Autosomal Recessive Nonsyndromic Hearing Loss 98

Mendelian MONDO:0013929 Pathograph 18 Show in embeddings browser Autosomal Recessive Nonsyndromic Hearing Loss Hereditary Hearing Loss

DFNB98 denotes a proposed autosomal recessive sensorineural hearing-loss association with TSPEAR. The founding report described congenital profound deafness in a consanguineous Iranian family, but ClinGen retained a Disputed classification for TSPEAR-related nonsyndromic hearing loss in October 2024. Later hearing-loss reports include candidate variants and incomplete segregation, while other individuals carrying biallelic TSPEAR variants have dental or ectodermal findings without hearing loss. A Tspear S475TfsX79 mouse also had preserved auditory function. These observations challenge a general auditory loss-of-function mechanism without proving that every reported hearing-loss association is incidental. The reported clinical findings and proposed mechanism require interpretation separately from the better-supported TSPEAR-related ectodermal dysplasia 14 association.

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1
Inheritance
4
Pathophys.
7
Phenotypes
1
Hypotheses
2
Gaps
18
Pathograph
1
Genes
10
Variants
4
Medical Actions
2
Differentials
3
Models
15
References
1
Deep Research
👪

Inheritance

1
Autosomal recessive HP:0000007
Autosomal recessive inheritance was proposed from the founding pedigree. Subsequent reports include homozygous and compound heterozygous candidate genotypes, but gene-disease validity remains disputed. In the mid-frequency hearing-loss family, the p.Glu624Ter proband was homozygous while his similarly affected sister was heterozygous, weakening simple recessive segregation of this allele with hearing loss.
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.
◈

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 1 refute 1 no evidence
The proposed auditory mechanism links defective secretion of the founding truncating allele to reduced TSPEAR availability at the hair-bundle surface and impaired cochlear function. Secretion impairment was measured in transfected cells, whereas localization was examined in mouse sensory cells. These separate observations do not demonstrate loss of bundle-localized protein or a causal auditory defect in the human variant carriers. Preserved hearing and stereociliary morphology in S475TfsX79 mice challenge a general frameshift mechanism, with allele and species limitations.
Pathograph links
Homozygous Founding TSPEAR Frameshift Variant -> Failure of TSPEAR Secretion DIRECT The founding truncating allele impaired protein secretion in transfected cells. This directly tested step does not establish its downstream auditory consequences.
Failure of TSPEAR Secretion -> Loss of TSPEAR from the Hair Bundle Surface INDIRECT KNOWN INTERMEDIATES Reduced secretion could reduce extracellular TSPEAR availability at the hair-bundle surface. Neither mutant bundle localization nor the functional consequences of reduced localization were directly measured in the cited human-allele experiment.
Loss of TSPEAR from the Hair Bundle Surface -> Impaired Cochlear Sound Transduction INDIRECT UNKNOWN INTERMEDIATES A connection between reduced bundle-localized TSPEAR and impaired auditory function remains hypothetical. Normal hearing in the S475TfsX79 model is contrary evidence for a general frameshift effect, with allele and species limits.
Impaired Cochlear Sound Transduction -> Sensorineural Hearing Loss in Reported TSPEAR Cases DIRECT Impaired cochlear function produces hearing loss, but attribution of that dysfunction to the upstream TSPEAR hypothesis remains disputed.
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."
Preserved stereociliary morphology and hearing challenge a general auditory frameshift mechanism in mice. This allele differs from the founding human allele, so the result does not directly test every human genotype.
PMID:41195743 NO_EVIDENCE Human Clinical
"However, the role of TSPEAR in auditory processes is unclear."
This introductory statement identifies uncertainty rather than reporting a negative experiment. The cohort observations are represented separately.
?

Discussions and Knowledge Gaps

2
Which, if any, TSPEAR genotypes confer hearing-loss risk independently of other genetic or acquired causes?
KNOWLEDGE GAP OPEN gap_tspear_hearing_gene_validity
Attached to
genetic#TSPEAR mechanistic_hypotheses#tspear_hair_bundle_deafness
Human reports combine segregation evidence, VUS, competing hearing-loss variants and a family with discordant TSPEAR zygosity among similarly affected siblings. Dental cohorts include people without hearing concerns, but audiometric ascertainment is incomplete in some studies. These observations leave allele-specific effects, reduced penetrance and alternative etiologies unresolved.
Proposed experiments
Standardized audiometry and genomic reassessment across TSPEAR genotypes
tspear_unselected_hearing_ascertainment
Recruit a genotype-defined series from hearing-loss and dental referrals with documented ascertainment. Obtain age-appropriate audiometry, otoacoustic emissions and ABR where indicated, and reassess genomic data for competing causes, phase, CNVs and noncoding variants. Compare hearing outcomes with suitable controls and stratify by allele.
Would support
genetic#TSPEAR
Supporting outcome
  • Replicated enrichment of hearing impairment for a particular genotype, with segregation and functional support and without a stronger competing explanation, would strengthen an allele-specific auditory association.
Refuting outcome
  • Normal hearing across adequately assessed carriers or identification of better-supported alternative causes would weaken the auditory association. Neither result alone predetermines an expert-panel classification or ontology action.
How do the molecular and auditory effects of the human founding allele compare with the mouse S475TfsX79 allele?
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
Normal hearing in the S475TfsX79 mouse contrasts with reported hearing loss in human variant carriers. Localization in normal mouse hair bundles is not proof of essential function, and the two alleles may differ in residual protein, secretion or compensation. Direct allele comparisons are needed before extrapolating this negative model result to every human TSPEAR genotype.
Proposed experiments
Knock-in of the human p.V576LfsX37 allele with EAR-paralogue compensation testing
tspear_human_allele_knockin_mouse
Compare the human founding allele with S475TfsX79 in matched genetic backgrounds, measuring transcript and protein abundance, secretion and bundle localization alongside auditory thresholds and stereociliary morphology. Assess proposed compensatory expression rather than assuming it.
Would support
pathophysiology#Loss of TSPEAR from the Hair Bundle Surface
Supporting outcome
  • An allele-dependent loss of secretion and bundle localization accompanied by an auditory deficit would support the proposed chain, with human relevance still requiring clinical corroboration.
Refuting outcome
  • Preserved hearing despite verified comparable disruption would weaken this proposed auditory mechanism under the tested conditions without excluding all possible allele- or species-specific effects.
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Pathophysiology

4
Homozygous Founding TSPEAR Frameshift Variant
The founding family carried the homozygous combined allele c.1726G>T+c.1728delC, reported as p.V576LfsX37 in 2012 and as c.1726_1728delGTCinsTT, p.Val576Leufs*38 in later literature. This node describes that allele and its secretion experiment, not the unassayed missense alleles in subsequent candidate cases.
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
Homozygosity and impaired secretion are documented for the founding allele. This does not establish complete loss of every protein function or extend a loss-of-function classification to unassayed missense variants.
Downstream
Failure of TSPEAR Secretion The founding truncating allele impaired protein secretion in transfected cells. This directly tested step does not establish its downstream auditory consequences. Loss of secreted TSPEAR from the hair bundle surface causes isolated sensorineural deafness
Show evidence (1 reference)
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.
Failure of TSPEAR Secretion
The founding truncating allele impaired TSPEAR secretion in transfected cells. This heterologous assay establishes a protein-trafficking effect under its experimental conditions, not a measurement of secretion or auditory function in patient hair cells.
Loss of secreted TSPEAR from the hair bundle surface causes isolated sensorineural deafness
secretion of TSPEAR into the extracellular matrix GO:0009306 ↓ DECREASED 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.
Experimental models
Founding TSPEAR frameshift transfection and secretion assay CELL LINE The experiment directly measures the secretion phenotype of the founding allele.
Downstream
Loss of TSPEAR from the Hair Bundle Surface Reduced secretion could reduce extracellular TSPEAR availability at the hair-bundle surface. Neither mutant bundle localization nor the functional consequences of reduced localization were directly measured in the cited human-allele experiment. 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
Mouse immunofluorescence localized TSPEAR to sensory-cell hair bundles. Reduced availability at this surface is a proposed consequence of impaired secretion, not a measured lesion in patients or in a model carrying the founding human allele. Localization does not establish an indispensable structural or transduction function.
Loss of secreted TSPEAR from the hair bundle surface causes isolated sensorineural deafness
cochlear sensory hair cell CL:4023120 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlear sensory hair cell, annotated with cochlea auditory hair cell (CL:4023120). CL:4023120 is a cell type from the Cell Ontology.
Downstream
Impaired Cochlear Sound Transduction A connection between reduced bundle-localized TSPEAR and impaired auditory function remains hypothetical. Normal hearing in the S475TfsX79 model is contrary evidence for a general frameshift effect, with allele and species limits. Loss of secreted TSPEAR from the hair bundle surface causes isolated sensorineural deafness
Show evidence (2 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."
This supports localization in normal mouse tissue, not loss of protein from a mutant bundle.
PMID:40716589 REFUTE Model Organism
"Intriguingly, stereociliary morphology and auditory function remain unaffected in TSPEAR S475TfsX79 mutant mice."
Normal morphology and hearing in this different frameshift model challenge a general auditory defect but do not measure TSPEAR localization at the bundle surface.
Impaired Cochlear Sound Transduction
Audiological testing in the founding family indicated at least a cochlear defect. The six-year-old p.Ser223Leu proband had absent ABR and severe bilateral hearing loss; the Chinese proband had measurable ABR thresholds and absent otoacoustic emissions. These findings establish auditory impairment in reported cases without resolving TSPEAR causality.
Loss of secreted TSPEAR from the hair bundle surface causes isolated sensorineural deafness
sensory perception of sound GO:0007605 ↓ DECREASED 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.
Animal models
Tspear S475TfsX79 CRISPR mouse Mouse fails to recapitulate This mouse challenges the proposed auditory consequence of TSPEAR disruption because hearing remained intact.
Downstream
Sensorineural Hearing Loss in Reported TSPEAR Cases Impaired cochlear function produces hearing loss, but attribution of that dysfunction to the upstream TSPEAR hypothesis remains disputed. 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."
All three newly reported hearing-loss cases carried competing variants. Their evidence strengths differ: some remain VUS, so alternative causality is not established uniformly.
PMID:41195743 REFUTE Human Clinical
"None of the individuals had hearing loss."
The dental-ascertained cohort had no clinical hearing concerns in 11 individuals; the full text reports normal audiometry in only four. This challenges general hearing-loss penetrance but does not exclude allele-specific effects.
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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

7
Ear 4
Sensorineural Hearing Loss in Reported TSPEAR Cases Sensorineural hearing impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 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:39720278 SUPPORT Human Clinical
"Her hearing thresholds at 6 months were 65 dBnHL in both ears with normal acoustic impedance results, and then she was diagnosed with congenital sensorineural hearing loss."
The reported hearing impairment is less severe than the profound loss in the founding family; the two TSPEAR missense variants were classified as VUS.
Progressive Hearing Loss in the Chinese Proband Progressive sensorineural hearing impairment HP:0000408 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive sensorineural hearing impairment (HP:0000408). HP:0000408 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39720278 SUPPORT Human Clinical
"An ABR test conducted at the age of 6 years showed that hearing thresholds of both ears were 80 dBnHL."
The later measurement follows bilateral thresholds of 65 dBnHL at six months in the same report.
Absent Otoacoustic Emissions in the Chinese Proband HP:6000182 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absent otoacoustic emissions (HP:6000182). HP:6000182 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39720278 SUPPORT Human Clinical
"Distortion product otoacoustic emission was not elicited on both sides."
Direct audiological finding in a single candidate case.
Enlarged Vestibular Aqueduct in a Reported Family HP:0011387 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Enlarged vestibular aqueduct (HP:0011387). HP:0011387 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34042254 SUPPORT INDIRECT Human Clinical
"a 2016 report describing siblings with childhood onset, nonsyndromic, bilateral hearing loss, EVA, and compound heterozygous TSPEAR variants"
The later cohort paper summarizes the reported family; gene attribution remains disputed.
Head and Neck 1
Ankyloglossia in the Chinese Proband 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
"The proband also demonstrated dental caries (Figure 1A), ankyloglossia (Figure 1B), and heart‐shaped tongue (Figure 1C)."
The primary case report directly names the tongue abnormality; causal attribution to TSPEAR remains uncertain.
Nervous System 2
Absent Auditory Brainstem Response Abnormal auditory evoked potentials HP:0006958 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal auditory evoked potentials (HP:0006958). HP:0006958 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID: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."
This describes the 2026 proband, not a universal finding in candidate TSPEAR-associated hearing loss.
Speech Difficulties in Reported Cases Poor speech HP:0002465 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Poor speech (HP:0002465). HP:0002465 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41486137 SUPPORT Human Clinical
"After the occurrence of this prelingual form of profound hearing loss, she had also speech disorders interfering with normal school performance."
The case describes speech and educational effects without establishing a separate developmental syndrome.
PMID:39720278 SUPPORT Human Clinical
"After three corrective surgeries, her tongue was still difficult to stick out and her speech was still compromised."
Tongue restriction and hearing impairment may both be relevant; the report does not quantify their individual contributions.
🧬

Genetic Associations

1
TSPEAR
Gene: TSPEAR hgnc:1268 gene page 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 (9 references)
CGGV:assertion_f0928b06-d3bb-41fe-8222-d7f0e6c0a25a-2024-10-31T160000.000Z NO_EVIDENCE Other
"More evidence is needed to either support or refute the role TSPEAR plays in this disease."
The panel explicitly describes unresolved causality; this sentence alone is not an experimental refutation.
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"
Discordant TSPEAR zygosity in similarly affected siblings weakens simple recessive segregation in this family.
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 ClinGen summary cites normal-hearing ectodermal families as conflicting evidence. The primary 2016 paper documents the founding combined genotype in family A and normal audiometry in families A and C; family C carried different missense variants.
+ 6 more references
🔬

Variants

10
TSPEAR c.1726G>T+c.1728delC (founding frameshift)
Gene: TSPEAR hgnc:1268 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in TSPEAR (hgnc:1268). hgnc:1268 is a gene from the HUGO Gene Nomenclature Committee. combined substitution and deletion causing frameshift
Homozygous in the founding Iranian family. The 2012 paper calls the predicted protein p.V576LfsX37; later literature represents the combined allele as c.1726_1728delGTCinsTT, p.Val576Leufs*38. Transfected cells showed impaired secretion. The same combined genotype was subsequently found with ectodermal findings and normal hearing, so the functional assay does not establish hearing-loss penetrance.
Show evidence (4 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: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.
PMID:27736875 SUPPORT Human Clinical
"All affected individuals of family A were found to carry a homozygous missense sequence variation, c.1726G>T, as well as a homozygous single base pair deletion in TSPEAR, c.1728delC (Fig 2A),"
The same combined genotype was observed in an ectodermal-dysplasia family whose examined patients had normal audiometry.
+ 1 more reference
TSPEAR NM_144991.3:c.668C>T (p.Ser223Leu)
Gene: TSPEAR hgnc:1268 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in TSPEAR (hgnc:1268). hgnc:1268 is a gene from the HUGO Gene Nomenclature Committee. missense variant
Reported homozygous in a six-year-old Iranian girl with prelingual hearing loss and unaffected heterozygous parents. The 2026 abstract calls it pathogenic, while the body calls it likely pathogenic citing PM2 and PP3. An earlier 2022 study had already reported this allele heterozygously in a dental/ectodermal case with normal hearing, so it is not a newly observed allele. Neither report establishes a general hearing-loss mechanism; no unqualified pathogenic hearing-loss classification is assigned here.
Show evidence (3 references)
PMID:41486137 SUPPORT Human Clinical
"WES conducted on the proband’s blood sample identified a novel homozygous variant in TSPEAR (NM_144991.3: c.668C > T, p. Ser223Leu)."
Records the 2026 genotype; the novelty claim is contradicted by the earlier 2022 report.
PMID:41486137 SUPPORT Human Clinical
"The variant is categorized as likely pathogenic on the basis of the standards for the interpretation of sequence variations recommended by ACMG 2015 criteria (PM2 and PP3 criteria) [11]."
This is the classification and limited criteria stated by the authors, not an independent gene-validity conclusion.
PMID:35741818 SUPPORT Human Clinical
"P2 had a heterozygous missense variant (c.668C>T; p.(Ser223Leu)) in exon 5 substituting serine for leucine."
The same allele was published in 2022 in a different clinical context. A second TSPEAR allele was not identified in that patient.
TSPEAR NM_144991.3:c.539A>T (p.Asp180Val) Uncertain Significance
Gene: TSPEAR hgnc:1268 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in TSPEAR (hgnc:1268). hgnc:1268 is a gene from the HUGO Gene Nomenclature Committee. missense variant
Maternal allele in the Chinese child with congenital hearing loss, later increased ABR thresholds and oral findings. The report classified it as VUS with PM2_Supporting; computational predictions disagreed. It was in trans with p.Arg122Gln.
Show evidence (1 reference)
PMID:39720278 SUPPORT Human Clinical
"Besides, the proband also carries compound heterozygous variants NM_144991.3 (TSPEAR): c.539A>T (p.Asp180Val) (Figure 1F) from her mother and NM_144991.3 (TSPEAR): c.365G>A, (p.Arg122Gln) (Figure 1G) from her father."
Parental testing establishes the variants in trans, but both were classified as VUS by the report.
TSPEAR NM_144991.3:c.365G>A (p.Arg122Gln) Uncertain Significance
Gene: TSPEAR hgnc:1268 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in TSPEAR (hgnc:1268). hgnc:1268 is a gene from the HUGO Gene Nomenclature Committee. missense variant
Paternal allele in trans with p.Asp180Val in the Chinese child. The paper classified it as VUS, citing BS1_Supporting and conflicting ClinVar interpretations. The child also carried a paternal P2RX2 intronic VUS; none of these findings alone proves the cause of hearing loss.
Show evidence (1 reference)
PMID:39720278 SUPPORT Human Clinical
"Besides, the proband also carries compound heterozygous variants NM_144991.3 (TSPEAR): c.539A>T (p.Asp180Val) (Figure 1F) from her mother and NM_144991.3 (TSPEAR): c.365G>A, (p.Arg122Gln) (Figure 1G) from her father."
Parental testing establishes the variants in trans, but both were classified as VUS by the report.
TSPEAR NM_144991.3:c.1870G>T (p.Glu624Ter) Uncertain Significance
Gene: TSPEAR hgnc:1268 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in TSPEAR (hgnc:1268). hgnc:1268 is a gene from the HUGO Gene Nomenclature Committee. nonsense variant
VUS found homozygously in a Roma proband with severe mid-frequency hearing loss. His similarly affected sister was heterozygous, weakening recessive cosegregation; the study did not investigate CNVs. The later dental cohort also included a homozygous 21-year-old with no clinical hearing concerns, without formal audiometry reported for that individual.
Show evidence (1 reference)
PMID:34795337 SUPPORT Human Clinical
"In the last family, FAM174, we detected VUS variant p.Glu624* in the TSPEAR gene (NM_144991.3). The proband’s sister (D1032) is also affected by HL but interestingly was found to only be a heterozygous carrier of the p.Glu624* variant."
The primary study describes discordant zygosity in similarly affected siblings. This is not straightforward recessive segregation.
TSPEAR p.Pro178Leu Uncertain Significance
Gene: TSPEAR hgnc:1268 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in TSPEAR (hgnc:1268). hgnc:1268 is a gene from the HUGO Gene Nomenclature Committee. missense variant
Homozygous TSPEAR VUS in a hearing-loss case who also carried a homozygous TMPRSS3 p.Gly402Arg VUS. Neither candidate was resolved as pathogenic in the cohort.
Show evidence (1 reference)
PMID:34042254 SUPPORT Human Clinical
"The TSPEAR and TMPRSS3 variants are currently classified as variants of uncertain significance (VUS; Table 2)."
Both variants in individual 1 remained uncertain, so a competing variant is not equivalent to a confirmed alternative diagnosis.
TSPEAR p.Val388Ala Uncertain Significance
Gene: TSPEAR hgnc:1268 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in TSPEAR (hgnc:1268). hgnc:1268 is a gene from the HUGO Gene Nomenclature Committee. missense variant
Homozygous TSPEAR VUS reported in an Iranian hearing-loss family, alongside homozygous TMPRSS3 p.Pro404Leu, which the study classified as likely pathogenic. The competing TMPRSS3 finding limits attribution to TSPEAR.
Show evidence (2 references)
PMID:34042254 SUPPORT Human Clinical
"Individual 2 is an Iranian male and one of two affected children born to consanguineous parents presenting with deafness and a homozygous c.1163C>T (p.Val388Ala) TSPEAR missense variant (Table 1)."
The source reports the protein change and candidate genotype; its nucleotide notation is retained only inside the exact quotation and is not independently normalized here.
PMID:34042254 SUPPORT Human Clinical
"Using the current available evidence, this TMPRSS3 variant was classified as likely pathogenic following review in this study (Table 2)."
The competing TMPRSS3 classification is stronger than the TSPEAR VUS attribution.
TSPEAR c.1566G>A (p.Pro522=)
Gene: TSPEAR hgnc:1268 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in TSPEAR (hgnc:1268). hgnc:1268 is a gene from the HUGO Gene Nomenclature Committee. synonymous variant with predicted splice effect
Reported with c.1676_1677delAT in a family with childhood-onset hearing loss and enlarged vestibular aqueduct. A splice effect was predicted rather than experimentally demonstrated. Transcript-specific alternative numbering in the original literature should not be mixed with this representation.
Show evidence (1 reference)
PMID:34042254 SUPPORT INDIRECT Human Clinical
"This individual underwent gene panel‐based hearing loss evaluation (OtoScope v5, 89 genes) which identified a c.1566G>A (p.Pro522Pro) TSPEAR variant which is predicted to impact splicing and a c.1676_1677delAT (p.Tyr559Cysfs*134) frame‐shift TSPEAR variant."
The cohort paper describes the earlier hearing-loss family. The synonymous allele has a predicted splice effect; this quotation does not report a splice assay.
TSPEAR c.1676_1677delAT (p.Tyr559CysfsTer134)
Gene: TSPEAR hgnc:1268 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in TSPEAR (hgnc:1268). hgnc:1268 is a gene from the HUGO Gene Nomenclature Committee. frameshift deletion
Reported with p.Pro522= in the hearing-loss family summarized by Bowles et al. The phenotype included enlarged vestibular aqueduct and proteinuria in the described index case; these observations do not establish that TSPEAR caused every finding.
Show evidence (1 reference)
PMID:34042254 SUPPORT INDIRECT Human Clinical
"This individual underwent gene panel‐based hearing loss evaluation (OtoScope v5, 89 genes) which identified a c.1566G>A (p.Pro522Pro) TSPEAR variant which is predicted to impact splicing and a c.1676_1677delAT (p.Tyr559Cysfs*134) frame‐shift TSPEAR variant."
The cohort paper describes the earlier hearing-loss family. The synonymous allele has a predicted splice effect; this quotation does not report a splice assay.
TSPEAR NM_144991.3:c.1728del (p.Lys577SerfsTer37), 2023 report
Gene: TSPEAR hgnc:1268 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in TSPEAR (hgnc:1268). hgnc:1268 is a gene from the HUGO Gene Nomenclature Committee. frameshift deletion
The 2023 Iranian sequencing cohort reports this homozygous deletion in a male with profound nonsyndromic hearing loss and consanguineous parents. Table 4 calls it pathogenic; this is the authors’ attribution. The table does not explicitly report the adjacent substitution of the founding combined allele, so that substitution is not inferred here.
Show evidence (1 reference)
PMID:37561809 SUPPORT Human Clinical
"TSPEAR(NM_144991.3):c.1728del:(p.Lys577SerfsTer37) | rs782540538 | Homo/AR | Pathogenic | Pathogenic | No/ ClinVar ID: 37311 | Profound SNHL | Male"
The source table supplies genotype and phenotype but not an independent resolution of the disputed gene-disease relationship.
🗃️

External Assertions

1
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 classified the autosomal recessive TSPEAR-nonsyndromic hearing loss relationship as Disputed in 2017 and retained that classification on 2024-10-31 under SOP v11 after reviewing newer case-level reports.
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.
💊

Medical Actions

4
Hearing Aids
Action: hearing aid amplificationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hearing aid amplification, annotated with Rehabilitation (NCIT:C15315), qualified as medical device hearing aid. NCIT:C15315 is a clinical intervention from the NCI Thesaurus. Ontology label: Rehabilitation NCIT:C15315
Platform: Device
Individualize amplification according to audiometry, aided benefit and communication needs. The Chinese child with two TSPEAR VUS received bilateral hearing aids at six months; her parents reported improved responses to quiet sounds. This is a subjective single-case observation, not a genotype-specific efficacy estimate.
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/books/NBK1434/ SUPPORT INDIRECT Other
"Hearing aids (sound amplification), ... customized by an audiologist to the degree and frequency of hearing loss, can be used in individuals with mild-to-severe hearing loss."
General guidance supports individualized amplification; it is not a DFNB98 outcome study.
PMID:39720278 SUPPORT Human Clinical
"The proband received bilateral hearing aids when she was 6 months old. According to her parents, she was able to respond normally to the minor sounds after wearing hearing aids."
The reported response comes from parental observation; standardized aided speech outcomes were not supplied.
Cochlear Implantation
Action: cochlear device implantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cochlear device implantation, annotated with Surgical Procedure (NCIT:C15329), qualified as medical device cochlear implant. NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Device
Consider cochlear implant evaluation for severe-to-profound hearing loss according to individual clinical and audiological assessment. General hearing-loss guidance supports this option; the disputed TSPEAR association does not predict candidacy or implant benefit.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/books/NBK1434/ SUPPORT INDIRECT Other
"Cochlear implantation can be considered in children with severe-to-profound hearing loss who are older than age nine months."
General guidance supports considering implantation after clinical assessment; this is not a DFNB98-specific efficacy claim.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Platform: Behavioral / lifestyle
Discuss family segregation, uncertainty in TSPEAR gene-disease validity and variant classification, and reproductive options. The conventional 25% recurrence risk applies when both parents carry the relevant recessive pathogenic allele and the molecular diagnosis is established; a candidate TSPEAR finding alone does not establish that risk attribution.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/books/NBK1434/ SUPPORT INDIRECT Other
"If both parents are known to be ... heterozygous ... autosomal recessive ... hearing loss-related ... pathogenic variant ... has at conception a 25% chance of having hearing loss"
The recurrence calculation is conditional on confirmed parental carrier genotypes, not merely a consanguineous pedigree.
Speech, Language and Communication Support
Action: speech and language therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is speech and language therapy, annotated with Speech Language Therapy (NCIT:C159273). NCIT:C159273 is a clinical intervention from the NCI Thesaurus. Ontology label: Speech Language Therapy NCIT:C159273
Platform: Behavioral / lifestyle
Early individualized speech, language, educational and communication support accompanies audiological care. D/deaf and hard-of-hearing community resources should be adapted to the child and family. This is general hearing-loss care; no DFNB98-specific intervention trial is implied.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/books/NBK1434/ SUPPORT INDIRECT Other
"A speech-language therapist as well as a neuropsychologist/psychologist for children with hearing loss provides access to resources within the community to aid in speech and language and D/deaf and hard of hearing (DHH) identity development."
General hearing-loss guidance supports communication services; no disease-specific treatment outcome is asserted.
🔬

Diagnosis

2
Genetic testing, interpreted against the disputed gene-disease relationship
Use comprehensive hearing-loss genetic testing with clinical correlation, segregation analysis and assessment of technical limitations. TSPEAR variants alone do not establish a hearing-loss diagnosis, and negative results for established genes do not prove TSPEAR causality. Competing TMPRSS3, GJB2 and GJB6 findings in reported cases require variant-specific interpretation rather than automatic attribution.
Show evidence (3 references)
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."
The cohort identified competing candidates; these included both uncertain and likely pathogenic findings, not three uniformly solved alternative diagnoses.
url:https://www.ncbi.nlm.nih.gov/books/NBK1434/ SUPPORT INDIRECT Other
"A multigene hearing loss panel ... can often identify the cause of genetic hearing loss while limiting identification of pathogenic variants and variants of ... uncertain significance ... in genes that are irrelevant to the underlying"
General guidance supports broad hearing-loss testing rather than isolated TSPEAR testing.
url:https://www.ncbi.nlm.nih.gov/books/NBK1434/ SUPPORT INDIRECT Other
"The identification of variant(s) of ... uncertain significance ... cannot be used to confirm or rule out the diagnosis."
Interpretation uncertainty must be preserved when considering candidate TSPEAR alleles.
Examination for dental and ectodermal features
Examine teeth, hair, nails, skin and sweating when TSPEAR variants are detected. Dental anomalies may indicate a separate TSPEAR-related ectodermal disorder; their absence does not validate a TSPEAR hearing-loss diagnosis. The six-year-old p.Ser223Leu proband had no abnormalities of teeth, skin, hair or nails on the reported examination.
Show evidence (1 reference)
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."
The report documents clinically normal ectodermal structures in this child; it does not establish lifelong absence or gene causality.
📊

Prevalence

1
Worldwide
Cases In Literature Not yet documented
No reliable population prevalence or hearing-loss penetrance estimate is established. The 2024 ClinGen review counted at least five distinct variants in at least four probands across four publications; this is a dated evidence summary, not an exhaustive current census. TSPEAR carrier-rate estimates for ectodermal dysplasia 14 do not estimate the prevalence of DFNB98.
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"
This is the case-evidence count in the October 2024 expert review; it does not include all subsequent reports or provide a population denominator.
🔀

Differential Diagnoses

2

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

🧫

Experimental Models

2
Founding TSPEAR frameshift transfection and secretion assay CELL_LINE
Cells transfected with the founding human truncating TSPEAR allele showed impaired secretion of the encoded protein. This heterologous assay tests secretion, not hair-cell physiology, cochlear localization or clinical penetrance.
Publication
PMID:22678063
Pathograph links
Failure of TSPEAR Secretion recapitulates fidelity: moderate The experiment directly measures the secretion phenotype of the founding allele.
Limitations: A transfected-cell assay does not reproduce the cochlear environment and does not establish the effects of later candidate missense variants.
Readouts
Secretion of mutant TSPEAR
Direction: DECREASED
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."
Secretion of the encoded mutant protein was reduced in the transfected-cell assay.
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 transfection experiment reproduces impaired secretion of the founding mutant protein, supporting the model link to this molecular event without establishing an auditory phenotype.
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 founding paper reports a cellular secretion experiment on the truncating allele, distinct from its clinical segregation and mouse-localization observations.
TSPEAR siRNA in keratinocytes and hair-follicle organ cultures OTHER
Comparative ectodermal-development experiments used primary human keratinocytes, a DLL1-stimulated HaCaT Notch reporter, and ex vivo skin strips from K14-H2B-GFP mice. Tspear was silenced by siRNA in the explants; K14-Cre generated the fluorescent lineage reporter, not a conditional Tspear knockout. Reduced Notch reporter activity and hair-follicle apoptosis support an ectodermal function but do not demonstrate an auditory causal pathway.
Publication
PMID:27736875
Show evidence (2 references)
PMID:27736875 SUPPORT In Vitro
"Luciferase activity in TSPEAR down-regulated cells was significantly decreased as compared with control cells, supporting a role for TSPEAR in the regulation of Notch signaling (Fig 3E)."
The measured Notch response comes from the transfected HaCaT system; it is not an inner-ear readout.
PMID:27736875 SUPPORT In Vitro
"Moreover, TSPEAR silencing in mouse hair follicle organ cultures was found to induce apoptosis in follicular epithelial cells, resulting in decreased hair bulb diameter."
This ex vivo mouse-tissue experiment supports an ectodermal function. No hearing test was part of this model.
🐁

Animal Models

1
Tspear S475TfsX79 CRISPR mouse
CRISPR-generated Tspear S475TfsX79 mice had preserved auditory function, stereociliary morphology, tooth morphology and hair development. The abstract reports reduced Notch1 and several downstream targets and increased Heyl in skin, plus increased Wnt4 in skin and inner ear. These tissue-specific molecular changes do not establish a Notch-mediated auditory lesion. The tested allele differs from the founding human allele; complete functional absence and human hearing penetrance cannot be inferred from the frameshift designation alone.
Species
Mouse
Genotype
Tspear S475TfsX79 frameshift, generated by CRISPR/Cas9 genome editing
Publication
PMID:40716589
Pathograph links
Impaired Cochlear Sound Transduction fails to recapitulate fidelity: moderate This mouse challenges the proposed auditory consequence of TSPEAR disruption because hearing remained intact.
Limitations: S475TfsX79 differs from the human founding allele. The available abstract does not establish the amount or activity of residual protein, test ages, or sensitivity to subtle deficits. Species-dependent effects and compensation remain hypotheses.
Readouts
Auditory function
Direction: UNCHANGED
Interpretation: The reported auditory measurements did not show impairment under the conditions examined; this is a measured negative finding for this model.
Show evidence (1 reference)
PMID:40716589 REFUTE Model Organism
"Intriguingly, stereociliary morphology and auditory function remain unaffected in TSPEAR S475TfsX79 mutant mice."
The specific mouse frameshift did not reproduce the predicted auditory dysfunction or bundle malformation. This does not establish that every human allele is functionally equivalent.
Show evidence (1 reference)
PMID:40716589 REFUTE Model Organism
"Intriguingly, stereociliary morphology and auditory function remain unaffected in TSPEAR S475TfsX79 mutant mice."
The absence of auditory impairment supports a FAILS_TO_RECAPITULATE link to the proposed cochlear dysfunction. Allele differences and the limited assay information in the abstract constrain extrapolation to human disease.
{ }

Source YAML

click to show 
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 denotes a proposed autosomal recessive sensorineural hearing-loss association with TSPEAR. The founding
  report described congenital profound deafness in a consanguineous Iranian family, but ClinGen retained a Disputed
  classification for TSPEAR-related nonsyndromic hearing loss in October 2024. Later hearing-loss reports include
  candidate variants and incomplete segregation, while other individuals carrying biallelic TSPEAR variants have
  dental or ectodermal findings without hearing loss. A Tspear S475TfsX79 mouse also had preserved auditory function.
  These observations challenge a general auditory loss-of-function mechanism without proving that every reported
  hearing-loss association is incidental. The reported clinical findings and proposed mechanism require interpretation
  separately from the better-supported TSPEAR-related ectodermal dysplasia 14 association.

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 classified the autosomal recessive TSPEAR-nonsyndromic hearing
    loss relationship as Disputed in 2017 and retained that classification on 2024-10-31 under SOP v11 after reviewing
    newer case-level reports.
  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.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    No reliable population prevalence or hearing-loss penetrance estimate is established. The 2024 ClinGen review
    counted at least five distinct variants in at least four probands across four publications; this is a dated
    evidence summary, not an exhaustive current census. TSPEAR carrier-rate estimates for ectodermal dysplasia 14
    do not estimate the prevalence of DFNB98.
  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: >-
      This is the case-evidence count in the October 2024 expert review; it does not include all subsequent reports
      or provide a population denominator.

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 auditory mechanism links defective secretion of the founding truncating allele to reduced TSPEAR
    availability at the hair-bundle surface and impaired cochlear function. Secretion impairment was measured in
    transfected cells, whereas localization was examined in mouse sensory cells. These separate observations do
    not demonstrate loss of bundle-localized protein or a causal auditory defect in the human variant carriers.
    Preserved hearing and stereociliary morphology in S475TfsX79 mice challenge a general frameshift mechanism,
    with allele and species limitations.
  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: >-
      Preserved stereociliary morphology and hearing challenge a general auditory frameshift mechanism in mice.
      This allele differs from the founding human allele, so the result does not directly test every human genotype.
  - reference: PMID:41195743
    reference_title: "Genotypes and Phenotypes of Patients With TSPEAR-Related Disorder: Evidence of a Predominant Dental Phenotype."
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, the role of TSPEAR in auditory processes is unclear.
    explanation: >-
      This introductory statement identifies uncertainty rather than reporting a negative experiment. The cohort
      observations are represented separately.

pathophysiology:
- name: Homozygous Founding TSPEAR Frameshift Variant
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    The founding family carried the homozygous combined allele c.1726G>T+c.1728delC, reported as p.V576LfsX37 in
    2012 and as c.1726_1728delGTCinsTT, p.Val576Leufs*38 in later literature. This node describes that allele and
    its secretion experiment, not the unassayed missense alleles in subsequent candidate cases.
  genetic_context:
    gene:
      preferred_term: TSPEAR
      term:
        id: hgnc:1268
        label: TSPEAR
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Homozygosity and impaired secretion are documented for the founding allele. This does not establish complete
      loss of every protein function or extend a loss-of-function classification to unassayed missense variants.
  downstream:
  - target: Failure of TSPEAR Secretion
    causal_link_type: DIRECT
    hypothesis_groups:
    - tspear_hair_bundle_deafness
    description: >-
      The founding truncating allele impaired protein secretion in transfected cells. This directly tested step
      does not establish its downstream auditory consequences.
  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.
- name: Failure of TSPEAR Secretion
  role: central_effector
  biological_scale: MOLECULAR
  description: >-
    The founding truncating allele impaired TSPEAR secretion in transfected cells. This heterologous assay establishes
    a protein-trafficking effect under its experimental conditions, not a measurement of secretion or auditory function
    in patient hair cells.
  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: >-
      Reduced secretion could reduce extracellular TSPEAR availability at the hair-bundle surface. Neither mutant
      bundle localization nor the functional consequences of reduced localization were directly measured in the
      cited human-allele experiment.
  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: >-
    Mouse immunofluorescence localized TSPEAR to sensory-cell hair bundles. Reduced availability at this surface
    is a proposed consequence of impaired secretion, not a measured lesion in patients or in a model carrying the
    founding human allele. Localization does not establish an indispensable structural or transduction function.
  cell_types:
  - preferred_term: cochlear sensory hair cell
    term:
      id: CL:4023120
      label: cochlea auditory hair cell
  downstream:
  - target: Impaired Cochlear Sound Transduction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - tspear_hair_bundle_deafness
    description: >-
      A connection between reduced bundle-localized TSPEAR and impaired auditory function remains hypothetical.
      Normal hearing in the S475TfsX79 model is contrary evidence for a general frameshift effect, with allele and
      species limits.
  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: >-
      This supports localization in normal mouse tissue, not loss of protein from a mutant bundle.
  - 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: >-
      Normal morphology and hearing in this different frameshift model challenge a general auditory defect but do
      not measure TSPEAR localization at the bundle surface.

- name: Impaired Cochlear Sound Transduction
  role: consequence
  biological_scale: ORGANISM
  description: >-
    Audiological testing in the founding family indicated at least a cochlear defect. The six-year-old p.Ser223Leu
    proband had absent ABR and severe bilateral hearing loss; the Chinese proband had measurable ABR thresholds
    and absent otoacoustic emissions. These findings establish auditory impairment in reported cases without resolving
    TSPEAR causality.
  biological_processes:
  - preferred_term: sensory perception of sound
    term:
      id: GO:0007605
      label: sensory perception of sound
    modifier: DECREASED
  downstream:
  - target: Sensorineural Hearing Loss in Reported TSPEAR Cases
    causal_link_type: DIRECT
    hypothesis_groups:
    - tspear_hair_bundle_deafness
    description: >-
      Impaired cochlear function produces hearing loss, but attribution of that dysfunction to the upstream TSPEAR
      hypothesis remains disputed.
  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: >-
      All three newly reported hearing-loss cases carried competing variants. Their evidence strengths differ: some
      remain VUS, so alternative causality is not established uniformly.
  - 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: >-
      The dental-ascertained cohort had no clinical hearing concerns in 11 individuals; the full text reports normal
      audiometry in only four. This challenges general hearing-loss penetrance but does not exclude allele-specific
      effects.

phenotypes:
- category: Otologic
  name: Sensorineural Hearing Loss in Reported TSPEAR Cases
  description: >-
    Reported candidate TSPEAR cases include congenital profound hearing loss in the founding family and bilateral
    severe-to-profound loss in a six-year-old Iranian girl. Hearing loss is not uniformly profound: the Chinese
    proband had bilateral ABR thresholds of 65 dBnHL at six months and 80 dBnHL at six years. These clinical observations
    do not establish TSPEAR causality. Mixed hearing-loss and dental referrals, uncertain variants and incomplete
    audiometry preclude a disease-wide phenotype frequency.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: 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: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: >-
      Her hearing thresholds at 6 months were 65 dBnHL in both ears with normal acoustic impedance results, and
      then she was diagnosed with congenital sensorineural hearing loss.
    explanation: >-
      The reported hearing impairment is less severe than the profound loss in the founding family; the two TSPEAR
      missense variants were classified as VUS.
- category: Otologic
  name: Absent Auditory Brainstem Response
  description: >-
    Absent auditory brainstem responses and a flat pure-tone audiogram were reported in the six-year-old girl with
    homozygous p.Ser223Leu. Other reported cases had measurable ABR thresholds; no frequency estimate is established.
  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: >-
      This describes the 2026 proband, not a universal finding in candidate TSPEAR-associated hearing loss.

- category: Oral
  name: Ankyloglossia in the Chinese Proband
  description: >-
    The Chinese proband with two TSPEAR missense VUS had ankyloglossia, a heart-shaped tongue and dental caries.
    Tongue restriction and speech difficulty persisted after three corrective operations. These are case-level observations;
    they do not establish an ectodermal-dysplasia diagnosis or a general DFNB98 oral phenotype.
  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: >-
      The proband also demonstrated dental caries (Figure 1A), ankyloglossia (Figure 1B), and heart‐shaped tongue
      (Figure 1C).
    explanation: >-
      The primary case report directly names the tongue abnormality; causal attribution to TSPEAR remains uncertain.

- name: Progressive Hearing Loss in the Chinese Proband
  category: Otologic
  description: >-
    Serial ABR thresholds in one child increased from 65 dBnHL bilaterally at six months to 80 dBnHL at six years.
    This documents worsening in that case, not a progression rate or established natural history for TSPEAR-related
    hearing loss.
  phenotype_term:
    preferred_term: Progressive sensorineural hearing impairment
    term:
      id: HP:0000408
      label: Progressive sensorineural hearing impairment
  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: >-
      An ABR test conducted at the age of 6 years showed that hearing thresholds of both ears were 80 dBnHL.
    explanation: >-
      The later measurement follows bilateral thresholds of 65 dBnHL at six months in the same report.
- name: Absent Otoacoustic Emissions in the Chinese Proband
  category: Otologic
  description: >-
    Bilateral distortion-product otoacoustic emissions were absent in the reported Chinese child; this clinical
    result does not establish a TSPEAR-specific cellular lesion.
  phenotype_term:
    preferred_term: Absent otoacoustic emissions
    term:
      id: HP:6000182
      label: Absent otoacoustic emissions
  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: >-
      Distortion product otoacoustic emission was not elicited on both sides.
    explanation: >-
      Direct audiological finding in a single candidate case.
- name: Enlarged Vestibular Aqueduct in a Reported Family
  category: Otologic
  description: >-
    Enlarged vestibular aqueduct accompanied childhood-onset hearing loss in the family with p.Pro522= and p.Tyr559CysfsTer134
    variants summarized in the 2021 cohort paper. This is a reported case feature rather than an established TSPEAR-specific
    malformation.
  phenotype_term:
    preferred_term: Enlarged vestibular aqueduct
    term:
      id: HP:0011387
      label: Enlarged vestibular aqueduct
  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: >-
      a 2016 report describing siblings with childhood onset, nonsyndromic, bilateral hearing loss, EVA, and compound
      heterozygous TSPEAR variants
    explanation: >-
      The later cohort paper summarizes the reported family; gene attribution remains disputed.
    directness: INDIRECT
- name: Speech Difficulties in Reported Cases
  category: Neurologic
  description: >-
    The six-year-old Iranian child had speech difficulties interfering with school performance after prelingual
    hearing loss. The Chinese child also had persistent speech difficulty with ankyloglossia despite corrective
    surgery. These observations do not establish a primary neurological TSPEAR phenotype.
  phenotype_term:
    preferred_term: Poor speech
    term:
      id: HP:0002465
      label: Poor speech
  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: >-
      After the occurrence of this prelingual form of profound hearing loss, she had also speech disorders interfering
      with normal school performance.
    explanation: >-
      The case describes speech and educational effects without establishing a separate developmental syndrome.
  - 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: >-
      Tongue restriction and hearing impairment may both be relevant; the report does not quantify their individual
      contributions.
genetic:
- name: TSPEAR
  gene_term:
    preferred_term: TSPEAR
    term:
      id: hgnc:1268
      label: TSPEAR
  relationship_type: DISPUTED
  notes: >-
    TSPEAR encodes a secreted protein containing a thrombospondin-type laminin G domain and seven epilepsy-associated
    repeats. Its association with nonsyndromic hearing loss remains Disputed. A biallelic candidate genotype alone
    does not establish a molecular explanation for hearing loss. TSPEAR-related ectodermal dysplasia 14 is a distinct,
    better-supported association.
  evidence:
  - reference: CGGV:assertion_f0928b06-d3bb-41fe-8222-d7f0e6c0a25a-2024-10-31T160000.000Z
    reference_title: TSPEAR / nonsyndromic genetic hearing loss (Disputed)
    supports: NO_EVIDENCE
    evidence_source: OTHER
    snippet: >-
      More evidence is needed to either support or refute the role TSPEAR plays in this
      disease.
    explanation: >-
      The panel explicitly describes unresolved causality; this sentence alone is not an experimental refutation.
  - 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: >-
      Discordant TSPEAR zygosity in similarly affected siblings weakens simple recessive segregation in this family.
  - 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 ClinGen summary cites normal-hearing ectodermal families as conflicting evidence. The primary 2016 paper
      documents the founding combined genotype in family A and normal audiometry in families A and C; family C carried
      different missense variants.
  - 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 dental-ascertained cohort had no clinical hearing concerns in 11 individuals; the full text reports normal
      audiometry in only four. This challenges general hearing-loss penetrance but does not exclude allele-specific
      effects.
  - 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.

  - reference: url:https://discovery.ucl.ac.uk/id/eprint/10174155/1/1-s2.0-S2666247723000180-main.pdf
    reference_title: https://discovery.ucl.ac.uk/id/eprint/10174155/1/1-s2.0-S2666247723000180-main.pdf
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, none of the affected individuals in our cohort were reported with sensorineural hearing impairment.
    explanation: >-
      Clinical, genetic, epidemiologic, evolutionary, and functional delineation of TSPEAR-related autosomal recessive
      ectodermal dysplasia 14. The 2023 study described 11 new individuals and combined phenotypes from 30 dental/ectodermal
      cases. Absence of reported hearing impairment in this ascertained cohort is conflicting evidence, not a population
      penetrance estimate.
  - reference: url:https://flore.unifi.it/retrieve/7d92d0aa-e251-46f0-8555-6584ec139e54/Vergani%20et%20al%202025%20TSPEAR.pdf
    reference_title: 'https://flore.unifi.it/retrieve/7d92d0aa-e251-46f0-8555-6584ec139e54/Vergani%20et%20al%202025%20TSPEAR.pdf'
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Audiometric testing was performed in 4/11 patients with normal results in all.
    explanation: >-
      Genotypes and Phenotypes of Patients With TSPEAR-Related Disorder: Evidence of a Predominant Dental Phenotype.
      The full text distinguishes four formally tested individuals from the seven assessed clinically. The cohort
      was selected for ectodermal manifestations or tooth agenesis; it cannot establish that hearing loss never
      occurs with TSPEAR variants.
  - reference: PMID:27736875
    reference_title: Mutations in TSPEAR, Encoding a Regulator of Notch Signaling, Affect Tooth and Hair Follicle Morphogenesis.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, this mutation was identified in the present study in a homozygous state in 2 different patients with
      hypotrichosis, hypodontia and normal hearing (Fig 1A).
    explanation: >-
      The 2016 study reports normal hearing in patients carrying the previously implicated deletion. Its clinical
      section specifies normal audiometry for families A and C; this observation challenges obligatory deafness
      from the founding genotype.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Autosomal recessive inheritance was proposed from the founding pedigree. Subsequent reports include homozygous
    and compound heterozygous candidate genotypes, but gene-disease validity remains disputed. In the mid-frequency
    hearing-loss family, the p.Glu624Ter proband was homozygous while his similarly affected sister was heterozygous,
    weakening simple recessive segregation of this allele with hearing loss.
  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: >-
    CRISPR-generated Tspear S475TfsX79 mice had preserved auditory function, stereociliary morphology, tooth morphology
    and hair development. The abstract reports reduced Notch1 and several downstream targets and increased Heyl
    in skin, plus increased Wnt4 in skin and inner ear. These tissue-specific molecular changes do not establish
    a Notch-mediated auditory lesion. The tested allele differs from the founding human allele; complete functional
    absence and human hearing penetrance cannot be inferred from the frameshift designation alone.
  modeled_mechanisms:
  - target: Impaired Cochlear Sound Transduction
    relationship: FAILS_TO_RECAPITULATE
    fidelity: MODERATE
    description: >-
      This mouse challenges the proposed auditory consequence of TSPEAR disruption because hearing remained intact.
    limitations: >-
      S475TfsX79 differs from the human founding allele. The available abstract does not establish the amount or
      activity of residual protein, test ages, or sensitivity to subtle deficits. Species-dependent effects and
      compensation remain hypotheses.
    readouts:
    - name: Auditory function
      target: Impaired Cochlear Sound Transduction
      direction: UNCHANGED
      interpretation: >-
        The reported auditory measurements did not show impairment under the conditions examined; this is a measured
        negative finding for this model.
      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 specific mouse frameshift did not reproduce the predicted auditory dysfunction or bundle malformation.
          This does not establish that every human allele is functionally equivalent.
    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 absence of auditory impairment supports a FAILS_TO_RECAPITULATE link to the proposed cochlear dysfunction.
        Allele differences and the limited assay information in the abstract constrain extrapolation to human disease.
diagnosis:
- name: Genetic testing, interpreted against the disputed gene-disease relationship
  description: >-
    Use comprehensive hearing-loss genetic testing with clinical correlation, segregation analysis and assessment
    of technical limitations. TSPEAR variants alone do not establish a hearing-loss diagnosis, and negative results
    for established genes do not prove TSPEAR causality. Competing TMPRSS3, GJB2 and GJB6 findings in reported cases
    require variant-specific interpretation rather than automatic attribution.
  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: >-
      The cohort identified competing candidates; these included both uncertain and likely pathogenic findings,
      not three uniformly solved alternative diagnoses.

  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1434/
    reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A multigene hearing loss panel ... can often identify the cause of genetic hearing loss while limiting identification
      of pathogenic variants and variants of ... uncertain significance ... in genes that are irrelevant to the
      underlying
    explanation: >-
      General guidance supports broad hearing-loss testing rather than isolated TSPEAR testing.
    directness: INDIRECT
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1434/
    reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The identification of variant(s) of ... uncertain significance ... cannot be used to confirm or rule out the
      diagnosis.
    explanation: >-
      Interpretation uncertainty must be preserved when considering candidate TSPEAR alleles.
    directness: INDIRECT
- name: Examination for dental and ectodermal features
  description: >-
    Examine teeth, hair, nails, skin and sweating when TSPEAR variants are detected. Dental anomalies may indicate
    a separate TSPEAR-related ectodermal disorder; their absence does not validate a TSPEAR hearing-loss diagnosis.
    The six-year-old p.Ser223Leu proband had no abnormalities of teeth, skin, hair or nails on the reported examination.
  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: >-
      The report documents clinically normal ectodermal structures in this child; it does not establish lifelong
      absence or gene causality.
differential_diagnoses:
- name: TSPEAR-related autosomal recessive ectodermal dysplasia 14 (ARED14/ECTD14)
  description: >-
    TSPEAR-related ectodermal dysplasia 14 has a predominantly dental phenotype, including conical teeth and hypodontia
    or oligodontia, sometimes with hair, nail or sweating abnormalities. It is distinct from the disputed nonsyndromic
    hearing-loss association. Published population estimates of TSPEAR deleterious-allele carrier frequency concern
    this dental/ectodermal association and include predicted deleterious missense alleles, not only truncating variants.
  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: >-
    Established hearing-loss genes remain relevant when TSPEAR variants are found. In the 2021 cohort, one hearing-loss
    case carried VUS in both TSPEAR and TMPRSS3, another carried a TSPEAR VUS and a TMPRSS3 variant judged likely
    pathogenic, and a third had TSPEAR variants together with a GJB2 frameshift and a GJB6-region deletion. These
    findings warrant case-specific review of phase, classification and assay coverage.
  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: >-
      These are competing genetic findings in the three newly described hearing-loss cases; they do not uniformly
      establish an alternative molecular diagnosis.

discussions:
- discussion_id: gap_tspear_hearing_gene_validity
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - genetic#TSPEAR
  - mechanistic_hypotheses#tspear_hair_bundle_deafness
  prompt: >-
    Which, if any, TSPEAR genotypes confer hearing-loss risk independently of other genetic or acquired causes?
  rationale: >-
    Human reports combine segregation evidence, VUS, competing hearing-loss variants and a family with discordant
    TSPEAR zygosity among similarly affected siblings. Dental cohorts include people without hearing concerns, but
    audiometric ascertainment is incomplete in some studies. These observations leave allele-specific effects, reduced
    penetrance and alternative etiologies unresolved.
  proposed_experiments:
  - experiment_id: tspear_unselected_hearing_ascertainment
    name: Standardized audiometry and genomic reassessment across TSPEAR genotypes
    description: >-
      Recruit a genotype-defined series from hearing-loss and dental referrals with documented ascertainment. Obtain
      age-appropriate audiometry, otoacoustic emissions and ABR where indicated, and reassess genomic data for competing
      causes, phase, CNVs and noncoding variants. Compare hearing outcomes with suitable controls and stratify by
      allele.
    would_support:
    - genetic#TSPEAR
    supporting_outcome:
    - >-
      Replicated enrichment of hearing impairment for a particular genotype, with segregation and functional support
      and without a stronger competing explanation, would strengthen an allele-specific auditory association.
    refuting_outcome:
    - >-
      Normal hearing across adequately assessed carriers or identification of better-supported alternative causes
      would weaken the auditory association. Neither result alone predetermines an expert-panel classification or
      ontology action.
- 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: >-
    How do the molecular and auditory effects of the human founding allele compare with the mouse S475TfsX79 allele?
  rationale: >-
    Normal hearing in the S475TfsX79 mouse contrasts with reported hearing loss in human variant carriers. Localization
    in normal mouse hair bundles is not proof of essential function, and the two alleles may differ in residual
    protein, secretion or compensation. Direct allele comparisons are needed before extrapolating this negative
    model result to every human TSPEAR genotype.
  proposed_experiments:
  - experiment_id: tspear_human_allele_knockin_mouse
    name: Knock-in of the human p.V576LfsX37 allele with EAR-paralogue compensation testing
    description: >-
      Compare the human founding allele with S475TfsX79 in matched genetic backgrounds, measuring transcript and
      protein abundance, secretion and bundle localization alongside auditory thresholds and stereociliary morphology.
      Assess proposed compensatory expression rather than assuming it.
    would_support:
    - pathophysiology#Loss of TSPEAR from the Hair Bundle Surface
    supporting_outcome:
    - >-
      An allele-dependent loss of secretion and bundle localization accompanied by an auditory deficit would support
      the proposed chain, with human relevance still requiring clinical corroboration.
    refuting_outcome:
    - >-
      Preserved hearing despite verified comparable disruption would weaken this proposed auditory mechanism under
      the tested conditions without excluding all possible allele- or species-specific effects.
notes: >-
  The clinical findings described here come from published hearing-loss cases with TSPEAR variants whose causal
  attribution remains disputed. Dental cohorts, computational structural analyses and ectodermal-development models
  provide comparative evidence; their phenotypes and carrier frequencies should not be treated as DFNB98 natural
  history.

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)
- reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1434/
  title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
  tags:
  - GeneReviews
- reference: url:https://discovery.ucl.ac.uk/id/eprint/10174155/1/1-s2.0-S2666247723000180-main.pdf
  title: https://discovery.ucl.ac.uk/id/eprint/10174155/1/1-s2.0-S2666247723000180-main.pdf
- reference: url:https://flore.unifi.it/retrieve/7d92d0aa-e251-46f0-8555-6584ec139e54/Vergani%20et%20al%202025%20TSPEAR.pdf
  title: 'https://flore.unifi.it/retrieve/7d92d0aa-e251-46f0-8555-6584ec139e54/Vergani%20et%20al%202025%20TSPEAR.pdf'
- reference: PMID:27736875
  title: Mutations in TSPEAR, Encoding a Regulator of Notch Signaling, Affect Tooth and Hair Follicle Morphogenesis.
- reference: PMID:35741818
  title: Confirmation of a Phenotypic Entity for TSPEAR Variants in Egyptian Ectodermal Dysplasia Patients and Role of Ethnicity.
- reference: PMID:37561809
  title: Exome sequencing identifies novel variants associated with non-syndromic hearing loss in the Iranian population.
treatments:
- name: Hearing Aids
  therapeutic_modality: DEVICE
  description: >-
    Individualize amplification according to audiometry, aided benefit and communication needs. The Chinese child
    with two TSPEAR VUS received bilateral hearing aids at six months; her parents reported improved responses to
    quiet sounds. This is a subjective single-case observation, not a genotype-specific efficacy estimate.
  treatment_term:
    preferred_term: hearing aid amplification
    term:
      id: NCIT:C15315
      label: Rehabilitation
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: hearing aid
        term:
          id: NCIT:C183182
          label: Hearing Aid
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1434/
    reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Hearing aids (sound amplification), ... customized by an audiologist to the degree and frequency of hearing
      loss, can be used in individuals with mild-to-severe hearing loss.
    explanation: >-
      General guidance supports individualized amplification; it is not a DFNB98 outcome study.
    directness: INDIRECT
  - 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: >-
      The proband received bilateral hearing aids when she was 6 months old. According to her parents, she was able
      to respond normally to the minor sounds after wearing hearing aids.
    explanation: >-
      The reported response comes from parental observation; standardized aided speech outcomes were not supplied.
- name: Cochlear Implantation
  description: >-
    Consider cochlear implant evaluation for severe-to-profound hearing loss according to individual clinical and
    audiological assessment. General hearing-loss guidance supports this option; the disputed TSPEAR association
    does not predict candidacy or implant benefit.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: cochlear device implantation
    term:
      id: NCIT:C15329
      label: Surgical Procedure
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: cochlear implant
        term:
          id: NCIT:C157820
          label: Cochlear Implant
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1434/
    reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Cochlear implantation can be considered in children with severe-to-profound hearing loss who are older than age nine months.
    explanation: >-
      General guidance supports considering implantation after clinical assessment; this is not a DFNB98-specific
      efficacy claim.
    directness: INDIRECT
- name: Genetic Counseling
  description: >-
    Discuss family segregation, uncertainty in TSPEAR gene-disease validity and variant classification, and reproductive
    options. The conventional 25% recurrence risk applies when both parents carry the relevant recessive pathogenic
    allele and the molecular diagnosis is established; a candidate TSPEAR finding alone does not establish that
    risk attribution.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1434/
    reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: If both parents are known to be ... heterozygous ... autosomal recessive ... hearing loss-related ... pathogenic variant ... has at conception a 25% chance of having hearing loss
    explanation: The recurrence calculation is conditional on confirmed parental carrier genotypes, not merely a consanguineous pedigree.
    directness: INDIRECT
- name: Speech, Language and Communication Support
  description: >-
    Early individualized speech, language, educational and communication support accompanies audiological care.
    D/deaf and hard-of-hearing community resources should be adapted to the child and family. This is general hearing-loss
    care; no DFNB98-specific intervention trial is implied.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: speech and language therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1434/
    reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: A speech-language therapist as well as a neuropsychologist/psychologist for children with hearing loss provides access to resources within the community to aid in speech and language and D/deaf and hard of hearing (DHH) identity development.
    explanation: General hearing-loss guidance supports communication services; no disease-specific treatment outcome is asserted.
    directness: INDIRECT
experimental_models:
- name: Founding TSPEAR frameshift transfection and secretion assay
  experimental_model_type: CELL_LINE
  publication: PMID:22678063
  description: >-
    Cells transfected with the founding human truncating TSPEAR allele showed impaired secretion of the encoded
    protein. This heterologous assay tests secretion, not hair-cell physiology, cochlear localization or clinical
    penetrance.
  modeled_mechanisms:
  - target: Failure of TSPEAR Secretion
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The experiment directly measures the secretion phenotype of the founding allele.
    limitations: >-
      A transfected-cell assay does not reproduce the cochlear environment and does not establish the effects of
      later candidate missense variants.
    readouts:
    - name: Secretion of mutant TSPEAR
      target: Failure of TSPEAR Secretion
      direction: DECREASED
      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: >-
          Secretion of the encoded mutant protein was reduced in the transfected-cell assay.

    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 transfection experiment reproduces impaired secretion of the founding mutant protein, supporting the
        model link to this molecular event without establishing an auditory phenotype.

  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 founding paper reports a cellular secretion experiment on the truncating allele, distinct from its clinical
      segregation and mouse-localization observations.
- name: TSPEAR siRNA in keratinocytes and hair-follicle organ cultures
  experimental_model_type: OTHER
  publication: PMID:27736875
  description: >-
    Comparative ectodermal-development experiments used primary human keratinocytes, a DLL1-stimulated HaCaT Notch
    reporter, and ex vivo skin strips from K14-H2B-GFP mice. Tspear was silenced by siRNA in the explants; K14-Cre
    generated the fluorescent lineage reporter, not a conditional Tspear knockout. Reduced Notch reporter activity
    and hair-follicle apoptosis support an ectodermal function but do not demonstrate an auditory causal pathway.
  evidence:
  - reference: PMID:27736875
    reference_title: Mutations in TSPEAR, Encoding a Regulator of Notch Signaling, Affect Tooth and Hair Follicle Morphogenesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Luciferase activity in TSPEAR down-regulated cells was significantly decreased as compared with control cells,
      supporting a role for TSPEAR in the regulation of Notch signaling (Fig 3E).
    explanation: >-
      The measured Notch response comes from the transfected HaCaT system; it is not an inner-ear readout.
  - reference: PMID:27736875
    reference_title: Mutations in TSPEAR, Encoding a Regulator of Notch Signaling, Affect Tooth and Hair Follicle Morphogenesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Moreover, TSPEAR silencing in mouse hair follicle organ cultures was found to induce apoptosis in follicular
      epithelial cells, resulting in decreased hair bulb diameter.
    explanation: >-
      This ex vivo mouse-tissue experiment supports an ectodermal function. No hearing test was part of this model.
variants:
- name: TSPEAR c.1726G>T+c.1728delC (founding frameshift)
  gene:
    preferred_term: TSPEAR
    term:
      id: hgnc:1268
      label: TSPEAR
  type: combined substitution and deletion causing frameshift
  description: >-
    Homozygous in the founding Iranian family. The 2012 paper calls the predicted protein p.V576LfsX37; later literature
    represents the combined allele as c.1726_1728delGTCinsTT, p.Val576Leufs*38. Transfected cells showed impaired
    secretion. The same combined genotype was subsequently found with ectodermal findings and normal hearing, so
    the functional assay does not establish hearing-loss penetrance.
  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: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.

  - reference: PMID:27736875
    reference_title: "Mutations in TSPEAR, Encoding a Regulator of Notch Signaling, Affect Tooth and Hair Follicle Morphogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All affected individuals of family A were found to carry a homozygous missense sequence variation, c.1726G>T,
      as well as a homozygous single base pair deletion in TSPEAR, c.1728delC (Fig 2A),
    explanation: >-
      The same combined genotype was observed in an ectodermal-dysplasia family whose examined patients had normal
      audiometry.
  - reference: PMID:27736875
    reference_title: "Mutations in TSPEAR, Encoding a Regulator of Notch Signaling, Affect Tooth and Hair Follicle Morphogenesis."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Audiometry performed in family A and family C patients was normal (clinical information on all families is
      summarized in S1 Table).
    explanation: >-
      Normal audiometry in family A is contrary to obligatory hearing loss from the founding genotype. Family C
      carried different missense variants.
- name: TSPEAR NM_144991.3:c.668C>T (p.Ser223Leu)
  gene:
    preferred_term: TSPEAR
    term:
      id: hgnc:1268
      label: TSPEAR
  type: missense variant
  description: >-
    Reported homozygous in a six-year-old Iranian girl with prelingual hearing loss and unaffected heterozygous
    parents. The 2026 abstract calls it pathogenic, while the body calls it likely pathogenic citing PM2 and PP3.
    An earlier 2022 study had already reported this allele heterozygously in a dental/ectodermal case with normal
    hearing, so it is not a newly observed allele. Neither report establishes a general hearing-loss mechanism;
    no unqualified pathogenic hearing-loss classification is assigned here.
  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: >-
      WES conducted on the proband’s blood sample identified a novel homozygous variant in TSPEAR (NM_144991.3:
      c.668C > T, p. Ser223Leu).
    explanation: >-
      Records the 2026 genotype; the novelty claim is contradicted by the earlier 2022 report.
  - 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 variant is categorized as likely pathogenic on the basis of the standards for the interpretation of sequence
      variations recommended by ACMG 2015 criteria (PM2 and PP3 criteria) [11].
    explanation: >-
      This is the classification and limited criteria stated by the authors, not an independent gene-validity conclusion.
  - reference: PMID:35741818
    reference_title: Confirmation of a Phenotypic Entity for TSPEAR Variants in Egyptian Ectodermal Dysplasia Patients and Role of Ethnicity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      P2 had a heterozygous missense variant (c.668C>T; p.(Ser223Leu)) in exon 5 substituting serine for leucine.
    explanation: >-
      The same allele was published in 2022 in a different clinical context. A second TSPEAR allele was not identified
      in that patient.
- name: TSPEAR NM_144991.3:c.539A>T (p.Asp180Val)
  gene:
    preferred_term: TSPEAR
    term:
      id: hgnc:1268
      label: TSPEAR
  type: missense variant
  description: >-
    Maternal allele in the Chinese child with congenital hearing loss, later increased ABR thresholds and oral findings.
    The report classified it as VUS with PM2_Supporting; computational predictions disagreed. It was in trans with
    p.Arg122Gln.
  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: >-
      Besides, the proband also carries compound heterozygous variants NM_144991.3 (TSPEAR): c.539A>T (p.Asp180Val)
      (Figure 1F) from her mother and NM_144991.3 (TSPEAR): c.365G>A, (p.Arg122Gln) (Figure 1G) from her father.
    explanation: >-
      Parental testing establishes the variants in trans, but both were classified as VUS by the report.
  clinical_significance: UNCERTAIN_SIGNIFICANCE
- name: TSPEAR NM_144991.3:c.365G>A (p.Arg122Gln)
  gene:
    preferred_term: TSPEAR
    term:
      id: hgnc:1268
      label: TSPEAR
  type: missense variant
  description: >-
    Paternal allele in trans with p.Asp180Val in the Chinese child. The paper classified it as VUS, citing BS1_Supporting
    and conflicting ClinVar interpretations. The child also carried a paternal P2RX2 intronic VUS; none of these
    findings alone proves the cause of hearing loss.
  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: >-
      Besides, the proband also carries compound heterozygous variants NM_144991.3 (TSPEAR): c.539A>T (p.Asp180Val)
      (Figure 1F) from her mother and NM_144991.3 (TSPEAR): c.365G>A, (p.Arg122Gln) (Figure 1G) from her father.
    explanation: >-
      Parental testing establishes the variants in trans, but both were classified as VUS by the report.
  clinical_significance: UNCERTAIN_SIGNIFICANCE
- name: TSPEAR NM_144991.3:c.1870G>T (p.Glu624Ter)
  gene:
    preferred_term: TSPEAR
    term:
      id: hgnc:1268
      label: TSPEAR
  type: nonsense variant
  description: >-
    VUS found homozygously in a Roma proband with severe mid-frequency hearing loss. His similarly affected sister
    was heterozygous, weakening recessive cosegregation; the study did not investigate CNVs. The later dental cohort
    also included a homozygous 21-year-old with no clinical hearing concerns, without formal audiometry reported
    for that individual.
  evidence:
  - reference: PMID:34795337
    reference_title: Comprehensive molecular-genetic analysis of mid-frequency sensorineural hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the last family, FAM174, we detected VUS variant p.Glu624* in the TSPEAR gene (NM_144991.3). The proband’s
      sister (D1032) is also affected by HL but interestingly was found to only be a heterozygous carrier of the
      p.Glu624* variant.
    explanation: >-
      The primary study describes discordant zygosity in similarly affected siblings. This is not straightforward
      recessive segregation.
  clinical_significance: UNCERTAIN_SIGNIFICANCE
- name: TSPEAR p.Pro178Leu
  gene:
    preferred_term: TSPEAR
    term:
      id: hgnc:1268
      label: TSPEAR
  type: missense variant
  description: >-
    Homozygous TSPEAR VUS in a hearing-loss case who also carried a homozygous TMPRSS3 p.Gly402Arg VUS. Neither
    candidate was resolved as pathogenic in the cohort.
  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: >-
      The TSPEAR and TMPRSS3 variants are currently classified as variants of uncertain significance (VUS; Table
      2).
    explanation: >-
      Both variants in individual 1 remained uncertain, so a competing variant is not equivalent to a confirmed
      alternative diagnosis.
  clinical_significance: UNCERTAIN_SIGNIFICANCE
- name: TSPEAR p.Val388Ala
  gene:
    preferred_term: TSPEAR
    term:
      id: hgnc:1268
      label: TSPEAR
  type: missense variant
  description: >-
    Homozygous TSPEAR VUS reported in an Iranian hearing-loss family, alongside homozygous TMPRSS3 p.Pro404Leu,
    which the study classified as likely pathogenic. The competing TMPRSS3 finding limits attribution to TSPEAR.
  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: >-
      Individual 2 is an Iranian male and one of two affected children born to consanguineous parents presenting
      with deafness and a homozygous c.1163C>T (p.Val388Ala) TSPEAR missense variant (Table 1).
    explanation: >-
      The source reports the protein change and candidate genotype; its nucleotide notation is retained only inside
      the exact quotation and is not independently normalized here.
  - 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: >-
      Using the current available evidence, this TMPRSS3 variant was classified as likely pathogenic following review
      in this study (Table 2).
    explanation: >-
      The competing TMPRSS3 classification is stronger than the TSPEAR VUS attribution.
  clinical_significance: UNCERTAIN_SIGNIFICANCE
- name: TSPEAR c.1566G>A (p.Pro522=)
  gene:
    preferred_term: TSPEAR
    term:
      id: hgnc:1268
      label: TSPEAR
  type: synonymous variant with predicted splice effect
  description: >-
    Reported with c.1676_1677delAT in a family with childhood-onset hearing loss and enlarged vestibular aqueduct.
    A splice effect was predicted rather than experimentally demonstrated. Transcript-specific alternative numbering
    in the original literature should not be mixed with this representation.
  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: >-
      This individual underwent gene panel‐based hearing loss evaluation (OtoScope v5, 89 genes) which identified
      a c.1566G>A (p.Pro522Pro) TSPEAR variant which is predicted to impact splicing and a c.1676_1677delAT (p.Tyr559Cysfs*134)
      frame‐shift TSPEAR variant.
    explanation: >-
      The cohort paper describes the earlier hearing-loss family. The synonymous allele has a predicted splice effect;
      this quotation does not report a splice assay.
    directness: INDIRECT
- name: TSPEAR c.1676_1677delAT (p.Tyr559CysfsTer134)
  gene:
    preferred_term: TSPEAR
    term:
      id: hgnc:1268
      label: TSPEAR
  type: frameshift deletion
  description: >-
    Reported with p.Pro522= in the hearing-loss family summarized by Bowles et al. The phenotype included enlarged
    vestibular aqueduct and proteinuria in the described index case; these observations do not establish that TSPEAR
    caused every finding.
  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: >-
      This individual underwent gene panel‐based hearing loss evaluation (OtoScope v5, 89 genes) which identified
      a c.1566G>A (p.Pro522Pro) TSPEAR variant which is predicted to impact splicing and a c.1676_1677delAT (p.Tyr559Cysfs*134)
      frame‐shift TSPEAR variant.
    explanation: >-
      The cohort paper describes the earlier hearing-loss family. The synonymous allele has a predicted splice effect;
      this quotation does not report a splice assay.
    directness: INDIRECT
- name: TSPEAR NM_144991.3:c.1728del (p.Lys577SerfsTer37), 2023 report
  gene:
    preferred_term: TSPEAR
    term:
      id: hgnc:1268
      label: TSPEAR
  type: frameshift deletion
  description: >-
    The 2023 Iranian sequencing cohort reports this homozygous deletion in a male with profound nonsyndromic hearing
    loss and consanguineous parents. Table 4 calls it pathogenic; this is the authors’ attribution. The table does
    not explicitly report the adjacent substitution of the founding combined allele, so that substitution is not
    inferred here.
  evidence:
  - reference: PMID:37561809
    reference_title: Exome sequencing identifies novel variants associated with non-syndromic hearing loss in the Iranian population.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TSPEAR(NM_144991.3):c.1728del:(p.Lys577SerfsTer37) | rs782540538 | Homo/AR | Pathogenic | Pathogenic | No/
      ClinVar ID: 37311 | Profound SNHL | Male
    explanation: >-
      The source table supplies genotype and phenotype but not an independent resolution of the disputed gene-disease
      relationship.
📚

References & Deep Research

References

15
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.
url:https://www.ncbi.nlm.nih.gov/books/NBK1434/
Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
No top-level findings curated for this source.
url:https://discovery.ucl.ac.uk/id/eprint/10174155/1/1-s2.0-S2666247723000180-main.pdf
https://discovery.ucl.ac.uk/id/eprint/10174155/1/1-s2.0-S2666247723000180-main.pdf
No top-level findings curated for this source.
url:https://flore.unifi.it/retrieve/7d92d0aa-e251-46f0-8555-6584ec139e54/Vergani%20et%20al%202025%20TSPEAR.pdf
https://flore.unifi.it/retrieve/7d92d0aa-e251-46f0-8555-6584ec139e54/Vergani%20et%20al%202025%20TSPEAR.pdf
No top-level findings curated for this source.
PMID:27736875
Mutations in TSPEAR, Encoding a Regulator of Notch Signaling, Affect Tooth and Hair Follicle Morphogenesis.
No top-level findings curated for this source.
PMID:35741818
Confirmation of a Phenotypic Entity for TSPEAR Variants in Egyptian Ectodermal Dysplasia Patients and Role of Ethnicity.
No top-level findings curated for this source.
PMID:37561809
Exome sequencing identifies novel variants associated with non-syndromic hearing loss in the Iranian population.
No top-level findings curated for this source.

Deep Research

1

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

Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 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

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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