooth cusps and hypodontia,
      like those seen in individuals with WNT10A-related odontoonychodermal dysplasia.
    explanation: >-
      Defines the differential entity by the features that separate it from an isolated
      hearing loss.
  - reference: PMID:37009414
    reference_title: "Clinical, genetic, epidemiologic, evolutionary, and functional delineation of TSPEAR-related autosomal recessive ectodermal dysplasia 14."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Analysis of gnomAD data showed that the non-Finnish European population TSPEAR
      gene-carrier rate is ∼1/140, making it one of the commonest AREDs.
    explanation: >-
      The carrier rate, attributed to the ectodermal entity where it was derived. Graded
      COMPUTATIONAL because it is a population-database analysis rather than a clinical
      observation.

- name: TMPRSS3-, GJB2- and GJB6-related nonsyndromic hearing loss
  description: >-
    The three genes that turned up as competing explanations in every deaf individual with
    biallelic TSPEAR variants in the cohort study. They are ordinary, common causes of
    recessive nonsyndromic hearing loss, and they are the reason a TSPEAR finding cannot be
    accepted without excluding them. This is not an abstract caution: it is what the largest
    study of the question actually found.
  evidence:
  - reference: PMID:34042254
    reference_title: "TSPEAR variants are primarily associated with ectodermal dysplasia and tooth agenesis but not hearing loss: A novel cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of the individuals displaying hearing loss, all have additional variants in other
      hearing-loss-associated genes, specifically TMPRSS3, GJB2, and GJB6, that present
      competing candidates for their hearing loss phenotype.
    explanation: >-
      Names the three differential genes and reports how often they were the better
      candidate.

discussions:

- discussion_id: gap_tspear_hearing_gene_validity
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - genetic#TSPEAR
  - mechanistic_hypotheses#tspear_hair_bundle_deafness
  prompt: >-
    Do biallelic TSPEAR variants cause isolated hearing loss at all, or is DFNB98 a
    misattribution of deafness that other genes explain?
  rationale: >-
    This is the entity's central open question, not a detail within it. The founding family
    remains unexplained by anything else. Two later isolated-deafness reports exist, one with
    teeth, skin, hair and nails specifically examined and normal. Against that: a
    thirteen-person biallelic cohort in which every deaf individual had a competing variant
    in TMPRSS3, GJB2 or GJB6; a non-segregating nonsense allele; a TSPEAR variant classified
    as a VUS rather than causal in a mid-frequency hearing-loss series; and a ClinGen
    re-review in 2024 that saw the newer cases and left the classification at Disputed.

    Two readings fit all of that. Either TSPEAR causes hearing loss with low penetrance or
    only for particular alleles, and the cohort study's competing variants are coincidental
    in a genetically noisy phenotype; or TSPEAR does not cause hearing loss and the reported
    cases are unexplained deafness in people who happen to carry a common
    ectodermal-dysplasia allele - which at a carrier rate near 1 in 140 will happen by chance
    reasonably often.

    The second study has now partly been done - the 2026 cohort was ascertained on the dental
    phenotype and reports hearing status - and it came back negative. What is still missing is
    a comprehensive hearing-loss panel sequenced in every reported isolated-deafness TSPEAR
    case, which is the half that would say whether the positive reports have competing
    explanations too.
  proposed_experiments:
  - experiment_id: tspear_unselected_hearing_ascertainment
    name: Audiometry in an unselected biallelic-TSPEAR series ascertained on dental phenotype
    description: >-
      Recruit individuals with biallelic TSPEAR variants ascertained through ectodermal
      dysplasia 14 rather than through deafness, and measure hearing formally in all of them
      with pure-tone audiometry, otoacoustic emissions and auditory brainstem responses.
      Sequence a comprehensive hearing-loss panel in anyone found to be affected.
    would_support:
    - genetic#TSPEAR
    supporting_outcome:
    - >-
      Hearing loss occurs in the dental-ascertained series above population rate and without
      competing variants in established hearing-loss genes, which would establish a real if
      incompletely penetrant TSPEAR auditory phenotype and would move the gene from DISPUTED.
    refuting_outcome:
    - >-
      Hearing is normal across the dental-ascertained series, or the affected minority all
      carry competing variants, which would confirm DFNB98 as a misattribution and make the
      right curation outcome retirement of the entity rather than this contested entry.

- discussion_id: mismatch_tspear_mouse_hears_normally
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - animal_models#Tspear S475TfsX79 CRISPR mouse
  - pathophysiology#Loss of TSPEAR from the Hair Bundle Surface
  prompt: >-
    Why does a mouse carrying a TSPEAR frameshift hear normally and have normal stereocilia,
    when TSPEAR protein was localised to the hair bundle surface in that same species?
  rationale: >-
    This is a mismatch rather than a gap: the model exists, the measurements were made, and
    they disagree with the human claim. Both observations come from mouse cochlea, so this is
    not even a species argument in the usual sense - the localisation that motivates the
    mechanism and the negative functional test are in the same animal.

    Three readings are live and the published work does not choose between them. The mouse
    allele is a different frameshift from the human founding allele and may retain function
    the human allele does not. Mouse may compensate through one of the other five mammalian
    EAR-domain proteins in a way human cochlea does not. Or TSPEAR is genuinely not required
    for hearing and the localisation, while real, is not load-bearing - which is also what
    the human cohort data suggest.

    The stake is that the localisation result is the whole mechanistic content of DFNB98. If
    it does not survive, the entity has a genotype and a phenotype and nothing joining them.
  proposed_experiments:
  - experiment_id: tspear_human_allele_knockin_mouse
    name: Knock-in of the human p.V576LfsX37 allele with EAR-paralogue compensation testing
    description: >-
      Generate a mouse carrying the exact founding human TSPEAR allele rather than a
      different frameshift, phenotype hearing and stereocilia, and in parallel measure
      expression of the other mammalian EAR-domain proteins in mouse and human cochlea to
      test whether paralogue compensation could mask a phenotype in mouse.
    would_support:
    - pathophysiology#Loss of TSPEAR from the Hair Bundle Surface
    supporting_outcome:
    - >-
      The human allele produces hearing loss in mouse where S475TfsX79 does not, which would
      make the negative result allele-specific and restore the hair-bundle mechanism.
    refuting_outcome:
    - >-
      The human allele also leaves hearing intact, and paralogue expression is comparable
      across species, which would leave no mechanistic account of DFNB98 standing and would
      substantially strengthen the case for retiring the entity.

notes: >-
  Named entity check, and it is the whole problem with this entry. TSPEAR causes two things
  and one of them is not this. Autosomal recessive ectodermal dysplasia 14 is the established
  TSPEAR disease, it is primarily dental, and its literature is larger than DFNB98's. Every
  citation in this entry was checked for whether it is about the hearing phenotype. Nothing
  about tooth agenesis, conical cusps, enamel knots, hypohidrosis or sparse hair was curated
  as a DFNB98 phenotype; that material appears only in the differential diagnoses section,
  attributed to ECTD14. The ECTD14 carrier rate of about 1 in 140 is quoted there for the
  same reason - so it is not later mistaken for a DFNB98 figure.

  The one place the boundary genuinely blurs is the 2024 Chinese proband, who had congenital
  sensorineural hearing loss and also dental caries, ankyloglossia and a heart-shaped tongue.
  That case is recorded with its oral findings rather than being tidied into one entity or
  the other, because the published report does not resolve it either.

  What is not cited. A larger 2023 TSPEAR delineation study is reported at second hand to
  state that evidence is insufficient to link TSPEAR to recessive hearing loss. Only its
  abstract is retrievable and the abstract does not contain that statement, so the claim is
  not quoted anywhere in this entry. The refuting case is made instead from sources whose
  text is in the cache: the 2021 cohort study, the ClinGen assertion, and the mouse.

  Evidence grading. The secretion assay in the founding paper is graded IN_VITRO and the
  cochlear expression work in the same paper is graded MODEL_ORGANISM, because
  evidence_source describes the experiment rather than the publication it appears in. The
  gnomAD carrier-rate analysis is graded COMPUTATIONAL for the same reason.

  Why this is curated at all. A Disputed gene-disease relationship is a fact worth recording
  in a mechanism knowledge base, and recording it here is more useful than leaving MONDO's
  term uncurated for someone to take at face value. The alternative - marking the stub
  OUT_OF_SCOPE - would have deleted the dispute along with the entity.

references:
- reference: PMID:22678063
  title: Defect in the gene encoding the EAR/EPTP domain-containing protein TSPEAR causes DFNB98 profound deafness.
- reference: PMID:34042254
  title: "TSPEAR variants are primarily associated with ectodermal dysplasia and tooth agenesis but not hearing loss: A novel cohort study."
- reference: PMID:41195743
  title: "Genotypes and Phenotypes of Patients With TSPEAR-Related Disorder: Evidence of a Predominant Dental Phenotype."
- reference: PMID:40716589
  title: TSPEAR S475TfsX79 mutation does not affect auditory function, tooth morphology or hair development in mice.
- reference: PMID:41486137
  title: "A novel pathogenic mutation in TSPEAR associated with sensorineural hearing loss: a case report and review of the literature."
- reference: PMID:39720278
  title: Novel compound heterozygous variants in the TSPEAR gene causing autosomal recessive hearing loss in a Chinese family.
- reference: PMID:34795337
  title: Comprehensive molecular-genetic analysis of mid-frequency sensorineural hearing loss.
- reference: PMID:37009414
  title: "Clinical, genetic, epidemiologic, evolutionary, and functional delineation of TSPEAR-related autosomal recessive ectodermal dysplasia 14."
- reference: CGGV:assertion_f0928b06-d3bb-41fe-8222-d7f0e6c0a25a-2024-10-31T160000.000Z
  title: TSPEAR / nonsyndromic genetic hearing loss (Disputed)
📚

References & Deep Research

References

9
PMID:22678063
Defect in the gene encoding the EAR/EPTP domain-containing protein TSPEAR causes DFNB98 profound deafness.
No top-level findings curated for this source.
PMID:34042254
TSPEAR variants are primarily associated with ectodermal dysplasia and tooth agenesis but not hearing loss: A novel cohort study.
No top-level findings curated for this source.
PMID:41195743
Genotypes and Phenotypes of Patients With TSPEAR-Related Disorder: Evidence of a Predominant Dental Phenotype.
No top-level findings curated for this source.
PMID:40716589
TSPEAR S475TfsX79 mutation does not affect auditory function, tooth morphology or hair development in mice.
No top-level findings curated for this source.
PMID:41486137
A novel pathogenic mutation in TSPEAR associated with sensorineural hearing loss: a case report and review of the literature.
No top-level findings curated for this source.
PMID:39720278
Novel compound heterozygous variants in the TSPEAR gene causing autosomal recessive hearing loss in a Chinese family.
No top-level findings curated for this source.
PMID:34795337
Comprehensive molecular-genetic analysis of mid-frequency sensorineural hearing loss.
No top-level findings curated for this source.
PMID:37009414
Clinical, genetic, epidemiologic, evolutionary, and functional delineation of TSPEAR-related autosomal recessive ectodermal dysplasia 14.
No top-level findings curated for this source.
CGGV:assertion_f0928b06-d3bb-41fe-8222-d7f0e6c0a25a-2024-10-31T160000.000Z
TSPEAR / nonsyndromic genetic hearing loss (Disputed)
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 18 citations 2026-08-28T19:17:27.452485

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 98 (DFNB98, TSPEAR-related)
  • MONDO ID: MONDO:0013929 (if available)
  • Category: Genetic

Research Objectives

Please provide a comprehensive research report on Autosomal Recessive Nonsyndromic Hearing Loss 98 (DFNB98, TSPEAR-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

  • 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 98 (DFNB98; historically TSPEAR-related)

Executive assessment

The central knowledge-base caveat is that DFNB98 should not currently be represented as a firmly established TSPEAR disorder. It is a historical/provisional autosomal-recessive nonsyndromic sensorineural hearing-loss entity based initially on one consanguineous Iranian family. Larger subsequent cohorts and functional studies support TSPEAR-related autosomal recessive ectodermal dysplasia 14 (ARED14/ECTD14)—especially a dental phenotype—much more strongly than isolated deafness. Bowles et al. found that all three hearing-impaired members of a 13-person biallelic-TSPEAR cohort had competing variants in established hearing-loss genes; Jackson et al. subsequently concluded that evidence was insufficient to link TSPEAR to autosomal-recessive hearing loss. Therefore, a biallelic TSPEAR result alone should not be considered a definitive molecular diagnosis of DFNB98. (bowles2021tspearvariantsare pages 1-2, jackson2023clinicalgeneticepidemiologic pages 5-8)

Evidence/date Design/sample Key finding Implication for gene-disease validity
Delmaghani et al., 2012 Original discovery report; 3 consanguineous Iranian siblings with profound SNHL; homozygous TSPEAR c.1726_1728delGTCinsTT, p.Val576Leufs*38 identified by WES Established the historical DFNB98 claim by linking biallelic TSPEAR to isolated profound hearing loss in one family; no alternative hearing-loss variants were reported in that initial study summary (bowles2021tspearvariantsare pages 2-4) Supportive but low-level evidence for DFNB98 because it rests on a single family and has not been robustly replicated without confounding (bowles2021tspearvariantsare pages 2-4)
Bowles et al., 2021 Cohort study of 13 newly reported individuals with biallelic TSPEAR variants 11/13 had tooth agenesis or ectodermal dysplasia; 3/13 had hearing loss, but all 3 also carried variants in other hearing-loss genes (TMPRSS3, GJB2, GJB6). Authors concluded the evidence “creates significant doubt” that TSPEAR is a monogenic hearing-loss gene (bowles2021tspearvariantsare pages 1-2) Major evidence against established DFNB98 validity; strongly shifts interpretation toward TSPEAR-related ectodermal/dental disease rather than isolated ARNSHL (bowles2021tspearvariantsare pages 1-2, bowles2021tspearvariantsare pages 10-11)
Jackson et al., 2023 Aggregate human + mechanistic study; 30 affected individuals analyzed across new and published cases; includes zebrafish double-knockout and mouse scRNA-seq Human phenotype was 100% dental anomalies; common findings included conical teeth (77%), hypodontia (50%), oligodontia (37%); none of their cohort had SNHL; authors state there is “insufficient evidence to link TSPEAR variants as a cause of AR hearing loss.” Functional work supported ARED14 biology (enamel-knot expression, ECM/WNT-related dental model), not an auditory mechanism (jackson2023clinicalgeneticepidemiologic pages 5-8, jackson2023clinicalgeneticepidemiologic pages 1-2, jackson2023clinicalgeneticepidemiologic pages 11-13, jackson2023clinicalgeneticepidemiologic pages 13-14, jackson2023clinicalgeneticepidemiologic pages 14-15) Strongest current evidence hierarchy item: supports TSPEAR-related autosomal recessive ectodermal dysplasia 14 (ARED14) as established; DFNB98 remains disputed/insufficient (jackson2023clinicalgeneticepidemiologic pages 5-8, jackson2023clinicalgeneticepidemiologic pages 1-2, jackson2023clinicalgeneticepidemiologic pages 11-13)
Shi et al., 2024 Small supportive case/family report from China; compound heterozygous TSPEAR variants reported with AR hearing loss Adds limited supportive case-level evidence for a hearing-loss association, but on its own does not overcome prior contradictory cohort data or the lack of replicated auditory functional evidence; details were not fully available in retrieved text (mentioned as unobtainable paper in search results) Weak supportive evidence only; does not resolve disputed DFNB98 validity
Ahmadkhani et al., 2026 Single case report; 6-year-old Iranian girl, consanguineous family; profound bilateral SNHL; homozygous TSPEAR c.668C>T, p.Ser223Leu by WES Reported isolated severe/profound bilateral SNHL with normal teeth/skin/hair/nails and absent ABR response; authors note isolated hearing presentation is rare (ahmadkhani2026anovelpathogenic pages 1-2) Additional anecdotal support for possible TSPEAR-related hearing loss, but still insufficient to overturn Bowles/Jackson or establish DFNB98 definitively (ahmadkhani2026anovelpathogenic pages 1-2)
Current synthesis Evidence hierarchy across original family reports, larger cohorts, and mechanistic studies Hearing-loss evidence remains sparse, partly confounded, and mechanistically unvalidated for the ear; by contrast, dental/ectodermal evidence is replicated across cohorts and supported by functional data (bowles2021tspearvariantsare pages 1-2, jackson2023clinicalgeneticepidemiologic pages 5-8, jackson2023clinicalgeneticepidemiologic pages 11-13, peled2016mutationsintspear pages 1-2) Current conclusion: DFNB98 (TSPEAR-related ARNSHL) = disputed / insufficient evidence; TSPEAR-related ARED14 = established gene-disease relationship (bowles2021tspearvariantsare pages 1-2, jackson2023clinicalgeneticepidemiologic pages 5-8, jackson2023clinicalgeneticepidemiologic pages 1-2)

Table: This table ranks the main published evidence bearing on the TSPEAR–DFNB98 relationship. It is useful because it distinguishes the early family-based hearing-loss claim from later larger cohort and functional studies that instead support TSPEAR-related ARED14.

1. Disease information

Definition and status

DFNB98 denotes a proposed form of autosomal-recessive nonsyndromic sensorineural hearing loss (ARNSHL) historically attributed to biallelic variants in TSPEAR. The original 2012 report described three consanguineous Iranian siblings with profound SNHL and homozygous c.1726_1728delGTCinsTT, p.(Val576LeufsTer38). No alternative hearing-loss variant was reported at that time. Later observations of hearing-normal individuals with the same genotype materially weakened the claimed association. (bowles2021tspearvariantsare pages 2-4)

The more secure TSPEAR disease association is ectodermal dysplasia 14, hair/tooth type, with or without hypohidrosis. In the 2023 aggregate analysis of 30 affected people, every individual had dental anomalies, whereas none of the authors’ newly assembled cohort had SNHL. (jackson2023clinicalgeneticepidemiologic pages 5-8)

Identifiers and synonyms

  • MONDO: MONDO:0013929, as supplied in the query; retain with a “disputed/provisional gene association” qualifier.
  • OMIM disease: Deafness, autosomal recessive 98/DFNB98 is historically catalogued separately from ECTD14, OMIM 618180. TSPEAR itself is OMIM 612920. The retrieved literature explicitly confirms the latter two numbers. (ahmadkhani2026anovelpathogenic pages 1-2)
  • Gene: TSPEAR, thrombospondin-type laminin G domain and epilepsy-associated repeats; chromosome 21q22 region. Common transcript used in recent reports: NM_144991.3. (ahmadkhani2026anovelpathogenic pages 1-2)
  • Synonyms: DFNB98; deafness, autosomal recessive 98; TSPEAR-related nonsyndromic hearing loss; TSPEAR-associated ARNSHL; historical “EAR/EPTP-domain-containing protein–related deafness.”
  • ICD-10-CM: no DFNB98-specific code; use phenotype-level codes such as H90.3 (sensorineural hearing loss, bilateral) where clinically appropriate.
  • ICD-11/MeSH/Orphanet: no confidently verified disease-specific mapping was found in the retrieved evidence; use broader hereditary or sensorineural hearing-loss concepts rather than asserting an exact code.

The evidence is aggregated disease-level literature, not an EHR-derived patient dataset, although the foundational evidence consists of individual pedigrees and case reports.

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

Proposed genetic cause

The proposed cause is germline biallelic TSPEAR variation, inherited recessively. Reported candidate alleles include truncating, frameshift, splice-predicted, missense, and in-frame deletion variants. However, pathogenicity for ECTD14 must not be conflated with pathogenicity for hearing loss: the phenotype-specific TSPEAR–DFNB98 relationship remains unproven. In ARED14, 27 reported disease-associated alleles comprised 11 predicted loss-of-function variants (41%) and 16 missense/in-frame variants (59%). Four recurrent founder alleles were p.Arg197Ter, p.Val576LeufsTer38, p.Ser585Ile, and p.Asp639Asn. (jackson2023clinicalgeneticepidemiologic pages 5-8, jackson2023clinicalgeneticepidemiologic pages 8-11)

Genetic risk factors and confounding

  • Consanguinity/family history increases the probability of homozygosity for rare recessive alleles but is not specific to TSPEAR.
  • Variants in nearby TMPRSS3 can be coinherited and are a particularly important alternative explanation. Bowles et al.’s hearing-loss cases also had variants involving GJB2/GJB6. (bowles2021tspearvariantsare pages 1-2, bowles2021tspearvariantsare pages 2-4)
  • The original p.Val576LeufsTer38 allele has been observed in hearing-normal individuals, arguing against simple complete penetrance for deafness. (bowles2021tspearvariantsare pages 2-4)
  • No validated modifier gene, protective TSPEAR allele, anticipation, or germline-mosaicism series has been reported.

Environmental risks and protective factors

DFNB98 is proposed as genetic, so environmental exposure is not considered its primary cause. Nevertheless, congenital CMV, rubella, meningitis, prematurity, noise, and ototoxic medication are alternative or additive causes of SNHL and must be evaluated rather than attributing hearing loss automatically to TSPEAR. Bowles et al. specifically emphasized prenatal/environmental causes such as CMV and rubella. (bowles2021tspearvariantsare pages 2-4)

No disease-specific diet, lifestyle factor, medication, vaccine, or protective variant has been demonstrated. Avoiding preventable noise and ototoxic exposure protects residual hearing generally but does not prevent a congenital Mendelian defect. No TSPEAR-specific gene–environment interaction is established.

3. Phenotypes

Proposed DFNB98 phenotype

The small number of reported patients suggests:

  • Bilateral sensorineural hearing loss — HPO HP:0000407 and HP:0008619.
  • Congenital/prelingual onset — HP:0008527 or HP:0012715, where documentation supports it.
  • Severe-to-profound hearing impairment — HP:0012714/HP:0012713, subject to local ontology-version verification.
  • Speech and language impairment secondary to deafness — HP:0000750 or more specific speech-development terms.
  • Occasionally reported enlarged vestibular aqueduct in two siblings with compound-heterozygous TSPEAR candidates, although this is not established as a TSPEAR feature. (bowles2021tspearvariantsare pages 1-2)

In the 2026 case report, a six-year-old girl had prelingual bilateral severe/profound SNHL, flat audiograms, absent bilateral ABR responses, speech disorder, and impaired school performance, with normal teeth, hair, skin, and nails. This is only single-case evidence. (ahmadkhani2026anovelpathogenic pages 1-2)

Frequency, severity, and natural history

Reliable frequencies cannot be estimated for DFNB98. The original family had three affected siblings; Bowles et al. identified hearing loss in 3/13 newly reported biallelic-TSPEAR individuals, but every hearing-loss case had a competing molecular explanation. Jackson et al.’s 30-person ARED14 synthesis found dental anomalies in 100%, conical teeth in 77%, hypodontia in 50%, oligodontia in 37%, sparse hair in 47%, hypohidrosis in 23%, and hyperhidrosis in 10%; these are ECTD14 statistics and must not be imported as DFNB98 frequencies. (bowles2021tspearvariantsare pages 1-2, jackson2023clinicalgeneticepidemiologic pages 5-8)

Onset appears congenital or prelingual and the condition is lifelong. Stable versus progressive course has not been established. No episodic or remitting pattern is documented. Quality-of-life effects are those expected from severe childhood deafness—communication, language acquisition, education, and social participation—but no DFNB98-specific EQ-5D, SF-36, PROMIS, or hearing-related QoL study exists.

4. Genetic and molecular information

Gene and protein

TSPEAR encodes a protein containing an N-terminal laminin-G-like domain and multiple EAR repeats. AlphaFold modeling predicts that the EAR domains form a conserved β-propeller, potentially functioning as a ligand-binding surface. Most ARED14-associated missense variants are predicted to destabilize this structure through steric clashes or loss of polar/disulfide interactions. (jackson2023clinicalgeneticepidemiologic pages 5-8)

Notable variants

  • NM_144991.x:c.1726_1728delGTCinsTT, p.(Val576LeufsTer38): original DFNB98 allele; predicted loss of function, but also reported in hearing-normal biallelic individuals, making hearing-specific classification uncertain. (bowles2021tspearvariantsare pages 2-4)
  • c.1566G>A, p.(Pro522=) plus c.1676_1677delAT, p.(Tyr559CysfsTer134): reported in siblings with bilateral SNHL and enlarged vestibular aqueduct; replication and exclusion of all alternatives remain limited. (bowles2021tspearvariantsare pages 1-2)
  • NM_144991.3:c.668C>T, p.(Ser223Leu): homozygous in a 2026 isolated-SNHL case; called pathogenic by the authors, but case-level evidence does not establish phenotype-specific causality. (ahmadkhani2026anovelpathogenic pages 1-2)
  • p.Asp639Asn: common ARED14 founder/hypomorphic candidate. Frequency was 0.0038 in the 100,000 Genomes Project and 0.0035 in non-Finnish Europeans in gnomAD v2.1.1; 449 heterozygotes were identified among 59,464 100KGP genomes. These frequencies pertain to ectodermal-dysplasia interpretation, not proven deafness risk. (jackson2023clinicalgeneticepidemiologic pages 5-8, jackson2023clinicalgeneticepidemiologic pages 11-13)

All reported constitutional variants are germline, not somatic. No recurrent pathogenic chromosomal rearrangement, aneuploidy, repeat expansion, mitochondrial defect, or disease-specific epigenetic signature has been established. No validated modifier genes are known.

Variant-interpretation recommendation

A laboratory may classify an allele as pathogenic for TSPEAR-related ECTD14 while the gene–phenotype relationship for DFNB98 remains disputed. Accordingly, hearing-loss reports should distinguish:

  1. allele-level classification under ACMG/AMP;
  2. phase and recessive genotype;
  3. phenotype-level gene validity;
  4. competing variants in established deafness genes;
  5. ectodermal/dental examination and radiography.

Computational structural destabilization is supporting evidence only. A 2023 deafness-proteome study noted that approximately 70% of 128,167 missense entries in the Deafness Variation Database were VUS, illustrating why modeling alone cannot establish clinical causality.

5. Environmental information

No toxin, radiation, pollutant, occupation, smoking pattern, diet, alcohol exposure, exercise pattern, or infectious agent is known to cause “TSPEAR-related DFNB98.” Environmental and infectious factors instead belong in the differential diagnosis and may worsen residual auditory function. Congenital CMV and rubella are particularly relevant alternatives in childhood SNHL. (bowles2021tspearvariantsare pages 2-4)

6. Mechanism and pathophysiology

What is demonstrated

Ectodermal mechanism: In keratinocytes, TSPEAR knockdown altered Notch-regulated genes and reduced a Notch reporter signal; NOTCH1 protein was reduced in patient scalp, while silencing in mouse hair-follicle organ culture induced epithelial-cell apoptosis and reduced hair-bulb diameter. This supports hair/tooth morphogenesis, not an auditory causal chain. Direct abstract wording states that TSPEAR silencing was “associated with decreased Notch signaling.” (peled2016mutationsintspear pages 1-2)

Jackson et al. proposed a broader extracellular-matrix model. TSPEAR may bind/sequester morphogens through a laminin-G/heparin-binding surface, coordinating spatial and temporal WNT, FGF, BMP, and NF-κB-related signaling in ectodermal placodes. Mouse single-cell RNA-seq localized Tspear predominantly to the enamel knot and anagen hair-follicle keratinocytes. (jackson2023clinicalgeneticepidemiologic pages 11-13)

What remains hypothetical for hearing

The proposed auditory chain is:

biallelic TSPEAR loss → altered ECM/Notch-dependent developmental signaling in cochlear sensory/supporting cells → abnormal hair-cell fate or maintenance → bilateral SNHL.

Every arrow in this hearing-specific chain remains inadequately validated. Earlier mouse immunohistochemistry suggested protein near the base of inner-ear hair cells, but public cochlear RNA-seq showed extremely low or absent Tspear transcript, and no study directly demonstrated hair-cell structural or physiological dysfunction after TSPEAR loss. (bowles2021tspearvariantsare pages 2-4)

Suggested annotations, with the caveat that several describe established ectodermal rather than proven auditory biology:

  • GO biological process: extracellular-matrix organization; regulation of Notch signaling; canonical Wnt signaling; epithelial morphogenesis; odontogenesis; hair-follicle development; sensory-organ development; auditory-receptor-cell development.
  • GO cellular component: extracellular region/extracellular matrix; protein-containing extracellular matrix; putative cell-surface/basal hair-cell localization remains uncertain.
  • Cell Ontology: keratinocyte; hair-follicle epithelial cell; enamel-knot epithelial cell; ameloblast; cochlear hair cell and supporting cell only as proposed auditory targets.
  • Upstream: TSPEAR structural loss or destabilization and altered ECM morphogen handling.
  • Downstream: altered developmental transcription, apoptosis, enamel-matrix/mineralization defects; cochlear dysfunction remains hypothetical.

No replicated disease-specific human inner-ear transcriptomic, proteomic, metabolomic, lipidomic, methylomic, spatial-transcriptomic, iPSC, organoid, or CRISPR-screen signature is available.

7. Anatomical structures affected

For the proposed DFNB98 phenotype, the principal organ is the inner ear, especially the cochlea and organ of Corti; laterality is characteristically bilateral in reported cases. Suggested mappings are UBERON:0001844 (cochlea), UBERON:0002227 (organ of Corti; verify release), and broader inner-ear/auditory-system terms. Candidate cells are inner and outer hair cells and cochlear supporting cells, but direct TSPEAR pathology in these populations is not established.

For established ECTD14, the affected structures are teeth/dental epithelium, hair follicles, skin, nails, and sweat glands. The 2023 evidence localizes expression particularly to enamel-knot cells and anagen hair-follicle keratinocytes. (jackson2023clinicalgeneticepidemiologic pages 11-13)

8. Temporal development

Reported hearing loss is congenital or recognized during early childhood, often prelingually. It is chronic and lifelong; progression rate and age-dependent penetrance are unknown. There are no recognized stages, attacks, remission, or spontaneous recovery. The critical intervention period is early childhood, because delayed auditory access can impair language acquisition and education, as illustrated by speech and school difficulties in the six-year-old case. (ahmadkhani2026anovelpathogenic pages 1-2)

9. Inheritance and population

The proposed inheritance pattern is autosomal recessive. If a specific biallelic genotype is eventually shown to be causal and both parents are heterozygous, each pregnancy has the conventional 25% affected, 50% carrier, and 25% non-carrier probability. Because hearing penetrance is uncertain, “affected” should not be predicted solely from a TSPEAR genotype without qualification.

No reliable DFNB98 prevalence, incidence, carrier frequency, sex ratio, or geographic distribution exists. Reports include Iranian/Middle Eastern and more recent Chinese cases, but ascertainment is too sparse for population inference. The 2023 estimate of an approximately 1/140 non-Finnish-European TSPEAR deleterious-allele carrier rate and ancestry-specific range from 1/287 in Finns to 1/43 in Ashkenazi Jewish individuals concerns ARED14 alleles, not validated DFNB98 carriers. (jackson2023clinicalgeneticepidemiologic pages 1-2, jackson2023clinicalgeneticepidemiologic pages 11-13)

Founder effects are documented for ARED14-associated p.Arg197Ter, p.Ser585Ile, p.Asp639Asn, and p.Val576LeufsTer38. Estimated most-recent-common-ancestor ages were approximately 12,000–20,211 years. This is evolutionary/population evidence, not proof of hearing pathogenicity. (jackson2023clinicalgeneticepidemiologic pages 8-11)

No sex bias, anticipation, or established germline mosaicism has been reported. Consanguinity contributed to ascertainment of the original family and the 2026 case. (bowles2021tspearvariantsare pages 2-4, ahmadkhani2026anovelpathogenic pages 1-2)

10. Diagnostics

Clinical evaluation

  1. Confirm hearing status with age-appropriate pure-tone/behavioral audiometry, tympanometry, otoacoustic emissions, and ABR when required.
  2. Determine sensorineural versus conductive/mixed loss, severity, configuration, symmetry, age at onset, and progression.
  3. Review newborn-screen results, congenital infection, prematurity, meningitis, trauma, noise, and ototoxic exposures.
  4. Perform otoscopy and consider temporal-bone MRI/CT according to standard pediatric-SNHL indications; enlarged vestibular aqueduct is not TSPEAR-specific.
  5. Examine teeth, hair, nails, skin, and sweating; obtain panoramic dental radiography when tooth agenesis is possible.

The 2026 case illustrates flat bilateral pure-tone thresholds and absent ABR responses, but these findings are not molecularly specific. (ahmadkhani2026anovelpathogenic pages 1-2)

Genetic testing

Preferred: a comprehensive hereditary-hearing-loss panel, exome, or genome with SNV/indel, exon-level and larger CNV detection, mitochondrial analysis where indicated, and periodic reanalysis. CNVs are important generally: in one 686-person NSHL cohort, 15.2% carried at least one CNV in a deafness gene and CNVs contributed to 18.7% of solved cases. TSPEAR should not be tested or interpreted in isolation.

Trio WES/WGS can establish phase and identify alternate etiologies. Bowles et al. used exome or panel testing and found competing TMPRSS3, GJB2, and GJB6 findings in every TSPEAR-biallelic person with hearing loss. (bowles2021tspearvariantsare pages 1-2)

CMA, karyotype, FISH, repeat-expansion testing, biopsy, proteomics, metabolomics, and liquid biopsy are not routine tests for isolated DFNB98. RNA studies may help resolve a suspected splice allele but are not validated diagnostics.

Differential diagnosis

Priority genetic differentials include GJB2/GJB6, STRC, OTOF, SLC26A4, TMPRSS3, OTOA, TMC1, MYO15A, and many other ARNSHL genes. The nearby TMPRSS3 locus deserves special attention. Environmental differentials include congenital CMV/rubella, meningitis, ototoxicity, and noise. If dental/hair/sweat abnormalities are present, evaluate ECTD14 and other ectodermal-dysplasia genes, particularly WNT10A, EDA, EDAR, and EDARADD. (bowles2021tspearvariantsare pages 2-4, jackson2023clinicalgeneticepidemiologic pages 5-8)

Screening

Universal newborn physiologic hearing screening remains appropriate regardless of genotype. At-risk relatives should receive audiology rather than genotype-only prediction. Once a credible familial diagnosis is established, cascade testing can identify carriers, but counseling must disclose disputed TSPEAR hearing validity.

11. Outcome and prognosis

No disease-specific mortality or reduced life expectancy is known; survival should be normal for isolated SNHL. Morbidity consists principally of persistent auditory disability and, without timely communication access, secondary speech/language, educational, and psychosocial consequences. No five- or ten-year survival statistics, prognostic biomarkers, validated progression predictors, or DFNB98-specific QoL scores exist.

Recovery of congenital severe/profound SNHL is not expected spontaneously. Functional outcome depends more on severity, age at intervention, communication access, rehabilitation, anatomy, and coexisting conditions than on an unvalidated TSPEAR genotype.

12. Treatment

There is no TSPEAR-specific approved pharmacotherapy, gene therapy, CRISPR therapy, RNA therapy, cell therapy, or immunotherapy, and the ClinicalTrials.gov search retrieved no relevant TSPEAR/DFNB98 trial.

Management follows standard SNHL practice:

  • hearing aids for aidable residual hearing;
  • cochlear implantation for appropriately evaluated severe-to-profound loss with inadequate hearing-aid benefit;
  • speech-language/auditory rehabilitation;
  • sign-language and/or other communication support according to family preference;
  • educational accommodations and psychosocial support;
  • treatment of middle-ear disease and protection from avoidable ototoxic/noise injury.

Suggested NCIt intervention concepts include Hearing Aid, Cochlear Implantation, Audiologic Rehabilitation, Speech Therapy, and Genetic Counseling; exact NCIt codes should be verified against the target terminology release. No genotype-specific response rate or adverse-event dataset exists.

13. Prevention

  • Primary: the congenital genotype cannot be prevented after conception. Carrier/couple counseling, reproductive options, and avoidance of preventable auditory injury are relevant. Vaccination and infection prevention reduce non-genetic congenital/acquired deafness but are not TSPEAR-specific.
  • Secondary: universal newborn hearing screening, rapid diagnostic audiology, and early communication intervention.
  • Tertiary: hearing technology, rehabilitation, educational support, and monitoring residual hearing.
  • Reproductive genetics: if a familial causal genotype is well established, prenatal diagnosis or PGT-M may be technically possible. For TSPEAR-only hearing-risk prediction, uncertainty about gene validity and penetrance must be explicit; decisions should not rest on the historical DFNB98 label alone.

14. Other species and natural disease

No naturally occurring veterinary TSPEAR deafness syndrome, breed predisposition, zoonosis, or cross-species transmission is established. TSPEAR is conserved across vertebrates. Its inferred Drosophila ortholog Closca participates in ECM-dependent sequestration of developmental morphogens; this comparative relationship supports an ectodermal-development function rather than proving auditory disease. (jackson2023clinicalgeneticepidemiologic pages 11-13)

Suggested taxa are Homo sapiens—NCBI Taxon 9606, Mus musculus—10090, Danio rerio—7955, and Drosophila melanogaster—7227. The condition is inherited, not infectious, and has no zoonotic potential.

15. Model organisms

Cellular and organ-culture systems

Human keratinocyte knockdown, patient scalp tissue, and mouse hair-follicle organ culture support reduced Notch signaling and increased follicular epithelial apoptosis. These systems model ECTD14 hair/skin biology and do not reproduce hearing loss. (peled2016mutationsintspear pages 1-2)

Mouse data

Mouse single-cell RNA-seq showed restricted Tspear expression in enamel-knot clusters and anagen hair-follicle keratinocytes. Earlier cochlear immunohistochemistry suggested basal hair-cell localization, but cochlear RNA-seq showed little or no transcript. No convincing Tspear-null mouse auditory phenotype was available in the core evidence. (bowles2021tspearvariantsare pages 2-4, jackson2023clinicalgeneticepidemiologic pages 11-13)

Zebrafish knockout

Because zebrafish have tspeara and tspearb, Jackson et al. generated a CRISPR double knockout. Mutants were viable, developed thin, aberrantly mineralized and missing teeth, lacked normal fin branching, and had severely reduced fin regeneration. Tooth/bone expression changes included downregulation of fgf1b, enam, scpp5, scpp7, mustn1a, and kcnk5a, with upregulation of dlx2b and cdkn1a. The model recapitulates human ARED14 dental biology and suggests interaction with WNT10A, but no auditory phenotype was demonstrated. (jackson2023clinicalgeneticepidemiologic pages 13-14, jackson2023clinicalgeneticepidemiologic pages 11-13)

Recent developments and authoritative interpretation

  • 2023: Jackson et al. supplied the strongest recent synthesis, integrating 30 human cases, 100KGP/gnomAD population data, AlphaFold, mouse single-cell expression, and zebrafish knockout experiments. Their direct conclusion was: “At present, there is insufficient evidence to link TSPEAR variants as a cause of AR hearing loss.” The same work robustly established ARED14 and quantified its predominantly dental phenotype. Published April 13, 2023; DOI: https://doi.org/10.1016/j.xhgg.2023.100186. (jackson2023clinicalgeneticepidemiologic pages 1-2, jackson2023clinicalgeneticepidemiologic pages 5-8)
  • 2024: Shi et al. reported a Chinese family with novel compound-heterozygous TSPEAR variants and AR hearing loss (Pediatric Investigation 8:313–315; DOI: https://doi.org/10.1002/ped4.12454). This provides limited family-level support but does not overcome contradictory cohorts or supply a validated auditory mechanism.
  • 2026: Ahmadkhani et al. reported one additional Iranian child with homozygous p.Ser223Leu and isolated profound SNHL. The authors themselves characterized an isolated hearing presentation as rare. DOI: https://doi.org/10.1186/s13256-025-05761-7. (ahmadkhani2026anovelpathogenic pages 1-2)

Knowledge-base recommendation

Represent MONDO:0013929/DFNB98 as a historical or provisional disease entity with disputed TSPEAR causality, not as an established molecular diagnosis. Store reported variants and hearing phenotypes as case-level evidence, with explicit conflicting evidence and alternative-gene review. Represent TSPEAR–ECTD14/ARED14 (OMIM 618180) separately as the established association. Key unavailable fields—true prevalence, penetrance, progression, validated cochlear mechanism, biomarkers, omics signatures, prognostic factors, and targeted therapies—should be recorded as unknown/not established, not inferred from general hereditary hearing loss.

References

  1. (bowles2021tspearvariantsare pages 1-2): Bradley Bowles, Alejandro Ferrer, Carla J. Nishimura, Filippo Pinto e Vairo, Tristan Rey, Bruno Leheup, Jennifer Sullivan, Kelly Schoch, Nicholas Stong, Emanuele Agolini, Dario Cocciadiferro, Abigail Williams, Alex Cummings, Sara Loddo, Silvia Genovese, Chelsea Roadhouse, Kirsty McWalter, Ingrid M. Wentzensen, Chumei Li, Dusica Babovic‐Vuksanovic, Brendan C. Lanpher, Maria Lisa Dentici, Arun Ankala, J. Austin Hamm, Bruno Dallapiccola, Francesca Clementina Radio, Vandana Shashi, Benedicte Gérard, Agnes Bloch‐Zupan, Richard J. Smith, and Eric W. Klee. Tspear variants are primarily associated with ectodermal dysplasia and tooth agenesis but not hearing loss: a novel cohort study. American Journal of Medical Genetics. Part a, 185:2417-2433, May 2021. URL: https://doi.org/10.1002/ajmg.a.62347, doi:10.1002/ajmg.a.62347. This article has 27 citations and is from a peer-reviewed journal.

  2. (jackson2023clinicalgeneticepidemiologic pages 5-8): Adam Jackson, Sheng-Jia Lin, Elizabeth A. Jones, Kate E. Chandler, David Orr, Celia Moss, Zahra Haider, Gavin Ryan, Simon Holden, Mike Harrison, Nigel Burrows, Wendy D. Jones, Mary Loveless, Cassidy Petree, Helen Stewart, Karen Low, Deirdre Donnelly, Simon Lovell, Konstantina Drosou, J.C. Ambrose, P. Arumugam, R. Bevers, M. Bleda, F. Boardman-Pretty, C.R. Boustred, H. Brittain, M.A. Brown, M.J. Caulfield, G.C. Chan, A. Giess, J.N. Griffin, A. Hamblin, S. Henderson, T.J.P. Hubbard, R. Jackson, L.J. Jones, D. Kasperaviciute, M. Kayikci, A. Kousathanas, L. Lahnstein, A. Lakey, S.E.A. Leigh, I.U.S. Leong, F.J. Lopez, F. Maleady-Crowe, M. McEntagart, F. Minneci, J. Mitchell, L. Moutsianas, M. Mueller, N. Murugaesu, A.C. Need, P. O‘Donovan, C.A. Odhams, C. Patch, D. Perez-Gil, M.B. Pereira, J. Pullinger, T. Rahim, A. Rendon, T. Rogers, K. Savage, K. Sawant, R.H. Scott, A. Siddiq, A. Sieghart, S.C. Smith, A. Sosinsky, A. Stuckey, M. Tanguy, A.L. Taylor Tavares, E.R.A. Thomas, S.R. Thompson, A. Tucci, M.J. Welland, E. Williams, K. Witkowska, S.M. Wood, M. Zarowiecki, Olaf Riess, Tobias B. Haack, Holm Graessner, Birte Zurek, Kornelia Ellwanger, Stephan Ossowski, German Demidov, Marc Sturm, Julia M. Schulze-Hentrich, Rebecca Schüle, Christoph Kessler, Melanie Wayand, Matthis Synofzik, Carlo Wilke, Andreas Traschütz, Ludger Schöls, Holger Hengel, Peter Heutink, Han Brunner, Hans Scheffer, Nicoline Hoogerbrugge, Alexander Hoischen, Peter A.C. ’t Hoen, Lisenka E.L.M. Vissers, Christian Gilissen, Wouter Steyaert, Karolis Sablauskas, Richarda M. de Voer, Erik-Jan Kamsteeg, Bart van de Warrenburg, Nienke van Os, Iris te Paske, Erik Janssen, Elke de Boer, Marloes Steehouwer, Burcu Yaldiz, Tjitske Kleefstra, Anthony J. Brookes, Colin Veal, Spencer Gibson, Marc Wadsley, Mehdi Mehtarizadeh, Umar Riaz, Greg Warren, Farid Yavari Dizjikan, Thomas Shorter, Ana Töpf, Volker Straub, Chiara Marini Bettolo, Sabine Specht, Jill Clayton-Smith, Siddharth Banka, Elizabeth Alexander, Adam Jackson, Laurence Faivre, Christel Thauvin, Antonio Vitobello, Anne-Sophie Denommé-Pichon, Yannis Duffourd, Emilie Tisserant, Ange-Line Bruel, Christine Peyron, Aurore Pélissier, Sergi Beltran, Ivo Glynne Gut, Steven Laurie, Davide Piscia, Leslie Matalonga, Anastasios Papakonstantinou, Gemma Bullich, Alberto Corvo, Carles Garcia, Marcos Fernandez-Callejo, Carles Hernández, Daniel Picó, Ida Paramonov, Hanns Lochmüller, Gulcin Gumus, Virginie Bros-Facer, Ana Rath, Marc Hanauer, Annie Olry, David Lagorce, Svitlana Havrylenko, Katia Izem, Fanny Rigour, Giovanni Stevanin, Alexandra Durr, Claire-Sophie Davoine, Léna Guillot-Noel, Anna Heinzmann, Giulia Coarelli, Gisèle Bonne, Teresinha Evangelista, Valérie Allamand, Isabelle Nelson, Rabah Ben Yaou, Corinne Metay, Bruno Eymard, Enzo Cohen, Antonio Atalaia, Tanya Stojkovic, Milan Macek, Marek Turnovec, Dana Thomasová, Radka Pourová Kremliková, Vera Franková, Markéta Havlovicová, Vlastimil Kremlik, Helen Parkinson, Thomas Keane, Dylan Spalding, Alexander Senf, Peter Robinson, Daniel Danis, Glenn Robert, Alessia Costa, Christine Patch, Mike Hanna, Henry Houlden, Mary Reilly, Jana Vandrovcova, Francesco Muntoni, Irina Zaharieva, Anna Sarkozy, Vincent Timmerman, Jonathan Baets, Liedewei Van de Vondel, Danique Beijer, Peter de Jonghe, Vincenzo Nigro, Sandro Banfi, Annalaura Torella, Francesco Musacchia, Giulio Piluso, Alessandra Ferlini, Rita Selvatici, Rachele Rossi, Marcella Neri, Stefan Aretz, Isabel Spier, Anna Katharina Sommer, Sophia Peters, Carla Oliveira, Jose Garcia Pelaez, Ana Rita Matos, Celina São José, Marta Ferreira, Irene Gullo, Susana Fernandes, Luzia Garrido, Pedro Ferreira, Fátima Carneiro, Morris A. Swertz, Lennart Johansson, Joeri K. van der Velde, Gerben van der Vries, Pieter B. Neerincx, Dieuwke Roelofs-Prins, Sebastian Köhler, Alison Metcalfe, Alain Verloes, Séverine Drunat, Caroline Rooryck, Aurelien Trimouille, Raffaele Castello, Manuela Morleo, Michele Pinelli, Alessandra Varavallo, Manuel Posada De la Paz, Eva Bermejo Sánchez, Estrella López Martín, Beatriz Martínez Delgado, F. Javier Alonso García de la Rosa, Andrea Ciolfi, Bruno Dallapiccola, Simone Pizzi, Francesca Clementina Radio, Marco Tartaglia, Alessandra Renieri, Elisa Benetti, Peter Balicza, Maria Judit Molnar, Ales Maver, Borut Peterlin, Alexander Münchau, Katja Lohmann, Rebecca Herzog, Martje Pauly, Alfons Macaya, Anna Marcé-Grau, Andres Nascimiento Osorio, Daniel Natera de Benito, Hanns Lochmüller, Rachel Thompson, Kiran Polavarapu, David Beeson, Judith Cossins, Pedro M. Rodriguez Cruz, Peter Hackman, Mridul Johari, Marco Savarese, Bjarne Udd, Rita Horvath, Gabriel Capella, Laura Valle, Elke Holinski-Feder, Andreas Laner, Verena Steinke-Lange, Evelin Schröck, Andreas Rump, Gaurav K. Varshney, and Siddharth Banka. Clinical, genetic, epidemiologic, evolutionary, and functional delineation of tspear-related autosomal recessive ectodermal dysplasia 14. Apr 2023. URL: https://doi.org/10.1016/j.xhgg.2023.100186, doi:10.1016/j.xhgg.2023.100186. This article has 13 citations and is from a peer-reviewed journal.

  3. (bowles2021tspearvariantsare pages 2-4): Bradley Bowles, Alejandro Ferrer, Carla J. Nishimura, Filippo Pinto e Vairo, Tristan Rey, Bruno Leheup, Jennifer Sullivan, Kelly Schoch, Nicholas Stong, Emanuele Agolini, Dario Cocciadiferro, Abigail Williams, Alex Cummings, Sara Loddo, Silvia Genovese, Chelsea Roadhouse, Kirsty McWalter, Ingrid M. Wentzensen, Chumei Li, Dusica Babovic‐Vuksanovic, Brendan C. Lanpher, Maria Lisa Dentici, Arun Ankala, J. Austin Hamm, Bruno Dallapiccola, Francesca Clementina Radio, Vandana Shashi, Benedicte Gérard, Agnes Bloch‐Zupan, Richard J. Smith, and Eric W. Klee. Tspear variants are primarily associated with ectodermal dysplasia and tooth agenesis but not hearing loss: a novel cohort study. American Journal of Medical Genetics. Part a, 185:2417-2433, May 2021. URL: https://doi.org/10.1002/ajmg.a.62347, doi:10.1002/ajmg.a.62347. This article has 27 citations and is from a peer-reviewed journal.

  4. (bowles2021tspearvariantsare pages 10-11): Bradley Bowles, Alejandro Ferrer, Carla J. Nishimura, Filippo Pinto e Vairo, Tristan Rey, Bruno Leheup, Jennifer Sullivan, Kelly Schoch, Nicholas Stong, Emanuele Agolini, Dario Cocciadiferro, Abigail Williams, Alex Cummings, Sara Loddo, Silvia Genovese, Chelsea Roadhouse, Kirsty McWalter, Ingrid M. Wentzensen, Chumei Li, Dusica Babovic‐Vuksanovic, Brendan C. Lanpher, Maria Lisa Dentici, Arun Ankala, J. Austin Hamm, Bruno Dallapiccola, Francesca Clementina Radio, Vandana Shashi, Benedicte Gérard, Agnes Bloch‐Zupan, Richard J. Smith, and Eric W. Klee. Tspear variants are primarily associated with ectodermal dysplasia and tooth agenesis but not hearing loss: a novel cohort study. American Journal of Medical Genetics. Part a, 185:2417-2433, May 2021. URL: https://doi.org/10.1002/ajmg.a.62347, doi:10.1002/ajmg.a.62347. This article has 27 citations and is from a peer-reviewed journal.

  5. (jackson2023clinicalgeneticepidemiologic pages 1-2): Adam Jackson, Sheng-Jia Lin, Elizabeth A. Jones, Kate E. Chandler, David Orr, Celia Moss, Zahra Haider, Gavin Ryan, Simon Holden, Mike Harrison, Nigel Burrows, Wendy D. Jones, Mary Loveless, Cassidy Petree, Helen Stewart, Karen Low, Deirdre Donnelly, Simon Lovell, Konstantina Drosou, J.C. Ambrose, P. Arumugam, R. Bevers, M. Bleda, F. Boardman-Pretty, C.R. Boustred, H. Brittain, M.A. Brown, M.J. Caulfield, G.C. Chan, A. Giess, J.N. Griffin, A. Hamblin, S. Henderson, T.J.P. Hubbard, R. Jackson, L.J. Jones, D. Kasperaviciute, M. Kayikci, A. Kousathanas, L. Lahnstein, A. Lakey, S.E.A. Leigh, I.U.S. Leong, F.J. Lopez, F. Maleady-Crowe, M. McEntagart, F. Minneci, J. Mitchell, L. Moutsianas, M. Mueller, N. Murugaesu, A.C. Need, P. O‘Donovan, C.A. Odhams, C. Patch, D. Perez-Gil, M.B. Pereira, J. Pullinger, T. Rahim, A. Rendon, T. Rogers, K. Savage, K. Sawant, R.H. Scott, A. Siddiq, A. Sieghart, S.C. Smith, A. Sosinsky, A. Stuckey, M. Tanguy, A.L. Taylor Tavares, E.R.A. Thomas, S.R. Thompson, A. Tucci, M.J. Welland, E. Williams, K. Witkowska, S.M. Wood, M. Zarowiecki, Olaf Riess, Tobias B. Haack, Holm Graessner, Birte Zurek, Kornelia Ellwanger, Stephan Ossowski, German Demidov, Marc Sturm, Julia M. Schulze-Hentrich, Rebecca Schüle, Christoph Kessler, Melanie Wayand, Matthis Synofzik, Carlo Wilke, Andreas Traschütz, Ludger Schöls, Holger Hengel, Peter Heutink, Han Brunner, Hans Scheffer, Nicoline Hoogerbrugge, Alexander Hoischen, Peter A.C. ’t Hoen, Lisenka E.L.M. Vissers, Christian Gilissen, Wouter Steyaert, Karolis Sablauskas, Richarda M. de Voer, Erik-Jan Kamsteeg, Bart van de Warrenburg, Nienke van Os, Iris te Paske, Erik Janssen, Elke de Boer, Marloes Steehouwer, Burcu Yaldiz, Tjitske Kleefstra, Anthony J. Brookes, Colin Veal, Spencer Gibson, Marc Wadsley, Mehdi Mehtarizadeh, Umar Riaz, Greg Warren, Farid Yavari Dizjikan, Thomas Shorter, Ana Töpf, Volker Straub, Chiara Marini Bettolo, Sabine Specht, Jill Clayton-Smith, Siddharth Banka, Elizabeth Alexander, Adam Jackson, Laurence Faivre, Christel Thauvin, Antonio Vitobello, Anne-Sophie Denommé-Pichon, Yannis Duffourd, Emilie Tisserant, Ange-Line Bruel, Christine Peyron, Aurore Pélissier, Sergi Beltran, Ivo Glynne Gut, Steven Laurie, Davide Piscia, Leslie Matalonga, Anastasios Papakonstantinou, Gemma Bullich, Alberto Corvo, Carles Garcia, Marcos Fernandez-Callejo, Carles Hernández, Daniel Picó, Ida Paramonov, Hanns Lochmüller, Gulcin Gumus, Virginie Bros-Facer, Ana Rath, Marc Hanauer, Annie Olry, David Lagorce, Svitlana Havrylenko, Katia Izem, Fanny Rigour, Giovanni Stevanin, Alexandra Durr, Claire-Sophie Davoine, Léna Guillot-Noel, Anna Heinzmann, Giulia Coarelli, Gisèle Bonne, Teresinha Evangelista, Valérie Allamand, Isabelle Nelson, Rabah Ben Yaou, Corinne Metay, Bruno Eymard, Enzo Cohen, Antonio Atalaia, Tanya Stojkovic, Milan Macek, Marek Turnovec, Dana Thomasová, Radka Pourová Kremliková, Vera Franková, Markéta Havlovicová, Vlastimil Kremlik, Helen Parkinson, Thomas Keane, Dylan Spalding, Alexander Senf, Peter Robinson, Daniel Danis, Glenn Robert, Alessia Costa, Christine Patch, Mike Hanna, Henry Houlden, Mary Reilly, Jana Vandrovcova, Francesco Muntoni, Irina Zaharieva, Anna Sarkozy, Vincent Timmerman, Jonathan Baets, Liedewei Van de Vondel, Danique Beijer, Peter de Jonghe, Vincenzo Nigro, Sandro Banfi, Annalaura Torella, Francesco Musacchia, Giulio Piluso, Alessandra Ferlini, Rita Selvatici, Rachele Rossi, Marcella Neri, Stefan Aretz, Isabel Spier, Anna Katharina Sommer, Sophia Peters, Carla Oliveira, Jose Garcia Pelaez, Ana Rita Matos, Celina São José, Marta Ferreira, Irene Gullo, Susana Fernandes, Luzia Garrido, Pedro Ferreira, Fátima Carneiro, Morris A. Swertz, Lennart Johansson, Joeri K. van der Velde, Gerben van der Vries, Pieter B. Neerincx, Dieuwke Roelofs-Prins, Sebastian Köhler, Alison Metcalfe, Alain Verloes, Séverine Drunat, Caroline Rooryck, Aurelien Trimouille, Raffaele Castello, Manuela Morleo, Michele Pinelli, Alessandra Varavallo, Manuel Posada De la Paz, Eva Bermejo Sánchez, Estrella López Martín, Beatriz Martínez Delgado, F. Javier Alonso García de la Rosa, Andrea Ciolfi, Bruno Dallapiccola, Simone Pizzi, Francesca Clementina Radio, Marco Tartaglia, Alessandra Renieri, Elisa Benetti, Peter Balicza, Maria Judit Molnar, Ales Maver, Borut Peterlin, Alexander Münchau, Katja Lohmann, Rebecca Herzog, Martje Pauly, Alfons Macaya, Anna Marcé-Grau, Andres Nascimiento Osorio, Daniel Natera de Benito, Hanns Lochmüller, Rachel Thompson, Kiran Polavarapu, David Beeson, Judith Cossins, Pedro M. Rodriguez Cruz, Peter Hackman, Mridul Johari, Marco Savarese, Bjarne Udd, Rita Horvath, Gabriel Capella, Laura Valle, Elke Holinski-Feder, Andreas Laner, Verena Steinke-Lange, Evelin Schröck, Andreas Rump, Gaurav K. Varshney, and Siddharth Banka. Clinical, genetic, epidemiologic, evolutionary, and functional delineation of tspear-related autosomal recessive ectodermal dysplasia 14. Apr 2023. URL: https://doi.org/10.1016/j.xhgg.2023.100186, doi:10.1016/j.xhgg.2023.100186. This article has 13 citations and is from a peer-reviewed journal.

  6. (jackson2023clinicalgeneticepidemiologic pages 11-13): Adam Jackson, Sheng-Jia Lin, Elizabeth A. Jones, Kate E. Chandler, David Orr, Celia Moss, Zahra Haider, Gavin Ryan, Simon Holden, Mike Harrison, Nigel Burrows, Wendy D. Jones, Mary Loveless, Cassidy Petree, Helen Stewart, Karen Low, Deirdre Donnelly, Simon Lovell, Konstantina Drosou, J.C. Ambrose, P. Arumugam, R. Bevers, M. Bleda, F. Boardman-Pretty, C.R. Boustred, H. Brittain, M.A. Brown, M.J. Caulfield, G.C. Chan, A. Giess, J.N. Griffin, A. Hamblin, S. Henderson, T.J.P. Hubbard, R. Jackson, L.J. Jones, D. Kasperaviciute, M. Kayikci, A. Kousathanas, L. Lahnstein, A. Lakey, S.E.A. Leigh, I.U.S. Leong, F.J. Lopez, F. Maleady-Crowe, M. McEntagart, F. Minneci, J. Mitchell, L. Moutsianas, M. Mueller, N. Murugaesu, A.C. Need, P. O‘Donovan, C.A. Odhams, C. Patch, D. Perez-Gil, M.B. Pereira, J. Pullinger, T. Rahim, A. Rendon, T. Rogers, K. Savage, K. Sawant, R.H. Scott, A. Siddiq, A. Sieghart, S.C. Smith, A. Sosinsky, A. Stuckey, M. Tanguy, A.L. Taylor Tavares, E.R.A. Thomas, S.R. Thompson, A. Tucci, M.J. Welland, E. Williams, K. Witkowska, S.M. Wood, M. Zarowiecki, Olaf Riess, Tobias B. Haack, Holm Graessner, Birte Zurek, Kornelia Ellwanger, Stephan Ossowski, German Demidov, Marc Sturm, Julia M. Schulze-Hentrich, Rebecca Schüle, Christoph Kessler, Melanie Wayand, Matthis Synofzik, Carlo Wilke, Andreas Traschütz, Ludger Schöls, Holger Hengel, Peter Heutink, Han Brunner, Hans Scheffer, Nicoline Hoogerbrugge, Alexander Hoischen, Peter A.C. ’t Hoen, Lisenka E.L.M. Vissers, Christian Gilissen, Wouter Steyaert, Karolis Sablauskas, Richarda M. de Voer, Erik-Jan Kamsteeg, Bart van de Warrenburg, Nienke van Os, Iris te Paske, Erik Janssen, Elke de Boer, Marloes Steehouwer, Burcu Yaldiz, Tjitske Kleefstra, Anthony J. Brookes, Colin Veal, Spencer Gibson, Marc Wadsley, Mehdi Mehtarizadeh, Umar Riaz, Greg Warren, Farid Yavari Dizjikan, Thomas Shorter, Ana Töpf, Volker Straub, Chiara Marini Bettolo, Sabine Specht, Jill Clayton-Smith, Siddharth Banka, Elizabeth Alexander, Adam Jackson, Laurence Faivre, Christel Thauvin, Antonio Vitobello, Anne-Sophie Denommé-Pichon, Yannis Duffourd, Emilie Tisserant, Ange-Line Bruel, Christine Peyron, Aurore Pélissier, Sergi Beltran, Ivo Glynne Gut, Steven Laurie, Davide Piscia, Leslie Matalonga, Anastasios Papakonstantinou, Gemma Bullich, Alberto Corvo, Carles Garcia, Marcos Fernandez-Callejo, Carles Hernández, Daniel Picó, Ida Paramonov, Hanns Lochmüller, Gulcin Gumus, Virginie Bros-Facer, Ana Rath, Marc Hanauer, Annie Olry, David Lagorce, Svitlana Havrylenko, Katia Izem, Fanny Rigour, Giovanni Stevanin, Alexandra Durr, Claire-Sophie Davoine, Léna Guillot-Noel, Anna Heinzmann, Giulia Coarelli, Gisèle Bonne, Teresinha Evangelista, Valérie Allamand, Isabelle Nelson, Rabah Ben Yaou, Corinne Metay, Bruno Eymard, Enzo Cohen, Antonio Atalaia, Tanya Stojkovic, Milan Macek, Marek Turnovec, Dana Thomasová, Radka Pourová Kremliková, Vera Franková, Markéta Havlovicová, Vlastimil Kremlik, Helen Parkinson, Thomas Keane, Dylan Spalding, Alexander Senf, Peter Robinson, Daniel Danis, Glenn Robert, Alessia Costa, Christine Patch, Mike Hanna, Henry Houlden, Mary Reilly, Jana Vandrovcova, Francesco Muntoni, Irina Zaharieva, Anna Sarkozy, Vincent Timmerman, Jonathan Baets, Liedewei Van de Vondel, Danique Beijer, Peter de Jonghe, Vincenzo Nigro, Sandro Banfi, Annalaura Torella, Francesco Musacchia, Giulio Piluso, Alessandra Ferlini, Rita Selvatici, Rachele Rossi, Marcella Neri, Stefan Aretz, Isabel Spier, Anna Katharina Sommer, Sophia Peters, Carla Oliveira, Jose Garcia Pelaez, Ana Rita Matos, Celina São José, Marta Ferreira, Irene Gullo, Susana Fernandes, Luzia Garrido, Pedro Ferreira, Fátima Carneiro, Morris A. Swertz, Lennart Johansson, Joeri K. van der Velde, Gerben van der Vries, Pieter B. Neerincx, Dieuwke Roelofs-Prins, Sebastian Köhler, Alison Metcalfe, Alain Verloes, Séverine Drunat, Caroline Rooryck, Aurelien Trimouille, Raffaele Castello, Manuela Morleo, Michele Pinelli, Alessandra Varavallo, Manuel Posada De la Paz, Eva Bermejo Sánchez, Estrella López Martín, Beatriz Martínez Delgado, F. Javier Alonso García de la Rosa, Andrea Ciolfi, Bruno Dallapiccola, Simone Pizzi, Francesca Clementina Radio, Marco Tartaglia, Alessandra Renieri, Elisa Benetti, Peter Balicza, Maria Judit Molnar, Ales Maver, Borut Peterlin, Alexander Münchau, Katja Lohmann, Rebecca Herzog, Martje Pauly, Alfons Macaya, Anna Marcé-Grau, Andres Nascimiento Osorio, Daniel Natera de Benito, Hanns Lochmüller, Rachel Thompson, Kiran Polavarapu, David Beeson, Judith Cossins, Pedro M. Rodriguez Cruz, Peter Hackman, Mridul Johari, Marco Savarese, Bjarne Udd, Rita Horvath, Gabriel Capella, Laura Valle, Elke Holinski-Feder, Andreas Laner, Verena Steinke-Lange, Evelin Schröck, Andreas Rump, Gaurav K. Varshney, and Siddharth Banka. Clinical, genetic, epidemiologic, evolutionary, and functional delineation of tspear-related autosomal recessive ectodermal dysplasia 14. Apr 2023. URL: https://doi.org/10.1016/j.xhgg.2023.100186, doi:10.1016/j.xhgg.2023.100186. This article has 13 citations and is from a peer-reviewed journal.

  7. (jackson2023clinicalgeneticepidemiologic pages 13-14): Adam Jackson, Sheng-Jia Lin, Elizabeth A. Jones, Kate E. Chandler, David Orr, Celia Moss, Zahra Haider, Gavin Ryan, Simon Holden, Mike Harrison, Nigel Burrows, Wendy D. Jones, Mary Loveless, Cassidy Petree, Helen Stewart, Karen Low, Deirdre Donnelly, Simon Lovell, Konstantina Drosou, J.C. Ambrose, P. Arumugam, R. Bevers, M. Bleda, F. Boardman-Pretty, C.R. Boustred, H. Brittain, M.A. Brown, M.J. Caulfield, G.C. Chan, A. Giess, J.N. Griffin, A. Hamblin, S. Henderson, T.J.P. Hubbard, R. Jackson, L.J. Jones, D. Kasperaviciute, M. Kayikci, A. Kousathanas, L. Lahnstein, A. Lakey, S.E.A. Leigh, I.U.S. Leong, F.J. Lopez, F. Maleady-Crowe, M. McEntagart, F. Minneci, J. Mitchell, L. Moutsianas, M. Mueller, N. Murugaesu, A.C. Need, P. O‘Donovan, C.A. Odhams, C. Patch, D. Perez-Gil, M.B. Pereira, J. Pullinger, T. Rahim, A. Rendon, T. Rogers, K. Savage, K. Sawant, R.H. Scott, A. Siddiq, A. Sieghart, S.C. Smith, A. Sosinsky, A. Stuckey, M. Tanguy, A.L. Taylor Tavares, E.R.A. Thomas, S.R. Thompson, A. Tucci, M.J. Welland, E. Williams, K. Witkowska, S.M. Wood, M. Zarowiecki, Olaf Riess, Tobias B. Haack, Holm Graessner, Birte Zurek, Kornelia Ellwanger, Stephan Ossowski, German Demidov, Marc Sturm, Julia M. Schulze-Hentrich, Rebecca Schüle, Christoph Kessler, Melanie Wayand, Matthis Synofzik, Carlo Wilke, Andreas Traschütz, Ludger Schöls, Holger Hengel, Peter Heutink, Han Brunner, Hans Scheffer, Nicoline Hoogerbrugge, Alexander Hoischen, Peter A.C. ’t Hoen, Lisenka E.L.M. Vissers, Christian Gilissen, Wouter Steyaert, Karolis Sablauskas, Richarda M. de Voer, Erik-Jan Kamsteeg, Bart van de Warrenburg, Nienke van Os, Iris te Paske, Erik Janssen, Elke de Boer, Marloes Steehouwer, Burcu Yaldiz, Tjitske Kleefstra, Anthony J. Brookes, Colin Veal, Spencer Gibson, Marc Wadsley, Mehdi Mehtarizadeh, Umar Riaz, Greg Warren, Farid Yavari Dizjikan, Thomas Shorter, Ana Töpf, Volker Straub, Chiara Marini Bettolo, Sabine Specht, Jill Clayton-Smith, Siddharth Banka, Elizabeth Alexander, Adam Jackson, Laurence Faivre, Christel Thauvin, Antonio Vitobello, Anne-Sophie Denommé-Pichon, Yannis Duffourd, Emilie Tisserant, Ange-Line Bruel, Christine Peyron, Aurore Pélissier, Sergi Beltran, Ivo Glynne Gut, Steven Laurie, Davide Piscia, Leslie Matalonga, Anastasios Papakonstantinou, Gemma Bullich, Alberto Corvo, Carles Garcia, Marcos Fernandez-Callejo, Carles Hernández, Daniel Picó, Ida Paramonov, Hanns Lochmüller, Gulcin Gumus, Virginie Bros-Facer, Ana Rath, Marc Hanauer, Annie Olry, David Lagorce, Svitlana Havrylenko, Katia Izem, Fanny Rigour, Giovanni Stevanin, Alexandra Durr, Claire-Sophie Davoine, Léna Guillot-Noel, Anna Heinzmann, Giulia Coarelli, Gisèle Bonne, Teresinha Evangelista, Valérie Allamand, Isabelle Nelson, Rabah Ben Yaou, Corinne Metay, Bruno Eymard, Enzo Cohen, Antonio Atalaia, Tanya Stojkovic, Milan Macek, Marek Turnovec, Dana Thomasová, Radka Pourová Kremliková, Vera Franková, Markéta Havlovicová, Vlastimil Kremlik, Helen Parkinson, Thomas Keane, Dylan Spalding, Alexander Senf, Peter Robinson, Daniel Danis, Glenn Robert, Alessia Costa, Christine Patch, Mike Hanna, Henry Houlden, Mary Reilly, Jana Vandrovcova, Francesco Muntoni, Irina Zaharieva, Anna Sarkozy, Vincent Timmerman, Jonathan Baets, Liedewei Van de Vondel, Danique Beijer, Peter de Jonghe, Vincenzo Nigro, Sandro Banfi, Annalaura Torella, Francesco Musacchia, Giulio Piluso, Alessandra Ferlini, Rita Selvatici, Rachele Rossi, Marcella Neri, Stefan Aretz, Isabel Spier, Anna Katharina Sommer, Sophia Peters, Carla Oliveira, Jose Garcia Pelaez, Ana Rita Matos, Celina São José, Marta Ferreira, Irene Gullo, Susana Fernandes, Luzia Garrido, Pedro Ferreira, Fátima Carneiro, Morris A. Swertz, Lennart Johansson, Joeri K. van der Velde, Gerben van der Vries, Pieter B. Neerincx, Dieuwke Roelofs-Prins, Sebastian Köhler, Alison Metcalfe, Alain Verloes, Séverine Drunat, Caroline Rooryck, Aurelien Trimouille, Raffaele Castello, Manuela Morleo, Michele Pinelli, Alessandra Varavallo, Manuel Posada De la Paz, Eva Bermejo Sánchez, Estrella López Martín, Beatriz Martínez Delgado, F. Javier Alonso García de la Rosa, Andrea Ciolfi, Bruno Dallapiccola, Simone Pizzi, Francesca Clementina Radio, Marco Tartaglia, Alessandra Renieri, Elisa Benetti, Peter Balicza, Maria Judit Molnar, Ales Maver, Borut Peterlin, Alexander Münchau, Katja Lohmann, Rebecca Herzog, Martje Pauly, Alfons Macaya, Anna Marcé-Grau, Andres Nascimiento Osorio, Daniel Natera de Benito, Hanns Lochmüller, Rachel Thompson, Kiran Polavarapu, David Beeson, Judith Cossins, Pedro M. Rodriguez Cruz, Peter Hackman, Mridul Johari, Marco Savarese, Bjarne Udd, Rita Horvath, Gabriel Capella, Laura Valle, Elke Holinski-Feder, Andreas Laner, Verena Steinke-Lange, Evelin Schröck, Andreas Rump, Gaurav K. Varshney, and Siddharth Banka. Clinical, genetic, epidemiologic, evolutionary, and functional delineation of tspear-related autosomal recessive ectodermal dysplasia 14. Apr 2023. URL: https://doi.org/10.1016/j.xhgg.2023.100186, doi:10.1016/j.xhgg.2023.100186. This article has 13 citations and is from a peer-reviewed journal.

  8. (jackson2023clinicalgeneticepidemiologic pages 14-15): Adam Jackson, Sheng-Jia Lin, Elizabeth A. Jones, Kate E. Chandler, David Orr, Celia Moss, Zahra Haider, Gavin Ryan, Simon Holden, Mike Harrison, Nigel Burrows, Wendy D. Jones, Mary Loveless, Cassidy Petree, Helen Stewart, Karen Low, Deirdre Donnelly, Simon Lovell, Konstantina Drosou, J.C. Ambrose, P. Arumugam, R. Bevers, M. Bleda, F. Boardman-Pretty, C.R. Boustred, H. Brittain, M.A. Brown, M.J. Caulfield, G.C. Chan, A. Giess, J.N. Griffin, A. Hamblin, S. Henderson, T.J.P. Hubbard, R. Jackson, L.J. Jones, D. Kasperaviciute, M. Kayikci, A. Kousathanas, L. Lahnstein, A. Lakey, S.E.A. Leigh, I.U.S. Leong, F.J. Lopez, F. Maleady-Crowe, M. McEntagart, F. Minneci, J. Mitchell, L. Moutsianas, M. Mueller, N. Murugaesu, A.C. Need, P. O‘Donovan, C.A. Odhams, C. Patch, D. Perez-Gil, M.B. Pereira, J. Pullinger, T. Rahim, A. Rendon, T. Rogers, K. Savage, K. Sawant, R.H. Scott, A. Siddiq, A. Sieghart, S.C. Smith, A. Sosinsky, A. Stuckey, M. Tanguy, A.L. Taylor Tavares, E.R.A. Thomas, S.R. Thompson, A. Tucci, M.J. Welland, E. Williams, K. Witkowska, S.M. Wood, M. Zarowiecki, Olaf Riess, Tobias B. Haack, Holm Graessner, Birte Zurek, Kornelia Ellwanger, Stephan Ossowski, German Demidov, Marc Sturm, Julia M. Schulze-Hentrich, Rebecca Schüle, Christoph Kessler, Melanie Wayand, Matthis Synofzik, Carlo Wilke, Andreas Traschütz, Ludger Schöls, Holger Hengel, Peter Heutink, Han Brunner, Hans Scheffer, Nicoline Hoogerbrugge, Alexander Hoischen, Peter A.C. ’t Hoen, Lisenka E.L.M. Vissers, Christian Gilissen, Wouter Steyaert, Karolis Sablauskas, Richarda M. de Voer, Erik-Jan Kamsteeg, Bart van de Warrenburg, Nienke van Os, Iris te Paske, Erik Janssen, Elke de Boer, Marloes Steehouwer, Burcu Yaldiz, Tjitske Kleefstra, Anthony J. Brookes, Colin Veal, Spencer Gibson, Marc Wadsley, Mehdi Mehtarizadeh, Umar Riaz, Greg Warren, Farid Yavari Dizjikan, Thomas Shorter, Ana Töpf, Volker Straub, Chiara Marini Bettolo, Sabine Specht, Jill Clayton-Smith, Siddharth Banka, Elizabeth Alexander, Adam Jackson, Laurence Faivre, Christel Thauvin, Antonio Vitobello, Anne-Sophie Denommé-Pichon, Yannis Duffourd, Emilie Tisserant, Ange-Line Bruel, Christine Peyron, Aurore Pélissier, Sergi Beltran, Ivo Glynne Gut, Steven Laurie, Davide Piscia, Leslie Matalonga, Anastasios Papakonstantinou, Gemma Bullich, Alberto Corvo, Carles Garcia, Marcos Fernandez-Callejo, Carles Hernández, Daniel Picó, Ida Paramonov, Hanns Lochmüller, Gulcin Gumus, Virginie Bros-Facer, Ana Rath, Marc Hanauer, Annie Olry, David Lagorce, Svitlana Havrylenko, Katia Izem, Fanny Rigour, Giovanni Stevanin, Alexandra Durr, Claire-Sophie Davoine, Léna Guillot-Noel, Anna Heinzmann, Giulia Coarelli, Gisèle Bonne, Teresinha Evangelista, Valérie Allamand, Isabelle Nelson, Rabah Ben Yaou, Corinne Metay, Bruno Eymard, Enzo Cohen, Antonio Atalaia, Tanya Stojkovic, Milan Macek, Marek Turnovec, Dana Thomasová, Radka Pourová Kremliková, Vera Franková, Markéta Havlovicová, Vlastimil Kremlik, Helen Parkinson, Thomas Keane, Dylan Spalding, Alexander Senf, Peter Robinson, Daniel Danis, Glenn Robert, Alessia Costa, Christine Patch, Mike Hanna, Henry Houlden, Mary Reilly, Jana Vandrovcova, Francesco Muntoni, Irina Zaharieva, Anna Sarkozy, Vincent Timmerman, Jonathan Baets, Liedewei Van de Vondel, Danique Beijer, Peter de Jonghe, Vincenzo Nigro, Sandro Banfi, Annalaura Torella, Francesco Musacchia, Giulio Piluso, Alessandra Ferlini, Rita Selvatici, Rachele Rossi, Marcella Neri, Stefan Aretz, Isabel Spier, Anna Katharina Sommer, Sophia Peters, Carla Oliveira, Jose Garcia Pelaez, Ana Rita Matos, Celina São José, Marta Ferreira, Irene Gullo, Susana Fernandes, Luzia Garrido, Pedro Ferreira, Fátima Carneiro, Morris A. Swertz, Lennart Johansson, Joeri K. van der Velde, Gerben van der Vries, Pieter B. Neerincx, Dieuwke Roelofs-Prins, Sebastian Köhler, Alison Metcalfe, Alain Verloes, Séverine Drunat, Caroline Rooryck, Aurelien Trimouille, Raffaele Castello, Manuela Morleo, Michele Pinelli, Alessandra Varavallo, Manuel Posada De la Paz, Eva Bermejo Sánchez, Estrella López Martín, Beatriz Martínez Delgado, F. Javier Alonso García de la Rosa, Andrea Ciolfi, Bruno Dallapiccola, Simone Pizzi, Francesca Clementina Radio, Marco Tartaglia, Alessandra Renieri, Elisa Benetti, Peter Balicza, Maria Judit Molnar, Ales Maver, Borut Peterlin, Alexander Münchau, Katja Lohmann, Rebecca Herzog, Martje Pauly, Alfons Macaya, Anna Marcé-Grau, Andres Nascimiento Osorio, Daniel Natera de Benito, Hanns Lochmüller, Rachel Thompson, Kiran Polavarapu, David Beeson, Judith Cossins, Pedro M. Rodriguez Cruz, Peter Hackman, Mridul Johari, Marco Savarese, Bjarne Udd, Rita Horvath, Gabriel Capella, Laura Valle, Elke Holinski-Feder, Andreas Laner, Verena Steinke-Lange, Evelin Schröck, Andreas Rump, Gaurav K. Varshney, and Siddharth Banka. Clinical, genetic, epidemiologic, evolutionary, and functional delineation of tspear-related autosomal recessive ectodermal dysplasia 14. Apr 2023. URL: https://doi.org/10.1016/j.xhgg.2023.100186, doi:10.1016/j.xhgg.2023.100186. This article has 13 citations and is from a peer-reviewed journal.

  9. (ahmadkhani2026anovelpathogenic pages 1-2): Alireza Ahmadkhani, Erfan Taherifard, Sina Zoghi, Hossein Jafari Khamirani, Mohammadreza Ahmadkhani, and Seyed Alireza Dastgheib. A novel pathogenic mutation in tspear associated with sensorineural hearing loss: a case report and review of the literature. Journal of Medical Case Reports, Jan 2026. URL: https://doi.org/10.1186/s13256-025-05761-7, doi:10.1186/s13256-025-05761-7. This article has 0 citations and is from a peer-reviewed journal.

  10. (peled2016mutationsintspear pages 1-2): Alon Peled, Ofer Sarig, Liat Samuelov, Marta Bertolini, Limor Ziv, Daphna Weissglas-Volkov, Marina Eskin-Schwartz, Christopher A. Adase, Natalia Malchin, Ron Bochner, Gilad Fainberg, Ilan Goldberg, Koji Sugawara, Avital Baniel, Daisuke Tsuruta, Chen Luxenburg, Noam Adir, Olivier Duverger, Maria Morasso, Stavit Shalev, Richard L. Gallo, Noam Shomron, Ralf Paus, and Eli Sprecher. Mutations in tspear, encoding a regulator of notch signaling, affect tooth and hair follicle morphogenesis. PLOS Genetics, 12:e1006369, Oct 2016. URL: https://doi.org/10.1371/journal.pgen.1006369, doi:10.1371/journal.pgen.1006369. This article has 70 citations and is from a domain leading peer-reviewed journal.

  11. (jackson2023clinicalgeneticepidemiologic pages 8-11): Adam Jackson, Sheng-Jia Lin, Elizabeth A. Jones, Kate E. Chandler, David Orr, Celia Moss, Zahra Haider, Gavin Ryan, Simon Holden, Mike Harrison, Nigel Burrows, Wendy D. Jones, Mary Loveless, Cassidy Petree, Helen Stewart, Karen Low, Deirdre Donnelly, Simon Lovell, Konstantina Drosou, J.C. Ambrose, P. Arumugam, R. Bevers, M. Bleda, F. Boardman-Pretty, C.R. Boustred, H. Brittain, M.A. Brown, M.J. Caulfield, G.C. Chan, A. Giess, J.N. Griffin, A. Hamblin, S. Henderson, T.J.P. Hubbard, R. Jackson, L.J. Jones, D. Kasperaviciute, M. Kayikci, A. Kousathanas, L. Lahnstein, A. Lakey, S.E.A. Leigh, I.U.S. Leong, F.J. Lopez, F. Maleady-Crowe, M. McEntagart, F. Minneci, J. Mitchell, L. Moutsianas, M. Mueller, N. Murugaesu, A.C. Need, P. O‘Donovan, C.A. Odhams, C. Patch, D. Perez-Gil, M.B. Pereira, J. Pullinger, T. Rahim, A. Rendon, T. Rogers, K. Savage, K. Sawant, R.H. Scott, A. Siddiq, A. Sieghart, S.C. Smith, A. Sosinsky, A. Stuckey, M. Tanguy, A.L. Taylor Tavares, E.R.A. Thomas, S.R. Thompson, A. Tucci, M.J. Welland, E. Williams, K. Witkowska, S.M. Wood, M. Zarowiecki, Olaf Riess, Tobias B. Haack, Holm Graessner, Birte Zurek, Kornelia Ellwanger, Stephan Ossowski, German Demidov, Marc Sturm, Julia M. Schulze-Hentrich, Rebecca Schüle, Christoph Kessler, Melanie Wayand, Matthis Synofzik, Carlo Wilke, Andreas Traschütz, Ludger Schöls, Holger Hengel, Peter Heutink, Han Brunner, Hans Scheffer, Nicoline Hoogerbrugge, Alexander Hoischen, Peter A.C. ’t Hoen, Lisenka E.L.M. Vissers, Christian Gilissen, Wouter Steyaert, Karolis Sablauskas, Richarda M. de Voer, Erik-Jan Kamsteeg, Bart van de Warrenburg, Nienke van Os, Iris te Paske, Erik Janssen, Elke de Boer, Marloes Steehouwer, Burcu Yaldiz, Tjitske Kleefstra, Anthony J. Brookes, Colin Veal, Spencer Gibson, Marc Wadsley, Mehdi Mehtarizadeh, Umar Riaz, Greg Warren, Farid Yavari Dizjikan, Thomas Shorter, Ana Töpf, Volker Straub, Chiara Marini Bettolo, Sabine Specht, Jill Clayton-Smith, Siddharth Banka, Elizabeth Alexander, Adam Jackson, Laurence Faivre, Christel Thauvin, Antonio Vitobello, Anne-Sophie Denommé-Pichon, Yannis Duffourd, Emilie Tisserant, Ange-Line Bruel, Christine Peyron, Aurore Pélissier, Sergi Beltran, Ivo Glynne Gut, Steven Laurie, Davide Piscia, Leslie Matalonga, Anastasios Papakonstantinou, Gemma Bullich, Alberto Corvo, Carles Garcia, Marcos Fernandez-Callejo, Carles Hernández, Daniel Picó, Ida Paramonov, Hanns Lochmüller, Gulcin Gumus, Virginie Bros-Facer, Ana Rath, Marc Hanauer, Annie Olry, David Lagorce, Svitlana Havrylenko, Katia Izem, Fanny Rigour, Giovanni Stevanin, Alexandra Durr, Claire-Sophie Davoine, Léna Guillot-Noel, Anna Heinzmann, Giulia Coarelli, Gisèle Bonne, Teresinha Evangelista, Valérie Allamand, Isabelle Nelson, Rabah Ben Yaou, Corinne Metay, Bruno Eymard, Enzo Cohen, Antonio Atalaia, Tanya Stojkovic, Milan Macek, Marek Turnovec, Dana Thomasová, Radka Pourová Kremliková, Vera Franková, Markéta Havlovicová, Vlastimil Kremlik, Helen Parkinson, Thomas Keane, Dylan Spalding, Alexander Senf, Peter Robinson, Daniel Danis, Glenn Robert, Alessia Costa, Christine Patch, Mike Hanna, Henry Houlden, Mary Reilly, Jana Vandrovcova, Francesco Muntoni, Irina Zaharieva, Anna Sarkozy, Vincent Timmerman, Jonathan Baets, Liedewei Van de Vondel, Danique Beijer, Peter de Jonghe, Vincenzo Nigro, Sandro Banfi, Annalaura Torella, Francesco Musacchia, Giulio Piluso, Alessandra Ferlini, Rita Selvatici, Rachele Rossi, Marcella Neri, Stefan Aretz, Isabel Spier, Anna Katharina Sommer, Sophia Peters, Carla Oliveira, Jose Garcia Pelaez, Ana Rita Matos, Celina São José, Marta Ferreira, Irene Gullo, Susana Fernandes, Luzia Garrido, Pedro Ferreira, Fátima Carneiro, Morris A. Swertz, Lennart Johansson, Joeri K. van der Velde, Gerben van der Vries, Pieter B. Neerincx, Dieuwke Roelofs-Prins, Sebastian Köhler, Alison Metcalfe, Alain Verloes, Séverine Drunat, Caroline Rooryck, Aurelien Trimouille, Raffaele Castello, Manuela Morleo, Michele Pinelli, Alessandra Varavallo, Manuel Posada De la Paz, Eva Bermejo Sánchez, Estrella López Martín, Beatriz Martínez Delgado, F. Javier Alonso García de la Rosa, Andrea Ciolfi, Bruno Dallapiccola, Simone Pizzi, Francesca Clementina Radio, Marco Tartaglia, Alessandra Renieri, Elisa Benetti, Peter Balicza, Maria Judit Molnar, Ales Maver, Borut Peterlin, Alexander Münchau, Katja Lohmann, Rebecca Herzog, Martje Pauly, Alfons Macaya, Anna Marcé-Grau, Andres Nascimiento Osorio, Daniel Natera de Benito, Hanns Lochmüller, Rachel Thompson, Kiran Polavarapu, David Beeson, Judith Cossins, Pedro M. Rodriguez Cruz, Peter Hackman, Mridul Johari, Marco Savarese, Bjarne Udd, Rita Horvath, Gabriel Capella, Laura Valle, Elke Holinski-Feder, Andreas Laner, Verena Steinke-Lange, Evelin Schröck, Andreas Rump, Gaurav K. Varshney, and Siddharth Banka. Clinical, genetic, epidemiologic, evolutionary, and functional delineation of tspear-related autosomal recessive ectodermal dysplasia 14. Apr 2023. URL: https://doi.org/10.1016/j.xhgg.2023.100186, doi:10.1016/j.xhgg.2023.100186. This article has 13 citations and is from a peer-reviewed journal.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 5
Resolved 5
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 5
On topic 2
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 10
Resolved 10
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:0013929 (3 mentions) - the report calls it "if available"; MONDO calls it autosomal recessive nonsyndromic hearing loss 98