Autosomal Recessive Nonsyndromic Hearing Loss 97

Mendelian MONDO:0014739 Pathograph 12 Show in embeddings browser Autosomal Recessive Nonsyndromic Hearing Loss Hereditary Hearing Loss

DFNB97 denotes severe prelingual nonsyndromic sensorineural hearing loss associated with a homozygous MET p.Phe841Val variant in a large Pakistani family. MET encodes the hepatocyte growth factor receptor. The ClinGen Hearing Loss Gene Curation Expert Panel classified the recessive MET–hearing loss association as Limited in March 2021; causality and the human cochlear lesion remain incompletely established. A Moroccan child with bilateral total hearing loss and homozygous p.Ile316Met was also reported, but that variant has a later likely benign ClinVar submission covering conditions including DFNB97 and should not be counted as independent confirmation of causality. Conditional mouse experiments support a proposed developmental mechanism involving failed melanocyte incorporation into the stria vascularis. These gene-level experiments do not demonstrate the effects of either human missense allele on receptor signaling.

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Inheritance
6
Pathophys.
3
Phenotypes
2
Gaps
12
Pathograph
1
Genes
2
Variants
4
Medical Actions
1
Differentials
3
Models
10
References
1
Deep Research
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Inheritance

1
Autosomal recessive HP:0000007
The founding consanguineous Pakistani pedigree supports recessive inheritance at the DFNB97 locus: p.Phe841Val was homozygous in nine affected relatives. This segregation does not independently establish the variant as causal. Recurrence counseling based on MET requires careful confirmation of the familial molecular diagnosis.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:25941349 SUPPORT Human Clinical
"Homozygosity mapping with a dense array of one million SNP markers allowed us to map the gene for recessively inherited severe hearing loss to chromosome 7q31.2, defining a new deafness locus designated DFNB97 (maximum logarithm of the odds score of 4.8)."
The linkage result establishing recessive inheritance and the locus itself.
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Discussions and Knowledge Gaps

2
Do the two reported DFNB97 missense alleles actually reduce HGF/MET signalling?
KNOWLEDGE GAP OPEN gap_met_allele_function_untested
Attached to
pathophysiology#Biallelic MET Missense Variant pathophysiology#Reduced HGF/MET Signalling in the Developing Cochlea genetic#MET
The founding study performed an exon-trap assay, but it was inconclusive and did not measure HGF binding, receptor activation or downstream signaling. Structural predictions for p.Phe841Val and molecular dynamics for p.Ile316Met cannot establish a receptor defect. The latter allele also has a later likely benign ClinVar assertion. Conditional mouse loss of Met supports a gene-level mechanism, while variant causality, linked regulatory alternatives and residual signaling remain unresolved.
Proposed experiments
Functional characterisation of p.Phe841Val and p.Ile316Met MET signalling
met_dfnb97_allele_signalling_assay
Express each variant receptor alongside wild type in a MET-null cell background, and measure HGF binding, receptor autophosphorylation and downstream ERK and AKT activation against wild type and against a known kinase-dead control.
Would support
pathophysiology#Reduced HGF/MET Signalling in the Developing Cochlea
Supporting outcome
  • A reproducible allele-specific reduction in receptor activation would support the proposed mechanism, with interpretation integrated with segregation and population data.
Refuting outcome
  • Normal signaling would weaken the proposed receptor defect in the tested system, while leaving possible tissue-specific, splice or linked regulatory effects to investigate. It would not by itself determine a ClinGen classification.
How closely does strial dysfunction in Hgf and conditional Met mouse models reproduce human MET-associated hearing loss?
HUMAN MODEL MISMATCH OPEN mismatch_endocochlear_potential_measured_in_hgf_arm
Attached to
pathophysiology#Reduced Endocochlear Potential animal_models#Conditional c-Met inner ear inactivation mouse animal_models#Hgf del10 pathway-comparator mouse
The Hgf del10 mouse provides a direct endocochlear-potential measurement and models DFNB39. The c-Met conditional-inactivation study establishes developmental strial and auditory abnormalities. Neither experiment directly measures the cochlear consequence of p.Phe841Val in humans. Variant-specific models and matched physiological measurements are needed to establish how far the ligand and receptor experiments generalize to the human candidate association.
Proposed experiments
Endocochlear potential measurement in conditional c-Met inner ear mutants
met_conditional_endocochlear_potential
Measure the endocochlear potential directly in the conditional c-Met inner ear mutant at the same age at which it was measured in the Hgf del10 mouse, alongside strial histology, and compare the magnitude of the reduction between the two arms.
Would support
pathophysiology#Reduced Endocochlear Potential
Supporting outcome
  • A reduced potential associated with strial abnormalities would strengthen the proposed receptor-to-strial physiology link while leaving human variant causality to be tested.
Refuting outcome
  • Preserved potential despite hearing loss would argue for an additional or alternative auditory mechanism in that model.
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Pathophysiology

6
Biallelic MET Missense Variant
Homozygous NM_000245.2:c.2521T>G (p.Phe841Val) segregated with severe early hearing loss in nine members of Pakistani family HLGM17 after linkage to 7q31.2. The variant lies in the extracellular IPT4 domain and was absent from the study controls and public databases examined in 2015. A linked regulatory variant remains an alternative explanation. Structural predictions suggest reduced protein stability, but receptor binding and signaling were not measured. An exon-trap assay was performed: 63 of 65 mutant-derived clones matched wild type, and the two aberrant products could reflect a small splice effect or artifacts. The separately reported p.Ile316Met variant is not treated as a confirmed pathogenic trigger.
Genetic context MET hgnc:7029 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns MET (hgnc:7029). hgnc:7029 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: HOMOZYGOUS
Homozygous p.Phe841Val in the founding family. The variant has segregation evidence, mixed computational predictions and an inconclusive exon-trap result; a loss-of-function category is not assigned without a demonstrated receptor defect.
Downstream
Reduced HGF/MET Signalling in the Developing Cochlea Reduced receptor signaling is a proposed consequence of p.Phe841Val based on its extracellular domain location and structural predictions; it has not been demonstrated by a receptor signaling assay.
Show evidence (5 references)
PMID:25941349 SUPPORT Human Clinical
"The variant co-segregated with the phenotype, being homozygous in all 9 affected individuals, and was absent from DNA of 400 ethnically matched individuals (800 chromosomes)."
Segregation and absence from the study controls support candidacy, without excluding a linked causal variant.
PMID:25941349 SUPPORT Human Clinical
"However, since we only analyzed exonic regions, it is possible that a mutation in a regulatory region of MET or in a cis-acting element of any of the other 16 genes in the critical DFNB97 interval may be responsible for the hearing loss in family HLGM17 and the p.F841V variant is in linkage..."
The founding study did not exclude linked regulatory variation as the actual cause.
PMID:25941349 SUPPORT In Vitro
"Results of the experiments revealed that all but 2 of the total 65 clones derived from the transfection of mutant construct were identical to those obtained after transfection of the wild-type construct."
The exon-trap experiment mostly reproduced wild-type splicing; two aberrant clones do not establish a pathogenic splice defect.
+ 2 more references
Reduced HGF/MET Signalling in the Developing Cochlea
HGF and c-Met are expressed in the developing cochlea. Conditional mouse disruption supports a requirement for this signaling pathway in strial melanocyte incorporation. Reduced signaling is proposed, rather than directly measured, for the human p.Phe841Val allele.
HGF receptor signalling through MET GO:0048012 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased HGF receptor signalling through MET, annotated with hepatocyte growth factor receptor signaling pathway (GO:0048012). GO:0048012 is a biological process from the Gene Ontology.
stria vascularis of the cochlear duct UBERON:0002282 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in stria vascularis of the cochlear duct, annotated with stria vascularis of cochlear duct (UBERON:0002282). UBERON:0002282 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Failed Melanocyte Incorporation into the Stria Vascularis Genetic dissection in mouse shows the incorporation step requires c-MET signalling.
Show evidence (2 references)
PMID:27488639 SUPPORT Model Organism
"we discovered that hepatocyte growth factor (Hgf) is expressed in the future stria vascularis of the cochlear epithelium."
Places the ligand at the anatomical site this node names.
PMID:27488639 SUPPORT Model Organism
"Its receptor tyrosine kinase, c-Met, is expressed in the cochlear epithelium and melanocyte-derived intermediate cells in the stria vascularis."
Receptor expression in cochlear epithelium and intermediate cells identifies sites where the pathway could act during strial development.
Failed Melanocyte Incorporation into the Stria Vascularis
Conditional mouse disruption of HGF–c-MET signaling impairs incorporation of neural-crest-derived melanocytes into the developing stria vascularis. This is a proposed mechanism for DFNB97; the corresponding human cochlear defect has not been demonstrated in the cited clinical families.
melanocyte CL:0000148 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves melanocyte (CL:0000148). CL:0000148 is a cell type from the Cell Ontology.
melanocyte migration into the developing stria vascularis GO:0097324 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased melanocyte migration into the developing stria vascularis, annotated with melanocyte migration (GO:0097324). GO:0097324 is a biological process from the Gene Ontology.
stria vascularis of the cochlear duct UBERON:0002282 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in stria vascularis of the cochlear duct, annotated with stria vascularis of cochlear duct (UBERON:0002282). UBERON:0002282 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Conditional c-Met inner ear inactivation mouse Mouse recapitulates Removing c-MET signalling in the developing inner ear stops the neural-crest-derived melanocytes entering the strial intermediate layer.
Downstream
Failure of Endolymphatic Potassium Homeostasis Loss of the intermediate cell layer disrupts the strial organization required for ion homeostasis. The effect in human DFNB97 remains inferred from model systems.
Show evidence (2 references)
PMID:27488639 SUPPORT Model Organism
"During mouse embryonic development, a subpopulation of neural crest cell-derived melanocytes migrates and incorporates into a subregion of the cochlear epithelium, forming the intermediate cell layer of the stria vascularis."
The normal developmental process this node describes the failure of.
PMID:27488639 SUPPORT Model Organism
"Genetic dissection of HGF signaling via c-MET reveals that the incorporation of the melanocytes into the future stria vascularis of the cochlear duct requires c-MET signaling."
The direct genetic demonstration that this step depends on MET.
Failure of Endolymphatic Potassium Homeostasis
Strial intermediate-cell development is required for normal ion homeostasis supporting auditory transduction. A noncoding Hgf deletion model of DFNB39 demonstrates strial abnormalities and reduced endocochlear potential. This supports a proposed shared downstream mechanism but is not a measurement in human DFNB97 or in a human MET missense-variant model.
endolymphatic potassium homeostasis maintained by the stria vascularis GO:0055075 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased endolymphatic potassium homeostasis maintained by the stria vascularis, annotated with potassium ion homeostasis (GO:0055075). GO:0055075 is a biological process from the Gene Ontology.
stria vascularis of the cochlear duct UBERON:0002282 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in stria vascularis of the cochlear duct, annotated with stria vascularis of cochlear duct (UBERON:0002282). UBERON:0002282 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Reduced Endocochlear Potential Disturbed strial ion transport is proposed to reduce the endocochlear potential, a functional consequence measured in the Hgf del10 model. This is indirect support for MET-associated disease.
Show evidence (2 references)
PMID:27488639 SUPPORT Model Organism
"The stria vascularis is a nonsensory structure that is essential for auditory hair cell function by maintaining potassium concentration of the scala media."
States the function of the structure whose development fails upstream.
PMID:32152201 SUPPORT INDIRECT Model Organism
"We conclude that, in the inner ear, the noncoding del10 mutation in Hgf leads to developmental defects of the SV and consequently dysfunctional ion homeostasis and a reduction in the EP, recapitulating human DFNB39 nonsyndromic deafness."
Direct measurement in the Hgf ligand model supplies indirect support for a shared pathway consequence; it does not establish the endocochlear potential in MET-associated human hearing loss.
Reduced Endocochlear Potential
Hgf del10 mice have a reduced endocochlear potential, diminishing the electrochemical driving force for sound transduction. This is a proposed downstream consequence of abnormal strial development in MET-associated hearing loss; it has not been measured in the reported patients.
stria vascularis of the cochlear duct UBERON:0002282 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in stria vascularis of the cochlear duct, annotated with stria vascularis of cochlear duct (UBERON:0002282). UBERON:0002282 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Hgf del10 pathway-comparator mouse Mouse partially recapitulates
Downstream
Severe Prelingual Sensorineural Hearing Loss Reduced electrochemical driving force can impair auditory hair-cell transduction. The link from human MET variants to this physiological deficit remains proposed.
Show evidence (2 references)
PMID:32152201 SUPPORT INDIRECT Model Organism
"The wild type (WT) 80 mV endocochlear potential was significantly reduced in homozygous del10 mice compared with WT littermates."
Direct electrical measurement in the Hgf del10 model of DFNB39 supports a shared pathway hypothesis, not a measurement in human DFNB97.
PMID:32152201 SUPPORT INDIRECT Model Organism
"Using a Hgf mutant mouse with a small 10 bp deletion recapitulating a human DFNB39 noncoding variant, we demonstrate that neural crest cells fail to migrate into the stria vascularis intermediate layer, resulting in a significantly reduced endocochlear potential, the driving force for sound..."
The Hgf experiment connects strial developmental defects with reduced endocochlear potential; its human disease model is DFNB39.
Severe Prelingual Sensorineural Hearing Loss
The founding family had severe prelingual sensorineural hearing loss. Conditional inactivation of Hgf or c-Met also impaired hearing in mice, supporting a developmental auditory role for the pathway without proving the effects of human missense alleles.
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
Conditional c-Met inner ear inactivation mouse Mouse recapitulates Developmental receptor inactivation produces profound hearing loss in young adult mice. This supports an auditory role for Met without equating mouse and human onset stages.
Downstream
Delayed Speech Development Early hearing loss can limit access to spoken language; speech delay was how hearing loss was recognized in the founding family.
Show evidence (2 references)
PMID:27488639 SUPPORT Model Organism
"In addition, inactivation of either the ligand or receptor developmentally resulted in a profound hearing loss at young adult stages."
Closes the mouse chain from signalling loss to deafness, and does so for the receptor as well as the ligand, which is what makes it evidence about DFNB97.
PMID:27488639 SUPPORT Model Organism
"Our findings reveal a novel mechanism that may underlie human deafness DFNB39 and DFNB97."
The authors' own statement that this mechanism is offered for DFNB97, hedged as they hedge it.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Autosomal Recessive Nonsyndromic Hearing Loss 97 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

3
Ear 2
Severe Prelingual Sensorineural Hearing Loss Severe sensorineural hearing impairment HP:0008625 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe sensorineural hearing impairment (HP:0008625). HP:0008625 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25941349 SUPPORT Human Clinical
"Audiometry in ambient noise conditions revealed a severe degree of sensorineural hearing loss (pure tone average, PTA500 Hz-4000 Hz, 74–89 dB HL) with intra-familial variations in thresholds, (figure 1B)."
The audiometric thresholds and the intrafamilial range.
PMID:31801140 SUPPORT Human Clinical
"We identified a novel pathogenic homozygous c.948A>G (p.Ile316Met) mutation in the MET gene in one deaf Moroccan young girl carrying a total bilateral non-syndromic hearing impairment."
Documents the phenotype of the reported Moroccan case, while the causal interpretation of p.Ile316Met is not accepted as established.
Prelingual Onset Prelingual sensorineural hearing impairment HP:0000399 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prelingual sensorineural hearing impairment (HP:0000399). HP:0000399 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25941349 SUPPORT Human Clinical
"The family includes 9 individuals (age range = 5–60 years old) with hearing loss at or before 2 years of age, noticeable due to delay in development of speech."
Onset age and how it was recognised, across nine affected individuals.
Nervous System 1
Delayed Speech Development Delayed speech and language development HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25941349 SUPPORT Human Clinical
"The family includes 9 individuals (age range = 5–60 years old) with hearing loss at or before 2 years of age, noticeable due to delay in development of speech."
Nine affected relatives had early hearing loss recognized through delayed speech.
🧬

Genetic Associations

1
MET (Candidate recessive hearing loss association; ClinGen Limited)
Gene: MET hgnc:7029 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MET (hgnc:7029). hgnc:7029 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (6 references)
CGGV:assertion_f0e6f9ac-f807-48fd-a5b6-bf67c4607e14-2021-03-26T160000.000Z SUPPORT Other
"Only one missense variant was scored as the probands with the other variant had inconsistent phenotypes with nonsyndromic hearing loss and the minor allele frequency of the other variant was too high to be considered pathogenic."
The specific reason the reported variant count overstates the evidence, and the reason the classification is Limited.
CGGV:assertion_f0e6f9ac-f807-48fd-a5b6-bf67c4607e14-2021-03-26T160000.000Z SUPPORT Other
"One missense variant in this gene segregated with disease in 8 additional family members (PMID: 25941349)."
The segregation count credited by the panel.
PMID:25941349 SUPPORT Human Clinical
"However, since we only analyzed exonic regions, it is possible that a mutation in a regulatory region of MET or in a cis-acting element of any of the other 16 genes in the critical DFNB97 interval may be responsible for the hearing loss in family HLGM17 and the p.F841V variant is in linkage..."
The founding study did not exclude linked regulatory variation as the actual cause.
+ 3 more references
🔬

Variants

2
MET NM_000245.2:c.2521T>G (p.Phe841Val)
Gene: MET hgnc:7029 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in MET (hgnc:7029). hgnc:7029 is a gene from the HUGO Gene Nomenclature Committee. missense variant
IPT4-domain candidate segregating in family HLGM17. SIFT predicted tolerated whereas several other programs predicted damaging. Exon trapping was largely normal and inconclusive. ClinVar reports pathogenic for DFNB97 through a literature-only submission, but human causality remains limited and a linked regulatory variant was not excluded.
Show evidence (4 references)
PMID:25941349 SUPPORT Human Clinical
"The variant co-segregated with the phenotype, being homozygous in all 9 affected individuals, and was absent from DNA of 400 ethnically matched individuals (800 chromosomes)."
Segregation and absence from the study controls support candidacy, without excluding a linked causal variant.
PMID:25941349 SUPPORT In Vitro
"Results of the experiments revealed that all but 2 of the total 65 clones derived from the transfection of mutant construct were identical to those obtained after transfection of the wild-type construct."
The exon-trap experiment mostly reproduced wild-type splicing; two aberrant clones do not establish a pathogenic splice defect.
PMID:25941349 SUPPORT Human Clinical
"However, since we only analyzed exonic regions, it is possible that a mutation in a regulatory region of MET or in a cis-acting element of any of the other 16 genes in the critical DFNB97 interval may be responsible for the hearing loss in family HLGM17 and the p.F841V variant is in linkage..."
The founding study did not exclude linked regulatory variation as the actual cause.
+ 1 more reference
MET NM_000245.4:c.948A>G (p.Ile316Met)
Gene: MET hgnc:7029 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in MET (hgnc:7029). hgnc:7029 is a gene from the HUGO Gene Nomenclature Committee. missense variant
SEMA-domain variant reported homozygous in a Moroccan child with total bilateral hearing loss. The publication called it pathogenic and molecular dynamics predicted reduced flexibility; later ClinVar RCV002490458.8 classifies it likely benign for multiple conditions including DFNB97. Retained as a disputed literature attribution, without assigning a pathogenic clinical-significance tag.
Show evidence (2 references)
PMID:31801140 SUPPORT Human Clinical
"We identified a novel pathogenic homozygous c.948A>G (p.Ile316Met) mutation in the MET gene in one deaf Moroccan young girl carrying a total bilateral non-syndromic hearing impairment."
Documents the phenotype of the reported Moroccan case, while the causal interpretation of p.Ile316Met is not accepted as established.
url:https://www.ncbi.nlm.nih.gov/clinvar/RCV002490458/ SUPPORT Other
"Germline classification ... Likely benign ... Last evaluated ... May 31, 2022"
RCV002490458.8 is a single-submitter likely benign assertion whose condition list includes autosomal recessive nonsyndromic hearing loss 97. It conflicts with the original case report and is not an expert-panel gene-validity assertion.
🗃️

External Assertions

1
ClinGen MET-nonsyndromic hearing loss gene-disease validity assertion
ClinGen gene disease validity CGGV:assertion_f0e6f9ac-f807-48fd-a5b6-bf67c4607e14-2021-03-26T160000.000Z
The ClinGen Hearing Loss Gene Curation Expert Panel classified the autosomal recessive MET–nonsyndromic hearing loss relationship as Limited on March 26, 2021. Only one of three reported missense variants was scored; the others had an inconsistent phenotype or an allele frequency incompatible with pathogenicity. Expression, biochemical and mouse evidence support biological plausibility, but the panel considered the evidence insufficient to establish causality.
The panel's evidence summary explains why only one of the three reported variants scored: "Only one missense variant was scored as the probands with the other variant had inconsistent phenotypes with nonsyndromic hearing loss and the minor allele frequency of the other variant was too high to be considered pathogenic." That is the specific reason the classification did not rise above Limited.
Show evidence (3 references)
CGGV:assertion_f0e6f9ac-f807-48fd-a5b6-bf67c4607e14-2021-03-26T160000.000Z SUPPORT Other
"MET | HGNC:7029 | nonsyndromic genetic hearing loss | MONDO:0019497 | AR | Limited"
The classification row directly documents Limited gene-disease validity; it does not establish a causative relationship.
CGGV:assertion_f0e6f9ac-f807-48fd-a5b6-bf67c4607e14-2021-03-26T160000.000Z SUPPORT Other
"In summary, there is limited evidence to support this gene-disease association."
The expert-panel summary supports retaining uncertainty in the human gene-disease association.
CGGV:assertion_f0e6f9ac-f807-48fd-a5b6-bf67c4607e14-2021-03-26T160000.000Z SUPPORT Other
"Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease association."
At the 2021 assessment the panel found insufficient support for causality without convincing contradictory gene-level evidence.
💊

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
Assess hearing-aid amplification according to individual audiometry, aided benefit and communication needs. This follows general hearing-loss guidance; benefit specific to MET-associated hearing loss has not been established in the cited clinical reports.
Show evidence (1 reference)
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 DFNB97 outcome study.
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 proposed strial mechanism does not establish preservation of the auditory nerve or predict a DFNB97-specific implant outcome.
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 DFNB97-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 MET 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 MET 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 DFNB97-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
Comprehensive genetic evaluation and cautious MET interpretation
Use a comprehensive hearing-loss panel or genomic testing with clinical correlation and segregation analysis. In the founding study, established recessive hearing-loss genes were excluded before the MET candidate was identified. That discovery workflow is not a requirement for sequential single-gene testing. A MET finding must be assessed in the context of Limited gene-disease validity; variants of uncertain significance cannot confirm a diagnosis.
Show evidence (3 references)
PMID:25941349 SUPPORT Human Clinical
"Mutations of GJB2 and all other genes reported to underlie recessive deafness were ruled out as the cause of the phenotype in the affected members of the participating family."
The exclusion step that preceded the DFNB97 diagnosis in the founding family.
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 MET 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 MET alleles.
Audiometry and clinical assessment
Establish hearing severity, onset and associated findings through audiometry and clinical evaluation. In the founding family, severe sensorineural loss was measured in ambient noise; clinical vestibular screening was reassuring, while laboratory and funduscopic examinations were reported for only two affected relatives.
Show evidence (1 reference)
PMID:25941349 SUPPORT Human Clinical
"Audiometry in ambient noise conditions revealed a severe degree of sensorineural hearing loss (pure tone average, PTA500 Hz-4000 Hz, 74–89 dB HL) with intra-familial variations in thresholds, (figure 1B)."
The audiometric thresholds and the intrafamilial range.
📊

Prevalence

1
Worldwide
Cases In Literature Not yet documented
Population prevalence is unknown. The founding report describes nine affected members of one Pakistani family. A later Moroccan case report claimed a second family, but the p.Ile316Met interpretation is disputed by a later likely benign ClinVar submission. These reports cannot be treated as two equally established molecular diagnoses. Screening 100 additional Pakistani families with unexplained moderate-to-profound hearing loss identified no additional families linked to DFNB97; this selected-family screen is not a population prevalence estimate.
Show evidence (2 references)
PMID:25941349 SUPPORT Human Clinical
"In order to find the contribution of the newly mapped locus to deafness, we screened 100 families in which the moderate to profound hearing loss was not attributable to a known deafness gene variant. No other families were identified, which suggests that DFNB97 is a rare cause of hearing loss in..."
The negative selected-family screen supports rarity in this ascertainment setting, not a population rate.
PMID:31801140 SUPPORT Human Clinical
"Moreover, this study reports the second family in the world associating deafness and mutation in the MET gene."
The authors reported a second candidate family; subsequent variant interpretation limits using that count as confirmed DFNB97.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Autosomal Recessive Nonsyndromic Hearing Loss 97:

🧫

Experimental Models

1
MET c.2521T>G exon-trap assay OTHER
Transfected wild-type and mutant constructs tested a predicted internal splice donor associated with c.2521T>G. Most mutant-derived clones matched wild type; two retained portions of flanking introns. The assay did not establish receptor loss of function.
Publication
PMID:25941349
Show evidence (2 references)
PMID:25941349 SUPPORT In Vitro
"Results of the experiments revealed that all but 2 of the total 65 clones derived from the transfection of mutant construct were identical to those obtained after transfection of the wild-type construct."
The exon-trap experiment mostly reproduced wild-type splicing; two aberrant clones do not establish a pathogenic splice defect.
PMID:25941349 SUPPORT In Vitro
"This indicates that the c.2521T>G mutation may have a limited effect on splicing or alternatively, the mutation does not affect splicing and the two aberrant splicing products are experimental artifacts."
The authors explicitly retain both a small splice effect and an experimental-artifact interpretation.
🐁

Animal Models

2
Conditional c-Met inner ear inactivation mouse
Separate neural-crest and cochlear-epithelium conditional c-Met deletions impaired melanocyte incorporation into the stria vascularis and produced profound hearing loss. Public full-text excerpts describe later hair-cell malformation and degeneration; that observation is not quoted in the abstract-only cache cited here. Sensory-cell preservation therefore cannot be assumed. The experiments establish a developmental role for Met without reproducing either reported human missense allele.
Species
Mouse
Genotype
Conditional c-Met deletion using Wnt1-Cre in neural crest cells or Pax2-Cre in cochlear epithelium
Publication
PMID:27488639
Pathograph links
Failed Melanocyte Incorporation into the Stria Vascularis recapitulates fidelity: moderate Removing c-MET signalling in the developing inner ear stops the neural-crest-derived melanocytes entering the strial intermediate layer.
Limitations: Conditional inactivation is not a knock-in of a human missense allele. The experiment establishes a developmental role for the gene, without demonstrating the signaling defect or cochlear histology in the reported patients.
Readouts
Melanocyte incorporation into the strial intermediate cell layer
Direction: DECREASED
Interpretation: The measured quantity is successful melanocyte incorporation, which decreases. The target node names the resulting failure of incorporation.
Show evidence (1 reference)
PMID:27488639 SUPPORT Model Organism
"Genetic dissection of HGF signaling via c-MET reveals that the incorporation of the melanocytes into the future stria vascularis of the cochlear duct requires c-MET signaling."
The genetic result behind this readout.
Show evidence (1 reference)
PMID:27488639 SUPPORT Model Organism
"Genetic dissection of HGF signaling via c-MET reveals that the incorporation of the melanocytes into the future stria vascularis of the cochlear duct requires c-MET signaling."
Conditional receptor inactivation tests the requirement for c-MET signaling during strial melanocyte incorporation, making this model informative for the proposed developmental lesion. It does not establish that either human missense allele produces the same defect.
Severe Prelingual Sensorineural Hearing Loss recapitulates fidelity: moderate Developmental receptor inactivation produces profound hearing loss in young adult mice. This supports an auditory role for Met without equating mouse and human onset stages.
Limitations: Conditional inactivation and human missense variation are different perturbations. Mouse young-adult hearing measurements do not establish congenital onset, progression or residual receptor activity in people with candidate MET variants.
Readouts
Hearing threshold after developmental inactivation
Direction: INCREASED
Interpretation: Hearing is profoundly impaired, closing the chain from signalling loss to the clinical endpoint within a single organism.
Show evidence (1 reference)
PMID:27488639 SUPPORT Model Organism
"In addition, inactivation of either the ligand or receptor developmentally resulted in a profound hearing loss at young adult stages."
The hearing measurement behind this readout, reported for the receptor arm as well as the ligand arm.
Show evidence (1 reference)
PMID:27488639 SUPPORT Model Organism
"These results suggest a novel connection between HGF signaling and deafness via melanocyte deficiencies."
Supports treating this model as informative for the clinical endpoint.
Hgf del10 pathway-comparator mouse
This model recapitulates the ligand-associated disorder DFNB39. It provides indirect pathway evidence for the strial hypothesis in DFNB97, including abnormal neural-crest-cell incorporation and reduced endocochlear potential. It is not a model of a human MET variant.
Species
Mouse
Genotype
Homozygous noncoding 10 bp intronic deletion in Hgf
Publication
PMID:32152201
Pathograph links
Reduced Endocochlear Potential partially recapitulates fidelity: moderate
Limitations: The perturbed gene is Hgf, not Met; physiological findings cannot establish the pathogenicity or effect size of a human MET missense variant.
Readouts
Endocochlear potential in Hgf del10 homozygotes
Direction: DECREASED
Interpretation: Endocochlear potential was lower than in wild-type littermates.
Show evidence (1 reference)
PMID:32152201 SUPPORT INDIRECT Model Organism
"The wild type (WT) 80 mV endocochlear potential was significantly reduced in homozygous del10 mice compared with WT littermates."
Direct electrical measurement in the Hgf del10 model of DFNB39 supports a shared pathway hypothesis, not a measurement in human DFNB97.
Show evidence (1 reference)
PMID:32152201 SUPPORT INDIRECT Model Organism
"The wild type (WT) 80 mV endocochlear potential was significantly reduced in homozygous del10 mice compared with WT littermates."
Direct electrical measurement in the Hgf del10 model of DFNB39 supports a shared pathway hypothesis, not a measurement in human DFNB97.
{ }

Source YAML

click to show 
name: Autosomal Recessive Nonsyndromic Hearing Loss 97
creation_date: '2026-08-28T21:00:00Z'
category: Mendelian
disease_term:
  preferred_term: autosomal recessive nonsyndromic hearing loss 97
  term:
    id: MONDO:0014739
    label: autosomal recessive nonsyndromic hearing loss 97
synonyms:
- DFNB97
- deafness, autosomal recessive 97
- MET-related autosomal recessive nonsyndromic hearing loss
- autosomal recessive nonsyndromic deafness 97
description: >-
  DFNB97 denotes severe prelingual nonsyndromic sensorineural hearing loss associated with a homozygous
  MET p.Phe841Val variant in a large Pakistani family. MET encodes the hepatocyte growth factor receptor.
  The ClinGen Hearing Loss Gene Curation Expert Panel classified the recessive MET–hearing loss association
  as Limited in March 2021; causality and the human cochlear lesion remain incompletely established. A
  Moroccan child with bilateral total hearing loss and homozygous p.Ile316Met was also reported, but that
  variant has a later likely benign ClinVar submission covering conditions including DFNB97 and should
  not be counted as independent confirmation of causality. Conditional mouse experiments support a proposed
  developmental mechanism involving failed melanocyte incorporation into the stria vascularis. These gene-level
  experiments do not demonstrate the effects of either human missense allele on receptor signaling.

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

external_assertions:
- name: ClinGen MET-nonsyndromic hearing loss gene-disease validity assertion
  source: ClinGen
  assertion_type: gene_disease_validity
  external_id: CGGV:assertion_f0e6f9ac-f807-48fd-a5b6-bf67c4607e14-2021-03-26T160000.000Z
  url: https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f0e6f9ac-f807-48fd-a5b6-bf67c4607e14-2021-03-26T160000.000Z
  description: >-
    The ClinGen Hearing Loss Gene Curation Expert Panel classified the autosomal recessive MET–nonsyndromic
    hearing loss relationship as Limited on March 26, 2021. Only one of three reported missense variants
    was scored; the others had an inconsistent phenotype or an allele frequency incompatible with pathogenicity.
    Expression, biochemical and mouse evidence support biological plausibility, but the panel considered
    the evidence insufficient to establish causality.
  evidence:
  - reference: CGGV:assertion_f0e6f9ac-f807-48fd-a5b6-bf67c4607e14-2021-03-26T160000.000Z
    reference_title: MET / nonsyndromic genetic hearing loss (Limited)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: MET | HGNC:7029 | nonsyndromic genetic hearing loss | MONDO:0019497 | AR | Limited
    explanation: >-
      The classification row directly documents Limited gene-disease validity; it does not establish a
      causative relationship.
  - reference: CGGV:assertion_f0e6f9ac-f807-48fd-a5b6-bf67c4607e14-2021-03-26T160000.000Z
    reference_title: MET / nonsyndromic genetic hearing loss (Limited)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In summary, there is limited evidence to support this gene-disease association.
    explanation: >-
      The expert-panel summary supports retaining uncertainty in the human gene-disease association.
  - reference: CGGV:assertion_f0e6f9ac-f807-48fd-a5b6-bf67c4607e14-2021-03-26T160000.000Z
    reference_title: MET / nonsyndromic genetic hearing loss (Limited)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Although more evidence is needed to support a causal role, no convincing evidence has
      emerged that contradicts the gene-disease association.
    explanation: >-
      At the 2021 assessment the panel found insufficient support for causality without convincing contradictory
      gene-level evidence.
  notes: >-
    The panel's evidence summary explains why only one of the three reported variants scored:
    "Only one missense variant was scored as the probands with the other variant had
    inconsistent phenotypes with nonsyndromic hearing loss and the minor allele frequency of
    the other variant was too high to be considered pathogenic." That is the specific reason
    the classification did not rise above Limited.

prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    Population prevalence is unknown. The founding report describes nine affected members of one Pakistani
    family. A later Moroccan case report claimed a second family, but the p.Ile316Met interpretation is
    disputed by a later likely benign ClinVar submission. These reports cannot be treated as two equally
    established molecular diagnoses. Screening 100 additional Pakistani families with unexplained moderate-to-profound
    hearing loss identified no additional families linked to DFNB97; this selected-family screen is not
    a population prevalence estimate.
  evidence:
  - reference: PMID:25941349
    reference_title: A mutation of MET, encoding hepatocyte growth factor receptor, is associated with human DFNB97 hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In order to find the contribution of the newly mapped locus to deafness, we screened 100 families
      in which the moderate to profound hearing loss was not attributable to a known deafness gene variant.
      No other families were identified, which suggests that DFNB97 is a rare cause of hearing loss in
      Pakistan.
    explanation: >-
      The negative selected-family screen supports rarity in this ascertainment setting, not a population
      rate.
  - reference: PMID:31801140
    reference_title: Further Evidence for the Implication of the MET Gene in Non-Syndromic Autosomal Recessive Deafness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Moreover, this study reports the second family in the world associating deafness and
      mutation in the MET gene.
    explanation: >-
      The authors reported a second candidate family; subsequent variant interpretation limits using that
      count as confirmed DFNB97.

pathophysiology:
- name: Biallelic MET Missense Variant
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    Homozygous NM_000245.2:c.2521T>G (p.Phe841Val) segregated with severe early hearing loss in nine members
    of Pakistani family HLGM17 after linkage to 7q31.2. The variant lies in the extracellular IPT4 domain
    and was absent from the study controls and public databases examined in 2015. A linked regulatory
    variant remains an alternative explanation. Structural predictions suggest reduced protein stability,
    but receptor binding and signaling were not measured. An exon-trap assay was performed: 63 of 65 mutant-derived
    clones matched wild type, and the two aberrant products could reflect a small splice effect or artifacts.
    The separately reported p.Ile316Met variant is not treated as a confirmed pathogenic trigger.
  genetic_context:
    gene:
      preferred_term: MET
      term:
        id: hgnc:7029
        label: MET
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    description: >-
      Homozygous p.Phe841Val in the founding family. The variant has segregation evidence, mixed computational
      predictions and an inconclusive exon-trap result; a loss-of-function category is not assigned without
      a demonstrated receptor defect.
  downstream:
  - target: Reduced HGF/MET Signalling in the Developing Cochlea
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Reduced receptor signaling is a proposed consequence of p.Phe841Val based on its extracellular domain
      location and structural predictions; it has not been demonstrated by a receptor signaling assay.
  evidence:
  - &id002
    reference: PMID:25941349
    reference_title: A mutation of MET, encoding hepatocyte growth factor receptor, is associated with human DFNB97 hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The variant co-segregated with the phenotype, being homozygous in all 9 affected individuals, and
      was absent from DNA of 400 ethnically matched individuals (800 chromosomes).
    explanation: >-
      Segregation and absence from the study controls support candidacy, without excluding a linked causal
      variant.
  - &id001
    reference: PMID:25941349
    reference_title: A mutation of MET, encoding hepatocyte growth factor receptor, is associated with human DFNB97 hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, since we only analyzed exonic regions, it is possible that a mutation in a regulatory region
      of MET or in a cis-acting element of any of the other 16 genes in the critical DFNB97 interval may
      be responsible for the hearing loss in family HLGM17 and the p.F841V variant is in linkage disequilibrium
      with the pathogenic allele.
    explanation: >-
      The founding study did not exclude linked regulatory variation as the actual cause.
  - &id003
    reference: PMID:25941349
    reference_title: A mutation of MET, encoding hepatocyte growth factor receptor, is associated with human DFNB97 hearing loss.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Results of the experiments revealed that all but 2 of the total 65 clones derived from the transfection
      of mutant construct were identical to those obtained after transfection of the wild-type construct.
    explanation: >-
      The exon-trap experiment mostly reproduced wild-type splicing; two aberrant clones do not establish
      a pathogenic splice defect.
  - &id006
    reference: PMID:25941349
    reference_title: A mutation of MET, encoding hepatocyte growth factor receptor, is associated with human DFNB97 hearing loss.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This indicates that the c.2521T>G mutation may have a limited effect on splicing or alternatively,
      the mutation does not affect splicing and the two aberrant splicing products are experimental artifacts.
    explanation: >-
      The authors explicitly retain both a small splice effect and an experimental-artifact interpretation.
  - reference: PMID:25941349
    reference_title: A mutation of MET, encoding hepatocyte growth factor receptor, is associated with human DFNB97 hearing loss.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Modelling the p.F841V mutation with CUPSAT and I-Mutant 2.0 using the crystal structure of IPT2-IPT410
      (PDB ID, 2CEW) and the amino acid sequence of MET (NP_000236.2) predicted a decrease in the overall
      stability of the resulting protein.
    explanation: >-
      Predicted destabilization is computational support, not measured receptor dysfunction.
- name: Reduced HGF/MET Signalling in the Developing Cochlea
  role: central_effector
  biological_scale: MOLECULAR
  description: >-
    HGF and c-Met are expressed in the developing cochlea. Conditional mouse disruption supports a requirement
    for this signaling pathway in strial melanocyte incorporation. Reduced signaling is proposed, rather
    than directly measured, for the human p.Phe841Val allele.
  locations:
  - preferred_term: stria vascularis of the cochlear duct
    term:
      id: UBERON:0002282
      label: stria vascularis of cochlear duct
  biological_processes:
  - preferred_term: HGF receptor signalling through MET
    term:
      id: GO:0048012
      label: hepatocyte growth factor receptor signaling pathway
    modifier: DECREASED
  downstream:
  - target: Failed Melanocyte Incorporation into the Stria Vascularis
    causal_link_type: DIRECT
    description: >-
      Genetic dissection in mouse shows the incorporation step requires c-MET signalling.
  evidence:
  - reference: PMID:27488639
    reference_title: Hepatocyte Growth Factor-c-MET Signaling Mediates the Development of Nonsensory Structures of the Mammalian Cochlea and Hearing.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we discovered that hepatocyte growth factor (Hgf) is expressed in the future stria
      vascularis of the cochlear epithelium.
    explanation: >-
      Places the ligand at the anatomical site this node names.
  - reference: PMID:27488639
    reference_title: Hepatocyte Growth Factor-c-MET Signaling Mediates the Development of Nonsensory Structures of the Mammalian Cochlea and Hearing.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Its receptor tyrosine kinase, c-Met, is expressed in the cochlear epithelium and
      melanocyte-derived intermediate cells in the stria vascularis.
    explanation: >-
      Receptor expression in cochlear epithelium and intermediate cells identifies sites where the pathway
      could act during strial development.

- name: Failed Melanocyte Incorporation into the Stria Vascularis
  role: central_effector
  biological_scale: TISSUE
  description: >-
    Conditional mouse disruption of HGF–c-MET signaling impairs incorporation of neural-crest-derived
    melanocytes into the developing stria vascularis. This is a proposed mechanism for DFNB97; the corresponding
    human cochlear defect has not been demonstrated in the cited clinical families.
  cell_types:
  - preferred_term: melanocyte
    term:
      id: CL:0000148
      label: melanocyte
  locations:
  - preferred_term: stria vascularis of the cochlear duct
    term:
      id: UBERON:0002282
      label: stria vascularis of cochlear duct
  biological_processes:
  - preferred_term: melanocyte migration into the developing stria vascularis
    term:
      id: GO:0097324
      label: melanocyte migration
    modifier: DECREASED
  downstream:
  - target: Failure of Endolymphatic Potassium Homeostasis
    causal_link_type: DIRECT
    description: >-
      Loss of the intermediate cell layer disrupts the strial organization required for ion homeostasis.
      The effect in human DFNB97 remains inferred from model systems.
  evidence:
  - reference: PMID:27488639
    reference_title: Hepatocyte Growth Factor-c-MET Signaling Mediates the Development of Nonsensory Structures of the Mammalian Cochlea and Hearing.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      During mouse embryonic development, a subpopulation of neural crest cell-derived
      melanocytes migrates and incorporates into a subregion of the cochlear epithelium,
      forming the intermediate cell layer of the stria vascularis.
    explanation: >-
      The normal developmental process this node describes the failure of.
  - reference: PMID:27488639
    reference_title: Hepatocyte Growth Factor-c-MET Signaling Mediates the Development of Nonsensory Structures of the Mammalian Cochlea and Hearing.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Genetic dissection of HGF signaling via c-MET reveals that the incorporation of the
      melanocytes into the future stria vascularis of the cochlear duct requires c-MET
      signaling.
    explanation: >-
      The direct genetic demonstration that this step depends on MET.

- name: Failure of Endolymphatic Potassium Homeostasis
  role: central_effector
  biological_scale: TISSUE
  description: >-
    Strial intermediate-cell development is required for normal ion homeostasis supporting auditory transduction.
    A noncoding Hgf deletion model of DFNB39 demonstrates strial abnormalities and reduced endocochlear
    potential. This supports a proposed shared downstream mechanism but is not a measurement in human
    DFNB97 or in a human MET missense-variant model.
  locations:
  - preferred_term: stria vascularis of the cochlear duct
    term:
      id: UBERON:0002282
      label: stria vascularis of cochlear duct
  biological_processes:
  - preferred_term: endolymphatic potassium homeostasis maintained by the stria vascularis
    term:
      id: GO:0055075
      label: potassium ion homeostasis
    modifier: DECREASED
  downstream:
  - target: Reduced Endocochlear Potential
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Disturbed strial ion transport is proposed to reduce the endocochlear potential, a functional consequence
      measured in the Hgf del10 model. This is indirect support for MET-associated disease.
  evidence:
  - reference: PMID:27488639
    reference_title: Hepatocyte Growth Factor-c-MET Signaling Mediates the Development of Nonsensory Structures of the Mammalian Cochlea and Hearing.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The stria vascularis is a nonsensory structure that is essential for auditory hair cell
      function by maintaining potassium concentration of the scala media.
    explanation: >-
      States the function of the structure whose development fails upstream.
  - reference: PMID:32152201
    reference_title: Noncoding Microdeletion in Mouse Hgf Disrupts Neural Crest Migration into the Stria Vascularis, Reduces the Endocochlear Potential, and Suggests the Neuropathology for Human Nonsyndromic Deafness DFNB39.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We conclude that, in the inner ear, the noncoding del10 mutation in Hgf leads to
      developmental defects of the SV and consequently dysfunctional ion homeostasis and a
      reduction in the EP, recapitulating human DFNB39 nonsyndromic deafness.
    explanation: >-
      Direct measurement in the Hgf ligand model supplies indirect support for a shared pathway consequence;
      it does not establish the endocochlear potential in MET-associated human hearing loss.
    directness: INDIRECT
- name: Reduced Endocochlear Potential
  role: central_effector
  biological_scale: TISSUE
  description: >-
    Hgf del10 mice have a reduced endocochlear potential, diminishing the electrochemical driving force
    for sound transduction. This is a proposed downstream consequence of abnormal strial development in
    MET-associated hearing loss; it has not been measured in the reported patients.
  locations:
  - preferred_term: stria vascularis of the cochlear duct
    term:
      id: UBERON:0002282
      label: stria vascularis of cochlear duct
  downstream:
  - target: Severe Prelingual Sensorineural Hearing Loss
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Reduced electrochemical driving force can impair auditory hair-cell transduction. The link from
      human MET variants to this physiological deficit remains proposed.
  evidence:
  - reference: PMID:32152201
    reference_title: Noncoding Microdeletion in Mouse Hgf Disrupts Neural Crest Migration into the Stria Vascularis, Reduces the Endocochlear Potential, and Suggests the Neuropathology for Human Nonsyndromic Deafness DFNB39.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The wild type (WT) 80 mV endocochlear potential was significantly reduced in homozygous del10 mice
      compared with WT littermates.
    explanation: >-
      Direct electrical measurement in the Hgf del10 model of DFNB39 supports a shared pathway hypothesis,
      not a measurement in human DFNB97.
    directness: INDIRECT
  - reference: PMID:32152201
    reference_title: Noncoding Microdeletion in Mouse Hgf Disrupts Neural Crest Migration into the Stria Vascularis, Reduces the Endocochlear Potential, and Suggests the Neuropathology for Human Nonsyndromic Deafness DFNB39.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Using a Hgf mutant mouse with a small 10 bp deletion recapitulating a human DFNB39 noncoding variant,
      we demonstrate that neural crest cells fail to migrate into the stria vascularis intermediate layer,
      resulting in a significantly reduced endocochlear potential, the driving force for sound transduction
      by inner ear hair cells.
    explanation: >-
      The Hgf experiment connects strial developmental defects with reduced endocochlear potential; its
      human disease model is DFNB39.
    directness: INDIRECT
- name: Severe Prelingual Sensorineural Hearing Loss
  role: consequence
  biological_scale: ORGANISM
  description: >-
    The founding family had severe prelingual sensorineural hearing loss. Conditional inactivation of
    Hgf or c-Met also impaired hearing in mice, supporting a developmental auditory role for the pathway
    without proving the effects of human missense alleles.
  biological_processes:
  - preferred_term: sensory perception of sound
    term:
      id: GO:0007605
      label: sensory perception of sound
    modifier: DECREASED
  evidence:
  - reference: PMID:27488639
    reference_title: Hepatocyte Growth Factor-c-MET Signaling Mediates the Development of Nonsensory Structures of the Mammalian Cochlea and Hearing.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In addition, inactivation of either the ligand or receptor developmentally resulted in a
      profound hearing loss at young adult stages.
    explanation: >-
      Closes the mouse chain from signalling loss to deafness, and does so for the receptor
      as well as the ligand, which is what makes it evidence about DFNB97.
  - reference: PMID:27488639
    reference_title: Hepatocyte Growth Factor-c-MET Signaling Mediates the Development of Nonsensory Structures of the Mammalian Cochlea and Hearing.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our findings reveal a novel mechanism that may underlie human deafness DFNB39 and
      DFNB97.
    explanation: >-
      The authors' own statement that this mechanism is offered for DFNB97, hedged as they
      hedge it.

  downstream:
  - target: Delayed Speech Development
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Early hearing loss can limit access to spoken language; speech delay was how hearing loss was recognized
      in the founding family.
phenotypes:
- category: Otologic
  name: Severe Prelingual Sensorineural Hearing Loss
  severity: SEVERE
  description: >-
    Nine affected relatives in the founding Pakistani family had severe sensorineural hearing loss. Pure-tone
    averages from 500 to 4000 Hz were 74–89 dB HL, measured in ambient noise. The separately reported
    Moroccan p.Ile316Met case had total bilateral hearing loss, but its uncertain molecular attribution
    precludes using it to establish the severity range of confirmed MET-related disease.
  phenotype_term:
    preferred_term: Severe sensorineural hearing impairment
    term:
      id: HP:0008625
      label: Severe sensorineural hearing impairment
  evidence:
  - reference: PMID:25941349
    reference_title: A mutation of MET, encoding hepatocyte growth factor receptor, is associated with human DFNB97 hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Audiometry in ambient noise conditions revealed a severe degree of sensorineural hearing
      loss (pure tone average, PTA500 Hz-4000 Hz, 74–89 dB HL) with intra-familial variations
      in thresholds, (figure 1B).
    explanation: >-
      The audiometric thresholds and the intrafamilial range.
  - reference: PMID:31801140
    reference_title: Further Evidence for the Implication of the MET Gene in Non-Syndromic Autosomal Recessive Deafness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a novel pathogenic homozygous c.948A>G (p.Ile316Met) mutation in the MET
      gene in one deaf Moroccan young girl carrying a total bilateral non-syndromic hearing
      impairment.
    explanation: >-
      Documents the phenotype of the reported Moroccan case, while the causal interpretation of p.Ile316Met
      is not accepted as established.

- category: Otologic
  name: Prelingual Onset
  description: >-
    Hearing loss at or before two years of age in the Pakistani family, recognised through
    delayed speech development.
  phenotype_term:
    preferred_term: Prelingual sensorineural hearing impairment
    term:
      id: HP:0000399
      label: Prelingual sensorineural hearing impairment
  evidence:
  - reference: PMID:25941349
    reference_title: A mutation of MET, encoding hepatocyte growth factor receptor, is associated with human DFNB97 hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The family includes 9 individuals (age range = 5–60 years old) with hearing loss at or
      before 2 years of age, noticeable due to delay in development of speech.
    explanation: >-
      Onset age and how it was recognised, across nine affected individuals.

- name: Delayed Speech Development
  category: Developmental
  description: >-
    Delayed speech development led to recognition of hearing loss in the founding family. This observation
    does not establish a separate primary language or intellectual disorder.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:25941349
    reference_title: A mutation of MET, encoding hepatocyte growth factor receptor, is associated with human DFNB97 hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The family includes 9 individuals (age range = 5–60 years old) with hearing loss at or before 2
      years of age, noticeable due to delay in development of speech.
    explanation: >-
      Nine affected relatives had early hearing loss recognized through delayed speech.
genetic:
- name: MET
  gene_term:
    preferred_term: MET
    term:
      id: hgnc:7029
      label: MET
  notes: >-
    The gene-disease association remains Limited. The strongest human evidence is segregation of p.Phe841Val
    with hearing loss in the founding family, but a linked regulatory cause was not excluded. The p.Ile316Met
    case should be distinguished from that pedigree: the 2019 paper called the allele pathogenic, whereas
    ClinVar RCV002490458.8 records a likely benign germline classification from a single submitter, evaluated
    May 31, 2022, for multiple conditions including DFNB97. The p.Phe841Val DFNB97 record RCV000202585.7
    records pathogenic from a literature-only OMIM submission without assertion criteria, evaluated May
    4, 2015; this variant assertion is not an expert-panel upgrade of gene-disease validity. The exon-trap
    experiment was inconclusive and did not measure receptor activation. Neither general MET oncogenic
    mechanisms nor another MET-related phenotype establishes the effect of these hearing-loss candidates.
    A separate p.Phe1186Cys report involved deafness with arthrogryposis in two siblings, as summarized
    by Naz and Friedman; those syndromic findings are not added to the DFNB97 phenotype spectrum. The
    older review considered this supportive of an auditory role for MET, whereas the later ClinGen assessment
    excluded phenotype-inconsistent evidence when scoring nonsyndromic hearing loss.
  evidence:
  - reference: CGGV:assertion_f0e6f9ac-f807-48fd-a5b6-bf67c4607e14-2021-03-26T160000.000Z
    reference_title: MET / nonsyndromic genetic hearing loss (Limited)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Only one missense variant was scored as the probands with the other variant had
      inconsistent phenotypes with nonsyndromic hearing loss and the minor allele frequency of
      the other variant was too high to be considered pathogenic.
    explanation: >-
      The specific reason the reported variant count overstates the evidence, and the reason
      the classification is Limited.
  - reference: CGGV:assertion_f0e6f9ac-f807-48fd-a5b6-bf67c4607e14-2021-03-26T160000.000Z
    reference_title: MET / nonsyndromic genetic hearing loss (Limited)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      One missense variant in this gene segregated with disease in 8 additional family
      members (PMID: 25941349).
    explanation: >-
      The segregation count credited by the panel.

  - *id001
  - &id005
    reference: url:https://www.ncbi.nlm.nih.gov/clinvar/RCV002490458/
    reference_title: NM_000245.4(MET):c.948A>G (p.Ile316Met) AND multiple conditions - ClinVar - NCBI
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Germline classification ... Likely benign ... Last evaluated ... May 31, 2022
    explanation: >-
      RCV002490458.8 is a single-submitter likely benign assertion whose condition list includes autosomal
      recessive nonsyndromic hearing loss 97. It conflicts with the original case report and is not an
      expert-panel gene-validity assertion.
  - &id004
    reference: url:https://www.ncbi.nlm.nih.gov/clinvar/RCV000202585/
    reference_title: NM_000245.4(MET):c.2521T>G (p.Phe841Val) AND Autosomal recessive nonsyndromic hearing loss 97 - ClinVar - NCBI
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Germline classification ... Pathogenic ... Last evaluated ... May 4, 2015
    explanation: >-
      The DFNB97 condition record carries a literature-only OMIM pathogenic assertion without provided
      criteria; the MET gene-disease association remains Limited.
  - reference: PMID:31506927
    reference_title: Growth factor and receptor malfunctions associated with human genetic deafness.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A second homozygous missense variant p.(Phe1186Cys) of MET is associated with arthrogryposis and
      deafness in two siblings,75 providing independent support for the conclusion that MET is required
      for normal hearing.
    explanation: >-
      The review summarizes a syndromic report; it is indirect evidence for that report and does not establish
      arthrogryposis as a DFNB97 manifestation.
    directness: INDIRECT
  association: Candidate recessive hearing loss association; ClinGen Limited
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    The founding consanguineous Pakistani pedigree supports recessive inheritance at the DFNB97 locus:
    p.Phe841Val was homozygous in nine affected relatives. This segregation does not independently establish
    the variant as causal. Recurrence counseling based on MET requires careful confirmation of the familial
    molecular diagnosis.
  evidence:
  - reference: PMID:25941349
    reference_title: A mutation of MET, encoding hepatocyte growth factor receptor, is associated with human DFNB97 hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Homozygosity mapping with a dense array of one million SNP markers allowed us to map the
      gene for recessively inherited severe hearing loss to chromosome 7q31.2, defining a new
      deafness locus designated DFNB97 (maximum logarithm of the odds score of 4.8).
    explanation: >-
      The linkage result establishing recessive inheritance and the locus itself.

animal_models:
- name: Conditional c-Met inner ear inactivation mouse
  species: Mouse
  genotype: Conditional c-Met deletion using Wnt1-Cre in neural crest cells or Pax2-Cre in cochlear epithelium
  publication: PMID:27488639
  description: >-
    Separate neural-crest and cochlear-epithelium conditional c-Met deletions impaired melanocyte incorporation
    into the stria vascularis and produced profound hearing loss. Public full-text excerpts describe
    later hair-cell malformation and degeneration; that observation is not quoted in the abstract-only
    cache cited here. Sensory-cell preservation therefore cannot be assumed. The experiments establish
    a developmental role for Met without reproducing
    either reported human missense allele.
  modeled_mechanisms:
  - target: Failed Melanocyte Incorporation into the Stria Vascularis
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Removing c-MET signalling in the developing inner ear stops the neural-crest-derived
      melanocytes entering the strial intermediate layer.
    limitations: >-
      Conditional inactivation is not a knock-in of a human missense allele. The experiment establishes
      a developmental role for the gene, without demonstrating the signaling defect or cochlear histology
      in the reported patients.
    readouts:
    - name: Melanocyte incorporation into the strial intermediate cell layer
      target: Failed Melanocyte Incorporation into the Stria Vascularis
      direction: DECREASED
      interpretation: >-
        The measured quantity is successful melanocyte incorporation, which decreases. The target node
        names the resulting failure of incorporation.
      evidence:
      - reference: PMID:27488639
        reference_title: Hepatocyte Growth Factor-c-MET Signaling Mediates the Development of Nonsensory Structures of the Mammalian Cochlea and Hearing.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Genetic dissection of HGF signaling via c-MET reveals that the incorporation of the
          melanocytes into the future stria vascularis of the cochlear duct requires c-MET
          signaling.
        explanation: >-
          The genetic result behind this readout.
    evidence:
    - reference: PMID:27488639
      reference_title: Hepatocyte Growth Factor-c-MET Signaling Mediates the Development of Nonsensory Structures of the Mammalian Cochlea and Hearing.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Genetic dissection of HGF signaling via c-MET reveals that the incorporation of the
        melanocytes into the future stria vascularis of the cochlear duct requires c-MET
        signaling.
      explanation: >-
        Conditional receptor inactivation tests the requirement for c-MET signaling during strial
        melanocyte incorporation, making this model informative for the proposed developmental lesion.
        It does not establish that either human missense allele produces the same defect.
  - target: Severe Prelingual Sensorineural Hearing Loss
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Developmental receptor inactivation produces profound hearing loss in young adult mice. This supports
      an auditory role for Met without equating mouse and human onset stages.
    limitations: >-
      Conditional inactivation and human missense variation are different perturbations. Mouse young-adult
      hearing measurements do not establish congenital onset, progression or residual receptor activity
      in people with candidate MET variants.
    readouts:
    - name: Hearing threshold after developmental inactivation
      target: Severe Prelingual Sensorineural Hearing Loss
      direction: INCREASED
      interpretation: >-
        Hearing is profoundly impaired, closing the chain from signalling loss to the clinical
        endpoint within a single organism.
      evidence:
      - reference: PMID:27488639
        reference_title: Hepatocyte Growth Factor-c-MET Signaling Mediates the Development of Nonsensory Structures of the Mammalian Cochlea and Hearing.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          In addition, inactivation of either the ligand or receptor developmentally resulted
          in a profound hearing loss at young adult stages.
        explanation: >-
          The hearing measurement behind this readout, reported for the receptor arm as well
          as the ligand arm.
    evidence:
    - reference: PMID:27488639
      reference_title: Hepatocyte Growth Factor-c-MET Signaling Mediates the Development of Nonsensory Structures of the Mammalian Cochlea and Hearing.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These results suggest a novel connection between HGF signaling and deafness via
        melanocyte deficiencies.
      explanation: >-
        Supports treating this model as informative for the clinical endpoint.

- name: Hgf del10 pathway-comparator mouse
  species: Mouse
  genotype: Homozygous noncoding 10 bp intronic deletion in Hgf
  publication: PMID:32152201
  description: >-
    This model recapitulates the ligand-associated disorder DFNB39. It provides indirect pathway evidence
    for the strial hypothesis in DFNB97, including abnormal neural-crest-cell incorporation and reduced
    endocochlear potential. It is not a model of a human MET variant.
  modeled_mechanisms:
  - target: Reduced Endocochlear Potential
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    limitations: >-
      The perturbed gene is Hgf, not Met; physiological findings cannot establish the pathogenicity or
      effect size of a human MET missense variant.
    readouts:
    - name: Endocochlear potential in Hgf del10 homozygotes
      target: Reduced Endocochlear Potential
      direction: DECREASED
      interpretation: >-
        Endocochlear potential was lower than in wild-type littermates.
      evidence:
      - reference: PMID:32152201
        reference_title: Noncoding Microdeletion in Mouse Hgf Disrupts Neural Crest Migration into the Stria Vascularis, Reduces the Endocochlear Potential, and Suggests the Neuropathology for Human Nonsyndromic Deafness DFNB39.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          The wild type (WT) 80 mV endocochlear potential was significantly reduced in homozygous del10
          mice compared with WT littermates.
        explanation: >-
          Direct electrical measurement in the Hgf del10 model of DFNB39 supports a shared pathway hypothesis,
          not a measurement in human DFNB97.
        directness: INDIRECT
    evidence:
    - reference: PMID:32152201
      reference_title: Noncoding Microdeletion in Mouse Hgf Disrupts Neural Crest Migration into the Stria Vascularis, Reduces the Endocochlear Potential, and Suggests the Neuropathology for Human Nonsyndromic Deafness DFNB39.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The wild type (WT) 80 mV endocochlear potential was significantly reduced in homozygous del10
        mice compared with WT littermates.
      explanation: >-
        Direct electrical measurement in the Hgf del10 model of DFNB39 supports a shared pathway hypothesis,
        not a measurement in human DFNB97.
      directness: INDIRECT
treatments:
- name: Hearing Aids
  therapeutic_modality: DEVICE
  description: >-
    Assess hearing-aid amplification according to individual audiometry, aided benefit and communication
    needs. This follows general hearing-loss guidance; benefit specific to MET-associated hearing loss
    has not been established in the cited clinical reports.
  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 DFNB97 outcome study.
    directness: INDIRECT
- 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 proposed strial
    mechanism does not establish preservation of the auditory nerve or predict a DFNB97-specific implant
    outcome.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: cochlear device implantation
    term:
      id: NCIT:C15329
      label: Surgical Procedure
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: cochlear implant
        term:
          id: NCIT:C157820
          label: Cochlear Implant
  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 DFNB97-specific
      efficacy claim.
    directness: INDIRECT
- name: Genetic Counseling
  description: >-
    Discuss family segregation, uncertainty in MET 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 MET 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 DFNB97-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
diagnosis:
- name: Comprehensive genetic evaluation and cautious MET interpretation
  description: >-
    Use a comprehensive hearing-loss panel or genomic testing with clinical correlation and segregation
    analysis. In the founding study, established recessive hearing-loss genes were excluded before the
    MET candidate was identified. That discovery workflow is not a requirement for sequential single-gene
    testing. A MET finding must be assessed in the context of Limited gene-disease validity; variants
    of uncertain significance cannot confirm a diagnosis.
  evidence:
  - reference: PMID:25941349
    reference_title: A mutation of MET, encoding hepatocyte growth factor receptor, is associated with human DFNB97 hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations of GJB2 and all other genes reported to underlie recessive deafness were ruled
      out as the cause of the phenotype in the affected members of the participating family.
    explanation: >-
      The exclusion step that preceded the DFNB97 diagnosis in the founding family.

  - 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 MET 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 MET alleles.
    directness: INDIRECT
- name: Audiometry and clinical assessment
  description: >-
    Establish hearing severity, onset and associated findings through audiometry and clinical evaluation.
    In the founding family, severe sensorineural loss was measured in ambient noise; clinical vestibular
    screening was reassuring, while laboratory and funduscopic examinations were reported for only two
    affected relatives.
  evidence:
  - reference: PMID:25941349
    reference_title: A mutation of MET, encoding hepatocyte growth factor receptor, is associated with human DFNB97 hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Audiometry in ambient noise conditions revealed a severe degree of sensorineural hearing
      loss (pure tone average, PTA500 Hz-4000 Hz, 74–89 dB HL) with intra-familial variations
      in thresholds, (figure 1B).
    explanation: >-
      The audiometric thresholds and the intrafamilial range.
differential_diagnoses:
- name: HGF-related nonsyndromic hearing loss (DFNB39)
  description: >-
    DFNB39 is associated with HGF variants affecting noncoding sequence or splicing, whereas DFNB97 is
    associated with candidate missense variation in the MET receptor. The two genes participate in a shared
    signaling pathway and can produce overlapping hearing phenotypes. Hgf mouse data support pathway-level
    inference but are not direct evidence for the human MET variants. Reported family counts from differently
    ascertained studies do not establish comparative population frequencies.
  evidence:
  - reference: PMID:19576567
    reference_title: Noncoding mutations of HGF are associated with nonsyndromic hearing loss, DFNB39.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We sequenced the noncoding sequences of genes, as well as noncoding genes, and found
      three mutations clustered in intron 4 and exon 5 in the hepatocyte growth factor gene
      (HGF).
    explanation: >-
      Establishes the variant class that distinguishes DFNB39 from DFNB97.
  - reference: PMID:19576567
    reference_title: Noncoding mutations of HGF are associated with nonsyndromic hearing loss, DFNB39.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We mapped an additional 40 consanguineous families segregating nonsyndromic hearing loss
      to the DFNB39 locus and refined the obligate interval to 1.2 Mb.
    explanation: >-
      Documents the linked families in this study; the count is not a population prevalence estimate.
  - reference: PMID:32152201
    reference_title: Noncoding Microdeletion in Mouse Hgf Disrupts Neural Crest Migration into the Stria Vascularis, Reduces the Endocochlear Potential, and Suggests the Neuropathology for Human Nonsyndromic Deafness DFNB39.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Previous studies showed that developmental incorporation of neural crest cells into the
      SV depends on signaling from HGF/MET.
    explanation: >-
      States the shared downstream mechanism that makes these two entities converge, which is
      why they need separating explicitly.

discussions:
- discussion_id: gap_met_allele_function_untested
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Biallelic MET Missense Variant
  - pathophysiology#Reduced HGF/MET Signalling in the Developing Cochlea
  - genetic#MET
  prompt: >-
    Do the two reported DFNB97 missense alleles actually reduce HGF/MET signalling?
  rationale: >-
    The founding study performed an exon-trap assay, but it was inconclusive and did not measure HGF binding,
    receptor activation or downstream signaling. Structural predictions for p.Phe841Val and molecular
    dynamics for p.Ile316Met cannot establish a receptor defect. The latter allele also has a later likely
    benign ClinVar assertion. Conditional mouse loss of Met supports a gene-level mechanism, while variant
    causality, linked regulatory alternatives and residual signaling remain unresolved.
  proposed_experiments:
  - experiment_id: met_dfnb97_allele_signalling_assay
    name: Functional characterisation of p.Phe841Val and p.Ile316Met MET signalling
    description: >-
      Express each variant receptor alongside wild type in a MET-null cell background, and
      measure HGF binding, receptor autophosphorylation and downstream ERK and AKT activation
      against wild type and against a known kinase-dead control.
    would_support:
    - pathophysiology#Reduced HGF/MET Signalling in the Developing Cochlea
    supporting_outcome:
    - >-
      A reproducible allele-specific reduction in receptor activation would support the proposed mechanism,
      with interpretation integrated with segregation and population data.
    refuting_outcome:
    - >-
      Normal signaling would weaken the proposed receptor defect in the tested system, while leaving possible
      tissue-specific, splice or linked regulatory effects to investigate. It would not by itself determine
      a ClinGen classification.
- discussion_id: mismatch_endocochlear_potential_measured_in_hgf_arm
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Reduced Endocochlear Potential
  - animal_models#Conditional c-Met inner ear inactivation mouse
  - animal_models#Hgf del10 pathway-comparator mouse
  prompt: >-
    How closely does strial dysfunction in Hgf and conditional Met mouse models reproduce human MET-associated
    hearing loss?
  rationale: >-
    The Hgf del10 mouse provides a direct endocochlear-potential measurement and models DFNB39. The c-Met
    conditional-inactivation study establishes developmental strial and auditory abnormalities. Neither
    experiment directly measures the cochlear consequence of p.Phe841Val in humans. Variant-specific models
    and matched physiological measurements are needed to establish how far the ligand and receptor experiments
    generalize to the human candidate association.
  proposed_experiments:
  - experiment_id: met_conditional_endocochlear_potential
    name: Endocochlear potential measurement in conditional c-Met inner ear mutants
    description: >-
      Measure the endocochlear potential directly in the conditional c-Met inner ear mutant at
      the same age at which it was measured in the Hgf del10 mouse, alongside strial
      histology, and compare the magnitude of the reduction between the two arms.
    would_support:
    - pathophysiology#Reduced Endocochlear Potential
    supporting_outcome:
    - >-
      A reduced potential associated with strial abnormalities would strengthen the proposed receptor-to-strial
      physiology link while leaving human variant causality to be tested.
    refuting_outcome:
    - >-
      Preserved potential despite hearing loss would argue for an additional or alternative auditory mechanism
      in that model.
notes: >-
  In the founding family, independent walking was reported at 12–13 months and tandem gait and Romberg
  tests were normal, suggesting intact or residual peripheral vestibular function. These bedside observations
  do not localize the cochlear lesion or exclude subtle vestibular dysfunction. No liver, kidney or heart
  conditions or cancer history were reported. Normal blood counts, serum chemistry, urinalysis, liver
  tests and funduscopy were documented in only two affected individuals aged 12 and 15 years; this is
  not evidence of lifelong absence of neoplasia or systemic disease in all affected people.

references:
- reference: PMID:25941349
  title: A mutation of MET, encoding hepatocyte growth factor receptor, is associated with human DFNB97 hearing loss.
- reference: PMID:27488639
  title: Hepatocyte Growth Factor-c-MET Signaling Mediates the Development of Nonsensory Structures of the Mammalian Cochlea and Hearing.
- reference: PMID:31801140
  title: Further Evidence for the Implication of the MET Gene in Non-Syndromic Autosomal Recessive Deafness.
- reference: PMID:19576567
  title: Noncoding mutations of HGF are associated with nonsyndromic hearing loss, DFNB39.
- reference: PMID:32152201
  title: Noncoding Microdeletion in Mouse Hgf Disrupts Neural Crest Migration into the Stria Vascularis, Reduces the Endocochlear Potential, and Suggests the Neuropathology for Human Nonsyndromic Deafness DFNB39.
- reference: CGGV:assertion_f0e6f9ac-f807-48fd-a5b6-bf67c4607e14-2021-03-26T160000.000Z
  title: MET / nonsyndromic genetic hearing loss (Limited)
- reference: url:https://www.ncbi.nlm.nih.gov/clinvar/RCV002490458/
  title: NM_000245.4(MET):c.948A>G (p.Ile316Met) AND multiple conditions - ClinVar - NCBI
- reference: url:https://www.ncbi.nlm.nih.gov/clinvar/RCV000202585/
  title: NM_000245.4(MET):c.2521T>G (p.Phe841Val) AND Autosomal recessive nonsyndromic hearing loss 97 - ClinVar - NCBI
- reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1434/
  title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
  tags:
  - GeneReviews
- reference: PMID:31506927
  title: Growth factor and receptor malfunctions associated with human genetic deafness.
variants:
- name: MET NM_000245.2:c.2521T>G (p.Phe841Val)
  gene:
    preferred_term: MET
    term:
      id: hgnc:7029
      label: MET
  type: missense variant
  description: >-
    IPT4-domain candidate segregating in family HLGM17. SIFT predicted tolerated whereas several other
    programs predicted damaging. Exon trapping was largely normal and inconclusive. ClinVar reports pathogenic
    for DFNB97 through a literature-only submission, but human causality remains limited and a linked
    regulatory variant was not excluded.
  evidence:
  - *id002
  - *id003
  - *id001
  - *id004
- name: MET NM_000245.4:c.948A>G (p.Ile316Met)
  gene:
    preferred_term: MET
    term:
      id: hgnc:7029
      label: MET
  type: missense variant
  description: >-
    SEMA-domain variant reported homozygous in a Moroccan child with total bilateral hearing loss. The
    publication called it pathogenic and molecular dynamics predicted reduced flexibility; later ClinVar
    RCV002490458.8 classifies it likely benign for multiple conditions including DFNB97. Retained as a
    disputed literature attribution, without assigning a pathogenic clinical-significance tag.
  evidence:
  - reference: PMID:31801140
    reference_title: Further Evidence for the Implication of the MET Gene in Non-Syndromic Autosomal Recessive Deafness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a novel pathogenic homozygous c.948A>G (p.Ile316Met) mutation in the MET
      gene in one deaf Moroccan young girl carrying a total bilateral non-syndromic hearing
      impairment.
    explanation: >-
      Documents the phenotype of the reported Moroccan case, while the causal interpretation of p.Ile316Met
      is not accepted as established.

  - *id005
experimental_models:
- name: MET c.2521T>G exon-trap assay
  experimental_model_type: OTHER
  publication: PMID:25941349
  description: >-
    Transfected wild-type and mutant constructs tested a predicted internal splice donor associated with
    c.2521T>G. Most mutant-derived clones matched wild type; two retained portions of flanking introns.
    The assay did not establish receptor loss of function.
  evidence:
  - *id003
  - *id006
📚

References & Deep Research

References

10
PMID:25941349
A mutation of MET, encoding hepatocyte growth factor receptor, is associated with human DFNB97 hearing loss.
No top-level findings curated for this source.
PMID:27488639
Hepatocyte Growth Factor-c-MET Signaling Mediates the Development of Nonsensory Structures of the Mammalian Cochlea and Hearing.
No top-level findings curated for this source.
PMID:31801140
Further Evidence for the Implication of the MET Gene in Non-Syndromic Autosomal Recessive Deafness.
No top-level findings curated for this source.
PMID:19576567
Noncoding mutations of HGF are associated with nonsyndromic hearing loss, DFNB39.
No top-level findings curated for this source.
PMID:32152201
Noncoding Microdeletion in Mouse Hgf Disrupts Neural Crest Migration into the Stria Vascularis, Reduces the Endocochlear Potential, and Suggests the Neuropathology for Human Nonsyndromic Deafness DFNB39.
No top-level findings curated for this source.
CGGV:assertion_f0e6f9ac-f807-48fd-a5b6-bf67c4607e14-2021-03-26T160000.000Z
MET / nonsyndromic genetic hearing loss (Limited)
No top-level findings curated for this source.
url:https://www.ncbi.nlm.nih.gov/clinvar/RCV002490458/
NM_000245.4(MET):c.948A>G (p.Ile316Met) AND multiple conditions - ClinVar - NCBI
No top-level findings curated for this source.
url:https://www.ncbi.nlm.nih.gov/clinvar/RCV000202585/
NM_000245.4(MET):c.2521T>G (p.Phe841Val) AND Autosomal recessive nonsyndromic hearing loss 97 - ClinVar - NCBI
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.
PMID:31506927
Growth factor and receptor malfunctions associated with human genetic deafness.
No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (1)

Create: Autosomal Recessive Nonsyndromic Hearing Loss 97 (DFNB97, MET) · 2026-08-29T02:47:28Z · View source

De novo curation of DFNB97 from MONDO:0014739. entry_type DISEASE: two published families, a conserved developmental pathograph running from a biallelic MET missense allele through failed neural-crest melanocyte incorporation into the stria vascularis to endolymphatic potassium failure and severe prelingual hearing loss, and its own OMIM and DFNB identity. ClinGen Hearing Loss GCEP rates MET-nonsyndromic hearing loss Limited; recorded as an external_assertion with the panel's own explanation of why only one of three reported variants scored. The gene is typed CAUSATIVE rather than DISPUTED because Limited means insufficient rather than contradicted, and the uncertainty is carried by a knowledge gap instead of being double-counted in the relationship type. Named entity handling for an oncogene: preflight flagged HGF at 33 percent of MET mentions in the deep-research report, so every citation was checked individually for whether it concerns the deafness phenotype. Nothing from the oncology literature is curated; hereditary papillary renal cell carcinoma appears only under differential_diagnoses, and the family's screened absence of tumours and organ disease is curated as a phenotype. HGF/DFNB39 separation: it is a separate differential entity with a different variant class, and the single place HGF evidence supports a DFNB97 node - the endocochlear potential, which has only ever been measured in the Hgf arm - is graded PARTIAL, labelled in the node description, and carries its own HUMAN_MODEL_MISMATCH discussion. Two examined-and-absent findings, preserved vestibular function and absence of neoplasia, are curated with the HP term for the absent thing and evidence graded REFUTE, because Phenotype has no presence slot and FrequencyEnum has no EXCLUDED value; the workaround is flagged in notes. functional_impact_category is deliberately omitted from the genetic_context because neither missense allele has been functionally assayed - that absence is the subject of the second knowledge gap. No treatments curated, since management is generic habilitation with no DFNB97-specific evidence. Validated: just validate exit 0, just validate-terms exit 0, validate-disorders exit 0 with 36/36 snippets verified.

Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 18 citations 2026-08-28T19:11:28.646658

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 97 (DFNB97, MET-related)
  • MONDO ID: MONDO:0014739 (if available)
  • Category: Genetic

Research Objectives

Please provide a comprehensive research report on Autosomal Recessive Nonsyndromic Hearing Loss 97 (DFNB97, MET-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:
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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 97 (DFNB97; MET-related)

Executive summary

DFNB97 is an ultra-rare, autosomal-recessive, nonsyndromic sensorineural hearing loss caused by biallelic variants in MET, which encodes the hepatocyte growth factor receptor, a receptor tyrosine kinase. The direct human evidence remains small: a large Pakistani pedigree containing nine affected people and a Moroccan family with one affected child. The characteristic presentation is bilateral, prelingual or early-childhood, severe-to-profound sensorineural hearing loss without established vestibular, structural inner-ear, or systemic abnormalities. The best-supported pathogenic model is impaired HGF–MET signaling during cochlear development, particularly defective incorporation or function of neural-crest-derived intermediate cells in the stria vascularis, followed by failure to maintain the endocochlear electrochemical environment required for hair-cell transduction. However, that chain is partly extrapolated from HGF and conditional animal models; no patient-variant knock-in model or patient-derived cochlear tissue has yet demonstrated it directly. (mujtaba2015amutationof pages 1-3, bousfiha2020furtherevidencefor pages 1-2, naz2020growthfactorand pages 7-8)

No MET-specific drug, gene therapy, validated biomarker, natural-history cohort, or DFNB97 clinical trial was identified. Current care therefore follows standard pediatric sensorineural-hearing-loss practice: early audiologic confirmation, hearing technology or cochlear implantation as appropriate, speech/language habilitation, educational support, and genetic counseling. A 2024 review records rapid progress in gene therapy for other hereditary deafness genes—especially OTOF/DFNB9—but this should not be represented as a treatment for DFNB97. (bousfiha2020furtherevidencefor pages 2-2, zhang2024aav‐mediatedgenetherapy pages 1-2)

Domain Established finding Evidence level/source Suggested ontology identifiers/terms Key caveat
Disease identity Autosomal recessive nonsyndromic hearing loss 97 (DFNB97) is a rare genetic form of bilateral sensorineural hearing loss linked to biallelic MET variants; MONDO association is available as MONDO:0014739. (OpenTargets Search: autosomal recessive nonsyndromic hearing loss 97-MET, mujtaba2015amutationof pages 1-3, bousfiha2020furtherevidencefor pages 1-2) Disease database association plus primary human family reports MONDO:0014739; term: autosomal recessive nonsyndromic hearing loss 97; term: nonsyndromic hearing loss Disease-level prevalence and natural-history data remain sparse.
Causal gene/protein Causal gene: MET (ENSG00000105976), encoding MET proto-oncogene, receptor tyrosine kinase / hepatocyte growth factor receptor (HGFR). (OpenTargets Search: autosomal recessive nonsyndromic hearing loss 97-MET, mujtaba2015amutationof pages 1-3, bousfiha2020furtherevidencefor pages 1-2) Primary human genetics; curated disease-target association ENSG00000105976; term: MET proto-oncogene, receptor tyrosine kinase; term: hepatocyte growth factor receptor HGNC/NCBI Gene/UniProt IDs should be verified separately if needed.
Inheritance Inheritance is autosomal recessive; reported cases occurred in consanguineous families with homozygous missense variants and unaffected heterozygous relatives. (mujtaba2015amutationof pages 1-3, bousfiha2020furtherevidencefor pages 1-2, bousfiha2020furtherevidencefor pages 2-2) Primary human pedigree/segregation evidence HPO term label: Autosomal recessive inheritance (ID verification required) Penetrance cannot be estimated robustly from two reported families.
Human family 1 / variant Pakistani family HLGM17: 9 affected individuals, severe sensorineural hearing loss, homozygous MET c.2521T>G, p.(Phe841Val) / p.F841V; mapped to 7q31.2 with maximum LOD 4.8. (mujtaba2015amutationof pages 1-3, mujtaba2015amutationof pages 3-4, mujtaba2015amutationof pages 8-10) Strong primary human linkage + exome + segregation term: MET c.2521T>G; term: p.Phe841Val; term: chromosome 7q31.2; HPO term label: Sensorineural hearing impairment Transcript/isoform numbering should be normalized before KB ingestion.
Human family 2 / variant Moroccan family SF190: one affected girl with total bilateral nonsyndromic hearing impairment; homozygous MET c.948A>G, p.(Ile316Met); heterozygous parents and brother had normal hearing. (bousfiha2020furtherevidencefor pages 1-2, bousfiha2020furtherevidencefor pages 2-4, bousfiha2020furtherevidencefor pages 2-2) Primary human exome + segregation evidence term: MET c.948A>G; term: p.Ile316Met; HPO term label: Bilateral hearing impairment Single-patient family report; broader phenotypic spectrum unknown.
Core phenotype Reported phenotype is early-onset/prelingual, bilateral, nonsyndromic sensorineural hearing loss, severe to profound, with speech delay and intrafamilial threshold variability. Vestibular bedside testing was normal in the Pakistani family. (mujtaba2015amutationof pages 1-3, mujtaba2015amutationof pages 3-4, bousfiha2020furtherevidencefor pages 2-2) Primary human clinical/audiometric evidence HPO term labels: Sensorineural hearing impairment; Severe hearing impairment; Profound hearing impairment; Prelingual hearing impairment; Delayed speech and language development; Bilateral hearing impairment Percent frequencies for individual phenotypes are unavailable beyond the reported families.
Onset/course Pakistani family: hearing loss noted at or before age 2 years; Moroccan case diagnosed in early childhood by BAEP/ABR. Available reports support congenital/early-childhood onset and lifelong course. (mujtaba2015amutationof pages 1-3, bousfiha2020furtherevidencefor pages 2-2) Primary human case evidence HPO term labels: Congenital or childhood onset hearing impairment (ID verification required) Progression is not well defined specifically for DFNB97.
Syndromic exclusion Reported DFNB97 cases lacked obvious extra-auditory disease; Pakistani cases had normal liver/kidney/heart history and normal selected laboratory/ophthalmic assessments; Moroccan imaging showed no inner-ear or cochleovestibular nerve malformation. (mujtaba2015amutationof pages 1-3, bousfiha2020furtherevidencefor pages 2-2) Primary human clinical evaluation term: nonsyndromic hearing loss; term: normal inner ear imaging Small numbers do not exclude subtle or age-dependent extra-auditory manifestations.
Anatomy/organs Primary affected organ is the inner ear, especially the cochlea; broader pathway evidence implicates the stria vascularis in maintaining endocochlear potential needed for sound transduction. (naz2020growthfactorand pages 7-8, shadab2024autosomalrecessivenon‐syndromic pages 8-9, zhang2024aav‐mediatedgenetherapy pages 1-2) Mechanistic synthesis from pathway/review and model evidence UBERON term labels: inner ear; cochlea; stria vascularis Direct human histopathology for DFNB97 is not available.
Cell types Most implicated cell populations are strial intermediate cells (neural crest-derived melanocyte-like cells) and possibly other cochlear nonsensory cells; MET/HGF expression has also been described in spiral ganglion cells and hair cells in embryonic rat cochlea. (bousfiha2020furtherevidencefor pages 5-6, naz2020growthfactorand pages 7-8) Indirect model/expression evidence CL term labels: intermediate cell of stria vascularis; melanocyte; hair cell; spiral ganglion neuron Exact causally affected human cell type in DFNB97 remains inferred, not proven.
Molecular mechanism Best-supported mechanism: deleterious MET variants impair HGF-MET receptor function. The IPT3/IPT4 region forms a high-affinity HGF-binding surface, while the SEMA domain is important for dimerization/activation; altered signaling is predicted to disrupt development of neural crest-derived intermediate cells in the stria vascularis, reducing endocochlear potential and causing hearing loss. (bousfiha2020furtherevidencefor pages 5-6, mujtaba2015amutationof pages 4-6, naz2020growthfactorand pages 7-8, shadab2024autosomalrecessivenon‐syndromic pages 8-9) Variant/domain interpretation plus pathway/model inference GO term labels: receptor tyrosine kinase signaling; epithelial to mesenchymal transition; neural crest cell migration; inner ear development; potassium ion homeostasis (ID verification required) No variant-specific functional assay directly demonstrated loss of MET signaling in patient tissue.
Variant functional evidence p.Phe841Val: conserved residue, predicted damaging by multiple tools, possible splicing effect in exon-trap assay, absent from large control/public datasets in 2015 study. p.Ile316Met: conserved residue, in silico pathogenicity support and molecular dynamics predicted loss of flexibility affecting receptor conformation/binding site. (mujtaba2015amutationof pages 3-4, bousfiha2020furtherevidencefor pages 1-2, bousfiha2020furtherevidencefor pages 2-4, mujtaba2015amutationof pages 4-6) Primary human variant interpretation with in vitro/in silico support ACMG term labels: pathogenic / likely pathogenic (case-specific review required) ClinVar/ACMG status should be checked live because classifications may change.
Diagnostics Recommended workup is standard hereditary hearing-loss evaluation: audiometry/ABR, clinical exam to exclude syndromic causes, and molecular testing via multigene hearing-loss panel or exome/genome sequencing with segregation testing. MET should be included in comprehensive hearing-loss analysis rather than isolated first-line testing. (mujtaba2015amutationof pages 1-3, bousfiha2020furtherevidencefor pages 1-2, zhang2024aav‐mediatedgenetherapy pages 1-2) Primary case reports plus 2024 field review term: pure-tone audiometry; term: auditory brainstem response; term: exome sequencing; term: segregation analysis No DFNB97-specific biomarker, pathology assay, or imaging signature is established.
Treatment / management No MET-specific disease-modifying therapy is established. Current real-world management is supportive/rehabilitative hearing-loss care, including hearing aids where useful, cochlear implantation when indicated, and speech/language habilitation; the Moroccan child underwent cochlear implantation at age 4. (bousfiha2020furtherevidencefor pages 2-2, zhang2024aav‐mediatedgenetherapy pages 1-2) Primary case implementation plus contemporary hereditary-deafness review NCIT term labels: Cochlear Implantation; Hearing Aid Device; Speech Therapy / Auditory rehabilitation (ID verification required) Published DFNB97-specific post-implant auditory outcomes were not reported in the retrieved evidence.
Experimental therapeutics No registered DFNB97- or MET-hearing-loss-specific interventional trial was identified. 2024 hearing-loss gene therapy advances are real but currently center on other genes such as OTOF, not MET. (zhang2024aav‐mediatedgenetherapy pages 1-2) 2024 field review; trial search context term: gene therapy for hereditary deafness; DFNB9/OTOF as field comparator MET pathway manipulation may have safety/oncology implications and is not a validated DFNB97 strategy.
Epidemiology DFNB97 appears ultra-rare: only two reported families were identified in the retrieved literature (Pakistan and Morocco). Screening of 100 unrelated Pakistani nonsyndromic hearing-loss families found no additional MET cases in the 2015 report. (mujtaba2015amutationof pages 3-4, bousfiha2020furtherevidencefor pages 1-2) Primary human evidence term: rare disease; term: ultra-rare genetic hearing loss No population prevalence, incidence, or carrier-frequency estimate is established for DFNB97 specifically.
Population/genetic context Reported families were consanguineous, consistent with recessive inheritance and enrichment of rare homozygous variants in some populations. Pakistan has high ARNSHL gene discovery yield, but MET contributes a very small fraction relative to major genes. (bousfiha2020furtherevidencefor pages 1-2, shadab2024autosomalrecessivenon‐syndromic pages 8-9, mujtaba2015amutationof pages 1-3) Primary cases plus 2024 population review term: consanguinity; term: founder effect evaluation There is no confirmed MET founder variant for DFNB97 at present.
Models Direct DFNB97 model is lacking. Relevant comparative evidence includes embryonic lethality of complete Met loss in mouse, reduced neuromast-derived hair cells in zebrafish met morphants, and HGF-pathway mouse data showing failure of neural crest/intermediate-cell incorporation into stria vascularis with reduced endocochlear potential and deafness. (mujtaba2015amutationof pages 4-6, naz2020growthfactorand pages 7-8, shadab2024autosomalrecessivenon‐syndromic pages 8-9) Model-organism/pathway evidence NCBI Taxon labels: Mus musculus; Danio rerio Mechanistic extrapolation from HGF or global Met perturbation may not fully mimic human missense DFNB97.
2023-2024 research status Recent literature mainly provides broader ARNSHL synthesis, stria-vascularis biology, and rapid progress in gene therapy for other deafness genes. No new 2023-2024 DFNB97 patient series, natural-history cohort, variant-specific functional animal model, or MET-targeted therapy was found in the retrieved evidence. (shadab2024autosomalrecessivenon‐syndromic pages 8-9, zhang2024aav‐mediatedgenetherapy pages 1-2) Recent expert synthesis/review term: precision medicine; term: stria vascularis biology Knowledge gaps remain large despite strong gene-disease validity.

Table: This table summarizes the most knowledge-base-ready findings for MET-related autosomal recessive nonsyndromic hearing loss 97, separating well-supported human evidence from pathway-based inference. It is useful for quickly populating core disease, gene, phenotype, mechanism, diagnosis, and treatment fields while flagging major gaps.

Evidence framework

  • Direct human DFNB97 evidence: Mujtaba et al., Journal of Medical Genetics, final publication August 2015, DOI 10.1136/jmedgenet-2015-103023, PMID 25941349; and Bousfiha et al., Human Heredity, published online December 4, 2019 and in volume 84 (2020), DOI 10.1159/000503450. (mujtaba2015amutationof pages 1-3, bousfiha2020furtherevidencefor pages 1-2)
  • Mechanistic evidence: structural prediction, an exon-trap experiment, expression studies, and HGF/MET-pathway mouse or zebrafish studies. This is biologically persuasive but not equivalent to functional proof for each human allele. (mujtaba2015amutationof pages 3-4, mujtaba2015amutationof pages 4-6, naz2020growthfactorand pages 7-8)
  • Recent context: 2024 literature concerns the broader Pakistani recessive-hearing-loss landscape, stria-vascularis biology, and gene therapy for other genotypes; no new 2023–2024 DFNB97 cohort or MET-directed treatment was found. (shadab2024autosomalrecessivenon‐syndromic pages 8-9, zhang2024aav‐mediatedgenetherapy pages 1-2)

1. Disease information

Definition and identifiers

DFNB97 is a monogenic form of isolated, recessively inherited hearing impairment associated with biallelic MET variants. Open Targets maps the disease to MONDO:0014739, MET Ensembl ENSG00000105976, and cites four disease-target evidence records, including PMID 25941349 and ClinVar record RCV000202585. (OpenTargets Search: autosomal recessive nonsyndromic hearing loss 97-MET)

Recommended database labels are:

  • Preferred name: autosomal recessive nonsyndromic hearing loss 97.
  • Synonyms: DFNB97; nonsyndromic autosomal recessive deafness 97; MET-related nonsyndromic hearing loss; MET-related deafness.
  • MONDO: MONDO:0014739.
  • Causal-gene OMIM identifier: MET, OMIM 164860. The disease-specific OMIM phenotype number should be verified directly in the current OMIM record before ingestion because it was not exposed reliably in the retrieved sources. (bousfiha2020furtherevidencefor pages 2-2)
  • ICD-10/ICD-11 and MeSH: there is no known DFNB97-specific billing or MeSH code. Use the appropriate bilateral sensorineural/congenital hearing-loss code plus a molecular diagnosis; do not treat a generic code as uniquely identifying DFNB97.

The evidence is aggregated disease-level literature and family-based research, not an EHR-derived patient series. The two primary reports nevertheless contain individual-level pedigree, audiometric, imaging, and laboratory observations. (mujtaba2015amutationof pages 1-3, bousfiha2020furtherevidencefor pages 1-2)

Landmark abstract quotation

The discovery paper states: “Homozygosity mapping with a dense array of one million SNP markers allowed us to map the gene for recessively inherited severe hearing loss to chromosome 7q31.2, defining a new deafness locus designated DFNB97 (maximum LOD score of 4.8).” It concludes: “We identified a missense mutation of MET, encoding the hepatocyte growth factor receptor, as a likely cause of hearing loss in humans.” (mujtaba2015amutationof pages 1-3)

2. Etiology, risks, protective factors, and gene–environment interaction

Causal factor

The established cause is germline biallelic MET variation. Both reported families were consanguineous and carried homozygous missense variants. Heterozygous relatives in the Moroccan family had normal hearing, supporting recessive inheritance. (bousfiha2020furtherevidencefor pages 1-2, bousfiha2020furtherevidencefor pages 2-4)

Risk factors

  • Primary genetic risk: two pathogenic or likely pathogenic MET alleles in trans—or a homozygous allele inherited through parental relatedness.
  • Family history/consanguinity: increases the probability that both parents carry the same rare allele; it is not itself a biological cause.
  • Sex: no sex-specific effect is established.
  • Age: age determines when hearing impairment becomes detectable but is not a causal risk factor.
  • Environmental risks: noise, congenital infection, and ototoxic drugs can independently cause or worsen hearing loss generally, but no DFNB97-specific interaction has been demonstrated.

Protective factors and modifiers

No protective MET allele, environmental protective factor, penetrance modifier, or confirmed DFNB97 modifier gene is known. GAB1, SPRY2, and METTL13/EEF1AKNMT provide relevant pathway biology: GAB1 is a MET-associated scaffold; SPRY2 down-regulates receptor-tyrosine-kinase signaling; and a METTL13 allele has been proposed to suppress GAB1-related DFNB26 deafness. These are not proven modifiers of MET-related DFNB97. (naz2020growthfactorand pages 7-8)

No DFNB97-specific gene–environment interaction has been reported. Ordinary hearing conservation and avoidance of unnecessary ototoxic exposure remain prudent tertiary measures, but they cannot prevent genetically programmed congenital cochlear dysfunction.

3. Phenotypes

Core auditory phenotype

In Pakistani family HLGM17, all nine affected relatives, aged 5–60 years, had hearing loss recognized at or before age two because of delayed speech. Pure-tone averages from 500–4,000 Hz were 74–89 dB HL, indicating severe sensorineural impairment with intrafamilial threshold variation. The original paper describes nine of nine evaluated affected relatives with the defining phenotype, but this is a pedigree-specific proportion, not a population frequency. (mujtaba2015amutationof pages 1-3)

The Moroccan proband was a seven-year-old girl with total bilateral nonsyndromic impairment, detected by brainstem auditory-evoked testing at age 3 years 9 months. She received a cochlear implant at age four. CT and MRI showed no inner-ear or cochleovestibular-nerve abnormality. (bousfiha2020furtherevidencefor pages 2-2)

Suggested HPO annotations include:

  • Sensorineural hearing impairment — HP:0000407.
  • Bilateral sensorineural hearing impairment — use the current HPO bilateral child term or combine HP:0000407 with a bilateral qualifier.
  • Severe hearing impairment and profound hearing impairment — verify current severity-specific HPO identifiers.
  • Prelingual hearing impairment — HP:0000399.
  • Delayed speech and language development — HP:0000750.
  • Normal vestibular function and normal inner-ear imaging are important negative observations but should not be encoded as universal defining features.

Vestibular and extra-auditory findings

Pakistani participants walked independently at 12–13 months and had normal Romberg and tandem-gait tests, suggesting intact or residual peripheral vestibular function. No liver, kidney, cardiac disease, or cancer history was reported; two affected adolescents had normal blood counts, serum chemistry, urinalysis, liver tests, and funduscopy. These observations support the designation “nonsyndromic,” but ten known patients are insufficient to exclude subtle, late-onset, or allele-specific systemic effects. (mujtaba2015amutationof pages 1-3)

Course and quality of life

Published DFNB97 data do not establish whether hearing thresholds are stable or progressive. The Pakistani pedigree spans ages 5–60 and shows variable thresholds, but no longitudinal audiometry was reported. Hearing loss of this degree can compromise spoken-language acquisition, education, communication, social participation, and psychosocial well-being. The Moroccan report emphasizes early intervention for speech, intellectual, cognitive, and social development, but no DFNB97-specific EQ-5D, SF-36, PROMIS, or hearing-related quality-of-life measurements exist. (bousfiha2020furtherevidencefor pages 1-2)

4. Genetic and molecular information

Gene

MET encodes the MET proto-oncogene receptor tyrosine kinase, also called hepatocyte growth factor receptor/HGFR. It lies at chromosome 7q31.2. HGF is its ligand; pathogenic noncoding HGF variants cause the distinct recessive locus DFNB39, making HGF–MET a ligand–receptor pair in which disruption of either partner can cause nonsyndromic hearing loss. (mujtaba2015amutationof pages 4-6, naz2020growthfactorand pages 7-8)

Reported DFNB97 variants

  1. c.2521T>G, p.(Phe841Val), commonly abbreviated p.F841V. This was homozygous in the nine affected Pakistani relatives and co-segregated perfectly. It was absent from 800 ethnically matched control chromosomes and 136,602 public-database chromosomes available in 2015; no additional case was found among 100 unrelated Pakistani families. The residue is evolutionarily conserved. PROVEAN, PolyPhen-2, MutationTaster, and Human Splicing Finder supported deleteriousness, whereas SIFT was tolerant. CUPSAT/I-Mutant predicted reduced stability, and an exon-trap assay suggested possible alternative intron retention. It lies in extracellular IPT4, part of the high-affinity HGF-binding region. (mujtaba2015amutationof pages 3-4, mujtaba2015amutationof pages 8-10, mujtaba2015amutationof pages 4-6)

  2. c.948A>G, p.(Ile316Met). This was homozygous in the Moroccan child and heterozygous in her unaffected parents and older brother. It affects a conserved residue in the extracellular SEMA domain, important for HGF binding, receptor dimerization, and activation. Computational scores supported damage, and molecular-dynamics simulation predicted loss of flexibility with altered receptor conformation and binding-site function. Reported database frequency was low but not absent, including one homozygote among 9,790 African individuals in the dataset used by the authors; this, the singleton phenotype, and absence of a direct signaling assay warrant contemporary ClinVar/ACMG re-evaluation rather than uncritical acceptance of the paper’s “pathogenic” label. (bousfiha2020furtherevidencefor pages 1-2, bousfiha2020furtherevidencefor pages 2-4)

An apparent p.Phe859Val/c.2575T>G label in the later paper likely reflects alternative transcript/isoform numbering for the Pakistani allele. A knowledge base should retain the publication-specific representation but normalize all alleles against a declared MANE transcript and genome build before merging records. (bousfiha2020furtherevidencefor pages 5-6)

Both are constitutional/germline missense variants, not somatic cancer alterations. Current gnomAD frequencies, ClinVar review status, HGNC ID, MANE transcript, and genomic coordinates should be refreshed through live database queries before clinical reporting.

Other molecular categories

No DFNB97-associated copy-number variant, translocation, inversion, repeat expansion, mitochondrial variant, epigenetic signature, methylation defect, somatic mosaicism, or validated modifier is known. No patient-specific transcriptomic, proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, or multi-omic profile has been published.

5. Environmental information

DFNB97 is genetic; no toxin, radiation exposure, pollutant, lifestyle behavior, diet, infection, smoking, alcohol use, or occupational exposure is established as a cause or trigger. Congenital CMV, meningitis, noise, and ototoxic agents remain important differential or additive causes of hearing loss, not demonstrated components of DFNB97 pathogenesis. Vaccination and avoidance of excessive noise or unnecessary ototoxic medication protect general auditory health but do not correct MET deficiency.

6. Mechanism and pathophysiology

Proposed causal chain

  1. Upstream lesion: biallelic MET missense variation changes the extracellular SEMA or IPT4 domain.
  2. Receptor defect: impaired folding, stability, HGF binding, dimerization, activation, or—specifically for p.Phe841Val—possibly transcript splicing reduces effective HGF–MET signaling.
  3. Developmental cellular defect: pathway evidence indicates that HGF–MET signaling is required for proper migration/incorporation of neural-crest-derived melanocytic intermediate cells into the middle layer of the developing stria vascularis.
  4. Tissue dysfunction: abnormal or thinned stria vascularis cannot adequately establish cochlear ionic homeostasis and the endocochlear potential.
  5. Physiologic failure: the normal stria supports approximately +80 to +120 mV and potassium near 154 mM in endolymph, conditions needed for sensory-hair-cell mechanotransduction.
  6. Clinical outcome: reduced cochlear transduction produces bilateral severe-to-profound sensorineural hearing loss and secondary delay in spoken-language development. (naz2020growthfactorand pages 7-8, shadab2024autosomalrecessivenon‐syndromic pages 8-9)

The downstream HGF-stimulated MET network has numerous branches and includes GAB1 scaffolding and SPRY2 negative regulation. Canonical MET signaling can engage RAS–MAPK, PI3K–AKT, PLCγ, STAT, survival, proliferation, motility, and epithelial–mesenchymal programs, but the precise branch responsible for DFNB97 has not been isolated experimentally. (naz2020growthfactorand pages 7-8)

Suggested ontology annotations

  • GO biological processes: hepatocyte growth factor receptor signaling pathway; transmembrane receptor protein tyrosine kinase signaling; neural crest cell migration; melanocyte migration/differentiation; inner-ear morphogenesis; stria-vascularis development; potassium-ion homeostasis; sensory perception of sound.
  • GO molecular function: HGF receptor activity; transmembrane receptor protein tyrosine kinase activity; ATP binding; protein-tyrosine-kinase activity.
  • GO cellular component: plasma membrane; receptor complex; basolateral plasma membrane, where supported by cell-specific evidence.
  • Cell Ontology labels: melanocyte; neural-crest-derived cell; strial intermediate cell; cochlear hair cell; spiral ganglion neuron. Exact CL identifiers should be validated because “strial intermediate cell” may not have a dedicated current class.

There is no demonstrated primary metabolic enzyme defect, immune-mediated process, autoinflammation, fibrosis, ischemia, or systemic biochemical abnormality. Hair cells and spiral ganglion cells express HGF/MET in embryonic rat cochlea, but whether they are primary cellular targets in human DFNB97 is unresolved. (bousfiha2020furtherevidencefor pages 5-6)

7. Anatomical structures affected

The primary organ is the inner ear, specifically the auditory cochlea. The strongest mechanistic localization is the stria vascularis along the lateral cochlear wall, particularly its neural-crest-derived intermediate-cell layer. Hair cells, spiral ganglion neurons, and nonsensory cochlear structures are biologically relevant but not proven primary sites of human disease. No secondary organ involvement is established. (bousfiha2020furtherevidencefor pages 5-6, naz2020growthfactorand pages 7-8)

Suggested anatomy terms are UBERON:0001846 inner ear, UBERON:0001851 cochlea, organ of Corti, cochlear duct, cochlear lateral wall, and stria vascularis; the latter identifiers should be checked in the current UBERON release. The clinical impairment is bilateral. CT/MRI can be anatomically normal, as in the Moroccan child. (bousfiha2020furtherevidencefor pages 2-2)

8. Temporal development and natural history

Available evidence supports congenital or very early childhood onset, usually recognized during the prelingual period. The Pakistani family’s onset was reported by age two; the Moroccan case was objectively identified in early childhood. The condition is chronic and lifelong without auditory rehabilitation. There are no validated clinical stages, remission pattern, spontaneous recovery rate, or quantified progression rate. (mujtaba2015amutationof pages 1-3, bousfiha2020furtherevidencefor pages 2-2)

The major intervention window is early childhood, when access to sound is important for spoken-language and educational development. This is a developmental and rehabilitative principle, not evidence that MET molecular pathology itself is reversible after a defined age.

9. Inheritance, penetrance, and population epidemiology

Inheritance is autosomal recessive. For two confirmed carrier parents, each pregnancy conventionally has a 25% probability of an affected child, 50% probability of an unaffected carrier, and 25% probability of inheriting neither familial allele, subject to confirmation that the allele is truly pathogenic.

Penetrance appears high in the Pakistani pedigree, where the homozygous allele tracked with hearing loss, but it cannot be estimated population-wide. Expressivity is variable in audiometric threshold. Anticipation is not expected; germline mosaicism has not been reported. No confirmed founder allele or sex bias is known. (mujtaba2015amutationof pages 1-3, mujtaba2015amutationof pages 3-4)

Only two families were documented in the retrieved direct literature. Screening 100 additional Pakistani nonsyndromic-hearing-loss families found no case, and a 2024 review indicates that uncommon Pakistani ARNSHL genes each account for under 2%, whereas 13 much more prevalent genes collectively explain over half of profound cases. Consequently, DFNB97-specific prevalence, incidence, carrier frequency, geographic distribution, and sex ratio are unknown; extrapolation from generic hearing-loss statistics would be misleading. (mujtaba2015amutationof pages 3-4, shadab2024autosomalrecessivenon‐syndromic pages 8-9)

10. Diagnostics

Clinical evaluation

  1. Confirm hearing status with newborn screening followed by diagnostic auditory brainstem response/BAEP, otoacoustic emissions where informative, tympanometry, and age-appropriate pure-tone and speech audiometry.
  2. Establish sensorineural rather than conductive loss and document laterality, frequency configuration, severity, and longitudinal change.
  3. Examine for syndromic findings; assess vestibular function and development. Consider ophthalmology, renal, cardiac, infectious, or other testing only when history or examination indicates it.
  4. CT or MRI is useful for cochlear-implant planning or suspected structural/nerve abnormality, but normal imaging does not exclude DFNB97. (bousfiha2020furtherevidencefor pages 2-2, mujtaba2015amutationof pages 1-3)

Molecular testing

A comprehensive hearing-loss multigene panel that includes MET is generally preferable to first-line MET-only sequencing because hereditary hearing loss is highly heterogeneous. Exome sequencing was decisive in both reported families; genome sequencing may improve detection of noncoding and structural alleles when panel/exome testing is negative. Candidate variants require read-quality review, population-frequency assessment, phenotype fit, ACMG/AMP interpretation, and parental/family segregation. (mujtaba2015amutationof pages 1-3, bousfiha2020furtherevidencefor pages 1-2)

CMA, karyotyping, FISH, mitochondrial sequencing, and repeat-expansion testing are not DFNB97-specific; use them only when phenotype or first-line results suggest another diagnosis. No blood chemistry, circulating protein, metabolite, biopsy, histopathology, RNA, proteomic, or liquid-biopsy marker diagnoses DFNB97.

Differential diagnosis

The differential includes common nonsyndromic genes such as GJB2, SLC26A4, OTOF, MYO15A, CDH23, TMC1, and TMPRSS3; HGF-related DFNB39; congenital CMV; auditory neuropathy; ototoxicity; structural malformations; and syndromes such as Usher or Pendred syndrome. Normal vestibular testing and imaging can support but do not uniquely identify DFNB97.

Screening

Universal newborn hearing screening detects impairment, not genotype. Once a familial MET diagnosis is established, targeted cascade testing can identify carriers and affected relatives. Population carrier screening is not currently supported by prevalence or clinical-utility data.

11. Outcome and prognosis

DFNB97 is not known to reduce survival or life expectancy; no disease-specific mortality has been reported. Prognosis primarily concerns auditory communication. Untreated severe-to-profound prelingual loss can produce persistent speech/language, educational, vocational, and social disability. Early, effective access to communication—spoken, signed, or multimodal—can substantially mitigate secondary developmental consequences, but DFNB97-specific response rates are unavailable. (bousfiha2020furtherevidencefor pages 1-2)

The Moroccan child’s cochlear implantation demonstrates real-world implementation, but the retrieved report did not provide postoperative speech-perception or threshold outcomes. No molecular prognostic biomarker predicts progression, hearing-aid benefit, or implant response. Cochleovestibular-nerve integrity, age at intervention, residual hearing, rehabilitation access, and communication environment are likely to matter as in other congenital hearing losses, but these have not been tested specifically in DFNB97. (bousfiha2020furtherevidencefor pages 2-2, zhang2024aav‐mediatedgenetherapy pages 1-2)

12. Treatment and current applications

Standard management

There is no approved pharmacotherapy that restores MET function. Management is individualized and may include:

  • hearing aids for aidable residual hearing;
  • cochlear implantation for severe/profound impairment with insufficient hearing-aid benefit;
  • auditory-verbal, speech/language, and listening therapy where spoken language is a family goal;
  • sign-language and multimodal communication access;
  • educational accommodations, assistive listening systems, and psychosocial support;
  • periodic audiologic and device monitoring.

Suggested NCIt intervention labels are Hearing Aid, Cochlear Implantation, Speech Therapy, Auditory Rehabilitation, and Genetic Counseling; exact current NCIt codes should be validated before database loading.

Advanced and experimental therapy

No MET replacement, gene editing, antisense RNA, cell therapy, HGF agonist, or small-molecule treatment has demonstrated efficacy in DFNB97. A 2024 authoritative review states that current hereditary-deafness options remain largely hearing aids and cochlear implants and that AAV therapy has restored hearing in more than 20 genetic mouse models. It also stresses that different deafness genes and target-cell transduction efficiencies require genotype- and cell-specific precision approaches. (zhang2024aav‐mediatedgenetherapy pages 1-2)

OTOF gene therapy restored hearing in early DFNB9 trials, making it an important translational proof of concept, not evidence of efficacy for MET-related disease. MET is broadly expressed and is also an oncogenic receptor; indiscriminate systemic HGF/MET activation would therefore require particularly careful safety evaluation. The clinical-trial search found no relevant DFNB97/MET-hearing-loss trial; oncology trials targeting MET and a middle-ear implant named “MET V” are unrelated and must not be linked to this disease.

13. Prevention

The inherited molecular lesion cannot be prevented by vaccination, diet, exercise, or medication.

  • Primary genetic prevention/family planning: genetic counseling, carrier testing of relatives, partner testing, prenatal diagnosis, or preimplantation genetic testing when a familial pathogenic variant is established. These are optional reproductive choices, not directives.
  • Secondary prevention: universal newborn hearing screening, rapid diagnostic ABR, early molecular testing, and prompt communication intervention can prevent or reduce secondary language deprivation.
  • Tertiary prevention: optimize hearing devices, educational access, and rehabilitation; avoid excessive noise and unnecessary ototoxic exposure; monitor residual hearing.

No vaccine or chemoprophylaxis is relevant specifically to DFNB97.

14. Other species and natural disease

No naturally occurring veterinary DFNB97 equivalent, breed predisposition, zoonotic potential, or cross-species transmission is established. Orthologous Met exists in common vertebrate models, including Mus musculus (NCBI Taxon 10090) and Danio rerio (Taxon 7955). MET’s developmental functions are evolutionarily conserved, but global Met deficiency in mice is embryonically lethal, whereas zebrafish met morphants have reduced neuromast-derived hair cells. Neither exactly reproduces the residual-function human missense disorder. (mujtaba2015amutationof pages 4-6, naz2020growthfactorand pages 7-8)

15. Model organisms and research models

No published p.Phe841Val or p.Ile316Met knock-in mouse, patient-derived iPSC cochlear model, organoid, or CRISPR model was identified.

Relevant indirect models include:

  • Mouse: complete Met loss is embryonically lethal, limiting conventional knockout analysis. Hgf overexpression and inner-ear Hgf deficiency both cause deafness, showing that HGF dosage must be tightly regulated. HGF-pathway models exhibit failed neural-crest-cell incorporation into the strial intermediate layer and reduced endocochlear potential. (mujtaba2015amutationof pages 4-6, naz2020growthfactorand pages 7-8, shadab2024autosomalrecessivenon‐syndromic pages 8-9)
  • Zebrafish: met morphants show fewer neuromast-derived hair cells. Neuromasts are experimentally accessible but are not anatomically equivalent to the mammalian stria vascularis. (naz2020growthfactorand pages 7-8)
  • Rat expression studies: HGF and MET have been detected in embryonic cochlear hair cells and spiral ganglion cells; expression alone does not establish the causal cell type. (bousfiha2020furtherevidencefor pages 5-6)
  • Future models: inner-ear-specific conditional Met loss, human-variant knock-in mice, patient iPSCs, and vascularized cochlear/strial organoids would allow direct measurement of MET phosphorylation, neural-crest migration, intermediate-cell differentiation, endocochlear potential, and therapeutic rescue.

2023–2024 developments and expert assessment

The principal recent conclusion is the persistence of a major evidence gap. A 2024 review of Pakistani ARNSHL emphasizes extreme heterogeneity and identifies 13 genes responsible for more than half of profound cases; MET is not among those common contributors. The same review supports the HGF–MET–stria-vascularis mechanism but does not report new DFNB97 families. (shadab2024autosomalrecessivenon‐syndromic pages 8-9)

The broader 2024 gene-therapy field has moved from numerous successful mouse models to human hearing restoration in OTOF deficiency. Expert analysis nevertheless emphasizes the complex cochlear anatomy, different target-cell requirements, and need for precision vectors for each genotype. For DFNB97, the immediate research priorities are therefore: (1) international case ascertainment and standardized longitudinal audiometry; (2) contemporary variant curation; (3) variant-specific functional assays; (4) definition of the critical human cochlear cell population; and (5) development of conditional or knock-in models before contemplating MET-directed therapy. (zhang2024aav‐mediatedgenetherapy pages 1-2)

Knowledge gaps and curation cautions

  1. The disease is supported by only two reported families; phenotype frequencies should not be generalized beyond them.
  2. Progression, penetrance, carrier frequency, prevalence, and implant outcomes are unknown.
  3. The mechanistic link to strial intermediate cells is strong pathway inference, not direct human histopathology.
  4. Transcript-dependent variant-number discrepancies require MANE normalization.
  5. Published pathogenicity labels—especially for p.Ile316Met—should be reconciled with current gnomAD, ClinVar, ClinGen, and ACMG/AMP evidence.
  6. HGF-related DFNB39, GAB1-related DFNB26, MET-related syndromic presentations, somatic oncogenic MET alterations, and DFNB97 must remain separate knowledge-base entities.

Overall, DFNB97 is a credible but exceptionally rare MET-associated cochlear developmental disorder. Its human phenotype is reasonably defined as early bilateral severe-to-profound nonsyndromic sensorineural hearing loss, whereas its detailed cellular mechanism, natural history, population burden, and disease-modifying treatment remain unresolved.

References

  1. (mujtaba2015amutationof pages 1-3): Ghulam Mujtaba, Julie M Schultz, Ayesha Imtiaz, Robert J Morell, Thomas B Friedman, and Sadaf Naz. A mutation of met, encoding hepatocyte growth factor receptor, is associated with human dfnb97 hearing loss. Journal of Medical Genetics, 52:548-552, May 2015. URL: https://doi.org/10.1136/jmedgenet-2015-103023, doi:10.1136/jmedgenet-2015-103023. This article has 49 citations and is from a domain leading peer-reviewed journal.

  2. (bousfiha2020furtherevidencefor pages 1-2): Amale Bousfiha, Zied Riahi, Lamiae Elkhattabi, Amina Bakhchane, Hicham Charoute, Khalid Snoussi, Crystel Bonnet, Christine Petit, and Abdelhamid Barakat. Further evidence for the implication of the met gene in non-syndromic autosomal recessive deafness. Human Heredity, 84:109-116, Dec 2020. URL: https://doi.org/10.1159/000503450, doi:10.1159/000503450. This article has 7 citations and is from a peer-reviewed journal.

  3. (naz2020growthfactorand pages 7-8): Sadaf Naz and Thomas B. Friedman. Growth factor and receptor malfunctions associated with human genetic deafness. Clinical Genetics, 97:138-155, Oct 2020. URL: https://doi.org/10.1111/cge.13641, doi:10.1111/cge.13641. This article has 17 citations and is from a peer-reviewed journal.

  4. (bousfiha2020furtherevidencefor pages 2-2): Amale Bousfiha, Zied Riahi, Lamiae Elkhattabi, Amina Bakhchane, Hicham Charoute, Khalid Snoussi, Crystel Bonnet, Christine Petit, and Abdelhamid Barakat. Further evidence for the implication of the met gene in non-syndromic autosomal recessive deafness. Human Heredity, 84:109-116, Dec 2020. URL: https://doi.org/10.1159/000503450, doi:10.1159/000503450. This article has 7 citations and is from a peer-reviewed journal.

  5. (zhang2024aav‐mediatedgenetherapy pages 1-2): Liyan Zhang, Fangzhi Tan, Jieyu Qi, Yicheng Lu, Xiaohan Wang, Xuehan Yang, Xiangyan Chen, Xinru Zhang, Jinyi Fan, Yinyi Zhou, Li Peng, Nianci Li, Lei Xu, Shiming Yang, and Renjie Chai. Aav‐mediated gene therapy for hereditary deafness: progress and perspectives. Advanced Science, Nov 2024. URL: https://doi.org/10.1002/advs.202402166, doi:10.1002/advs.202402166. This article has 41 citations and is from a peer-reviewed journal.

  6. (OpenTargets Search: autosomal recessive nonsyndromic hearing loss 97-MET): Open Targets Query (autosomal recessive nonsyndromic hearing loss 97-MET, 1 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  7. (mujtaba2015amutationof pages 3-4): Ghulam Mujtaba, Julie M Schultz, Ayesha Imtiaz, Robert J Morell, Thomas B Friedman, and Sadaf Naz. A mutation of met, encoding hepatocyte growth factor receptor, is associated with human dfnb97 hearing loss. Journal of Medical Genetics, 52:548-552, May 2015. URL: https://doi.org/10.1136/jmedgenet-2015-103023, doi:10.1136/jmedgenet-2015-103023. This article has 49 citations and is from a domain leading peer-reviewed journal.

  8. (mujtaba2015amutationof pages 8-10): Ghulam Mujtaba, Julie M Schultz, Ayesha Imtiaz, Robert J Morell, Thomas B Friedman, and Sadaf Naz. A mutation of met, encoding hepatocyte growth factor receptor, is associated with human dfnb97 hearing loss. Journal of Medical Genetics, 52:548-552, May 2015. URL: https://doi.org/10.1136/jmedgenet-2015-103023, doi:10.1136/jmedgenet-2015-103023. This article has 49 citations and is from a domain leading peer-reviewed journal.

  9. (bousfiha2020furtherevidencefor pages 2-4): Amale Bousfiha, Zied Riahi, Lamiae Elkhattabi, Amina Bakhchane, Hicham Charoute, Khalid Snoussi, Crystel Bonnet, Christine Petit, and Abdelhamid Barakat. Further evidence for the implication of the met gene in non-syndromic autosomal recessive deafness. Human Heredity, 84:109-116, Dec 2020. URL: https://doi.org/10.1159/000503450, doi:10.1159/000503450. This article has 7 citations and is from a peer-reviewed journal.

  10. (shadab2024autosomalrecessivenon‐syndromic pages 8-9): Madiha Shadab, Ansar Ahmed Abbasi, Ahsan Ejaz, Afif Ben‐Mahmoud, Vijay Gupta, Hyung‐Goo Kim, and Barbara Vona. Autosomal recessive non‐syndromic hearing loss genes in pakistan during the previous three decades. Journal of Cellular and Molecular Medicine, Mar 2024. URL: https://doi.org/10.1111/jcmm.18119, doi:10.1111/jcmm.18119. This article has 9 citations and is from a peer-reviewed journal.

  11. (bousfiha2020furtherevidencefor pages 5-6): Amale Bousfiha, Zied Riahi, Lamiae Elkhattabi, Amina Bakhchane, Hicham Charoute, Khalid Snoussi, Crystel Bonnet, Christine Petit, and Abdelhamid Barakat. Further evidence for the implication of the met gene in non-syndromic autosomal recessive deafness. Human Heredity, 84:109-116, Dec 2020. URL: https://doi.org/10.1159/000503450, doi:10.1159/000503450. This article has 7 citations and is from a peer-reviewed journal.

  12. (mujtaba2015amutationof pages 4-6): Ghulam Mujtaba, Julie M Schultz, Ayesha Imtiaz, Robert J Morell, Thomas B Friedman, and Sadaf Naz. A mutation of met, encoding hepatocyte growth factor receptor, is associated with human dfnb97 hearing loss. Journal of Medical Genetics, 52:548-552, May 2015. URL: https://doi.org/10.1136/jmedgenet-2015-103023, doi:10.1136/jmedgenet-2015-103023. This article has 49 citations and is from a domain leading peer-reviewed journal.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 6
Resolved 6
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 6
On topic 6
Off topic 0

All extracted references resolved successfully.

Term Validation

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

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

Terms the report names something else

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

  • MONDO:0014739 (5 mentions) - the report calls it "if available"; MONDO calls it autosomal recessive nonsyndromic hearing loss 97