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Inheritance

1

Autosomal recessive HP:0000007

Both families are consanguineous and both probands are homozygous. In the Pakistani kindred the allele cosegregated across nine affected individuals spanning ages 5 to 60, with heterozygous relatives unaffected - the deepest segregation evidence this entity has.

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

Neither allele has been assayed. p.Phe841Val was called damaging by prediction programs; p.Ile316Met was run through a molecular dynamics simulation that reported loss of flexibility in the SEMA domain. Both are computational, and neither has been followed by a binding, phosphorylation or downstream-signalling measurement in any system. This is the specific gap that keeps the gene-disease classification at Limited. The mouse supplies a complete developmental mechanism, but it does so by removing the receptor entirely; the human alleles are missense and might be hypomorphic, or might be neutral in a consanguineous genome full of other homozygous variants. Nothing published distinguishes those. It is also tractable. MET signalling assays are routine because of the oncology literature, so the reagents to test a germline missense allele already exist - the experiment has simply not been done for these two.

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

Both alleles reduce HGF-dependent receptor activation relative to wild type, which would supply the variant-level functional evidence ClinGen names as missing and would connect the human genotype to the mouse mechanism.

Refuting outcome

The alleles signal normally, which would leave the two families' hearing loss without a mechanistic account through MET and would push the gene-disease relationship toward Disputed rather than Limited.

Is the endocochlear potential actually reduced in MET-deficient cochleae, or is that inferred from the HGF arm of the same pathway?

HUMAN MODEL MISMATCH OPEN mismatch_endocochlear_potential_measured_in_hgf_arm

Attached to

pathophysiology#Failure of Endolymphatic Potassium Homeostasis animal_models#Conditional c-Met inner ear inactivation mouse

It is inferred. The endocochlear potential has been measured in a mouse carrying a noncoding Hgf deletion, where it is significantly reduced alongside failed neural crest infiltration of the strial intermediate layer. That mouse models DFNB39. The c-Met inactivation study reports failed melanocyte incorporation and profound hearing loss but does not report an endocochlear potential. The inference is a good one - the two manipulations disable the same ligand-receptor pair at the same structure - but it is an inference, and the entry marks it by grading the HGF measurement PARTIAL wherever it appears. The gap matters because the endocochlear potential is the step that converts a developmental defect into a functional one, and because a reduced-but-present potential and an abolished one imply different residual hearing and different windows for intervention.

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#Failure of Endolymphatic Potassium Homeostasis

Supporting outcome

The potential is reduced in the receptor arm to a comparable degree, which would let the HGF measurement be retired from this entry and the node stand on MET evidence alone.

Refuting outcome

The potential is preserved despite failed melanocyte incorporation, which would mean the deafness in the receptor arm runs through some other consequence of the strial defect and this node is wrong as written.

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Pathophysiology

5

Biallelic MET Missense Variant

Both published alleles are homozygous missense variants and both are private to their family. The Pakistani allele c.2521T>G, p.Phe841Val, was found after homozygosity mapping placed the locus on 7q31.2 with a LOD of 4.8. It cosegregated with hearing loss in the family and was absent from 800 ethnically matched control chromosomes and from 136,602 chromosomes in public variant databases. The Moroccan allele c.948A>G, p.Ile316Met, lies in the SEMA domain - the ligand-binding region of the receptor - and molecular dynamics simulation predicted that it costs the domain flexibility. Neither allele has been characterised functionally at the bench. That absence is what the ClinGen review means by case-level evidence only, and it is why the receptor-signalling node below is inferred rather than measured in a patient allele.

Genetic context MET hgnc:7029 variant_origin: GERMLINE zygosity: HOMOZYGOUS

Homozygous in both consanguineous families. functional_impact_category is deliberately omitted: the alleles are missense, no functional assay has been performed on either, and the only mechanistic prediction available is an in silico structural one. Asserting LOSS_OF_FUNCTION here would be inferring the very thing the evidence base does not supply.

Downstream

Reduced HGF/MET Signalling in the Developing Cochlea The inference from a missense receptor allele to reduced signalling. It is plausible for a SEMA-domain variant and it has not been measured for either allele.

Show evidence (4 references)

PMID:25941349 SUPPORT Human Clinical

"Whole-exome sequencing revealed a novel missense mutation c.2521T>G (p.F841V) in MET (mesenchymal epithelial transition factor), which encodes the receptor for hepatocyte growth factor."

The founding allele.

PMID:25941349 SUPPORT Human Clinical

"The mutation cosegregated with the hearing loss phenotype in the family and was absent from 800 chromosomes of ethnically matched control individuals as well as from 136"

Cosegregation plus population absence, which is the strongest genetic evidence this entity has. The quote stops before the control-chromosome count because the source separates its digits with a thin space.

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."

The second family's allele.

+ 1 more reference

Reduced HGF/MET Signalling in the Developing Cochlea

HGF is expressed in the cochlear epithelium at the site that will become the stria vascularis, and its receptor MET is expressed both in that epithelium and on the melanocyte-derived intermediate cells. The signalling is therefore local, developmental and reciprocal, which is what makes an otherwise ubiquitous growth-factor pathway produce a phenotype confined to the ear.

HGF receptor signalling through MET GO:0048012 ↓ DECREASED

stria vascularis of the cochlear duct UBERON:0002282

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."

Places the receptor on both partners, which is what makes this a local signalling relationship rather than a systemic one.

Failed Melanocyte Incorporation into the Stria Vascularis

In normal development a subpopulation of neural-crest-derived melanocytes migrates into a subregion of the cochlear epithelium and becomes the intermediate cell layer of the stria vascularis. Removing c-MET signalling stops that incorporation. This is the step that makes DFNB97 a neurocristopathy in the ear - a migration failure of a neural crest derivative - even though nothing outside the cochlea is affected.

melanocyte CL:0000148

melanocyte migration into the developing stria vascularis GO:0097324 ↓ DECREASED

stria vascularis of the cochlear duct UBERON:0002282

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 The intermediate cell layer is what the stria vascularis needs in order to do its ion transport job; without it, the job is not done.

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

The stria vascularis is a nonsensory structure whose function is to maintain the potassium concentration of the scala media and, with it, the endocochlear potential - the standing voltage across the endolymph that supplies the driving force for hair cell transduction. Two clinical observations in the founding family fit a lesion confined to this structure and are recorded here rather than as phenotypes. Vestibular function was spared: the affected individuals walked independently at 12 to 13 months and had normal tandem gait and Romberg testing, which is what a defect of the stria vascularis of the cochlear duct predicts and a general inner-ear defect would not. The testing was clinical rather than VEMP or video head-impulse, so mild dysfunction would not have been detected, and the authors hedge to "intact, or at least residual". A caveat about provenance. The endocochlear potential itself has been measured in the HGF arm of this pathway, not the MET arm: a mouse carrying a noncoding Hgf deletion has neural crest cells failing to enter the strial intermediate layer and a significantly reduced endocochlear potential. That animal models DFNB39, the paired locus, not DFNB97. It is cited here because it measures the step, and the reader should know the measurement comes from the ligand side.

endolymphatic potassium homeostasis maintained by the stria vascularis GO:0006813 ↓ DECREASED

stria vascularis of the cochlear duct UBERON:0002282

Downstream

Severe Prelingual Sensorineural Hearing Loss Hair cells that are structurally intact cannot transduce without the endocochlear potential to drive current through them.

Show evidence (3 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 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."

The only direct measurement of the endocochlear potential in this pathway. Graded PARTIAL because it is the HGF ligand arm, modelling DFNB39 rather than DFNB97; it supports the shared downstream step and is not evidence about MET.

PMID:25941349 SUPPORT Human Clinical

"The results of tandem gait and Romberg tests were normal, suggesting intact, or at least residual, peripheral vestibular function."

Preserved vestibular function in the affected family, which localises the lesion to the cochlear duct rather than the inner ear generally. A positive argument for this node built from an examined-and-negative clinical finding, which is why it sits here rather than as an absent phenotype.

Severe Prelingual Sensorineural Hearing Loss

The clinical endpoint, and it is confined to hearing. In the Pakistani family the affected individuals walked at 12 to 13 months, had normal tandem gait and Romberg testing, and had normal blood counts, serum chemistry, liver function and fundoscopy. In mouse, developmental inactivation of either the ligand or the receptor produced profound hearing loss in young adults.

sensory perception of sound GO:0007605 ↓ DECREASED

Animal models

Conditional c-Met inner ear inactivation mouse Mouse recapitulates Developmental inactivation of the receptor produces profound hearing loss in young adult mice, matching the severity and the developmental timing of the human phenotype.

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.

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Phenotypes

2

Severe Prelingual Sensorineural Hearing Loss OBLIGATE Otologic HP:0008625

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."

Confirms bilateral involvement in the second family.

Prelingual Onset OBLIGATE Otologic HP:0000399

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.

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Genetic Associations

1

MET

Gene: MET hgnc:7029 relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:31801140 SUPPORT Human Clinical

"Mutations in the mesenchymal epithelial transition factor (MET) gene are frequently associated with multiple human cancers but can also lead to human non-syndromic autosomal recessive deafness (DFNB97)."

States the two-identity problem explicitly and separates the deafness relationship from the cancer one.

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.

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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 classifies the autosomal recessive MET-nonsyndromic hearing loss relationship as Limited. This sits above Disputed and below Definitive: the panel found no contradicting evidence, but the supporting evidence is case-level, and of the three reported missense variants only one scored - the other probands had phenotypes inconsistent with nonsyndromic hearing loss or an allele frequency too high to be pathogenic. The mouse work is what the panel credits as experimental support.

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

The expert-panel classification row. Graded PARTIAL because Limited neither supports nor refutes the relationship - it says the evidence is real but insufficient.

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 panel's summary sentence, which is the calibration this entry is written to.

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."

The half of the classification that distinguishes Limited from Disputed, and the reason this entry asserts a mechanism where the TSPEAR entry curated alongside it does not.

💊

Medical Actions

2

Cochlear Implantation

Action: cochlear device implantation Ontology label: Surgical Procedure NCIT:C15329

The standard intervention for severe prelingual sensorineural hearing loss, and the mechanism of this disease argues for it more directly than most. The lesion is in the stria vascularis: it removes the endocochlear potential that drives current through the hair cells, but the hair cells and the spiral ganglion are not themselves the target of the defect, and no cochlear structural malformation has been described in either family. An implant stimulates the auditory nerve directly and so does not need the missing battery. No outcome data exist for DFNB97 patients specifically - there are two families - and this is recorded without an evidence item rather than with a quote from the general cochlear-implant literature, which would not be about this disease.

Mechanism Target:

BYPASSES Failure of Endolymphatic Potassium Homeostasis — Electrical stimulation of the spiral ganglion substitutes for the transduction current the endocochlear potential is no longer there to drive, so the implant works downstream of the node that fails.

Early Identification and Habilitation

Action: auditory habilitation Ontology label: Rehabilitation NCIT:C15315

The loss is prelingual and severe, so the modifiable outcome is spoken-language development and the modifier is how early the loss is found and habilitated. In the Pakistani family it was noticed through delayed speech rather than by screening, which is late. As with implantation, there are no disease-specific data.

🔬

Diagnosis

1

Exome or comprehensive panel sequencing after excluding common causes

DFNB97 has no distinguishing clinical feature; severe prelingual nonsyndromic hearing loss looks the same whatever causes it. Both published families reached the diagnosis the same way - by excluding GJB2 and the other established recessive deafness genes first, then sequencing. Given a Limited gene-disease classification and two families worldwide, a MET finding should be treated as a candidate that requires the common causes to have been ruled out, not as a first-line result.

Show evidence (1 reference)

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.

📊

Prevalence

1

Worldwide

Cases In Literature Not yet documented

Two families. The 2019 Moroccan report describes itself as the second family in the world. No prevalence estimate exists. There is one measurement of how rare this is, and it is a negative result worth keeping: after mapping DFNB97, the discovering group screened a further 100 Pakistani families whose hearing loss was unexplained by known deafness genes and found no additional families at this locus.

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."

The screening effort that establishes DFNB97 as a rare cause even in the population where it was found.

PMID:31801140 SUPPORT Human Clinical

"Moreover, this study reports the second family in the world associating deafness and mutation in the MET gene."

Fixes the published family count at two as of 2019.

🔀

Differential Diagnoses

2

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

HGF-related nonsyndromic hearing loss (DFNB39)

Overlapping Features The paired locus, and a genuinely different disease. DFNB39 is caused by noncoding variants in HGF - two deletions in a conserved part of the 3' untranslated region of a short HGF isoform, and a silent substitution that alters splicing - rather than by coding variants in the receptor. It is common in Pakistani families where DFNB97 is not: 40 consanguineous families mapped to the locus, against the single family that defines DFNB97 after 100 more were screened. The two converge downstream. Both disable HGF/MET signalling at the developing stria vascularis, and the mouse modelling the DFNB39 noncoding deletion is the animal in which the endocochlear potential reduction was actually measured. They are curated as separate entities because the gene, the variant class and the population frequency all differ, and evidence from the HGF side is graded PARTIAL wherever it appears in this entry.

Show evidence (3 references)

PMID:19576567 SUPPORT Human Clinical

"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)."

Establishes the variant class that distinguishes DFNB39 from DFNB97.

PMID:19576567 SUPPORT Human Clinical

"We mapped an additional 40 consanguineous families segregating nonsyndromic hearing loss to the DFNB39 locus and refined the obligate interval to 1.2 Mb."

The family count, which is the practical reason DFNB39 is the likelier diagnosis in the population where both were found.

PMID:32152201 SUPPORT Model Organism

"Previous studies showed that developmental incorporation of neural crest cells into the SV depends on signaling from HGF/MET."

States the shared downstream mechanism that makes these two entities converge, which is why they need separating explicitly.

🐁

Animal Models

1

Conditional c-Met inner ear inactivation mouse

The source of the entire mechanism. It establishes where the ligand and receptor are expressed in the developing cochlea, shows by genetic dissection that melanocyte incorporation into the future stria vascularis requires c-MET signalling, and shows that developmental inactivation produces profound hearing loss in young adults. The paper names DFNB97 as one of the human diseases its mechanism may underlie.

Species

Mouse

Genotype

Conditional inactivation of c-Met (and, in parallel arms, of Hgf) in the developing inner ear

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: This is a conditional inactivation, not a knock-in of either human missense allele. Whether p.Phe841Val or p.Ile316Met reduces signalling enough to reproduce the developmental failure is exactly what has not been tested, and it is the reason ClinGen rates the human relationship Limited. Human cochlear histology in DFNB97 does not exist and will not, so the strial defect in patients is inferred from the mouse rather than observed.

Readouts

Melanocyte incorporation into the strial intermediate cell layer

Direction: DECREASED

Interpretation: Incorporation fails without c-MET signalling, which is the developmental defect this node describes.

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

"Our findings reveal a novel mechanism that may underlie human deafness DFNB39 and DFNB97."

The authors' statement that this model is offered as the mechanism for DFNB97.

Severe Prelingual Sensorineural Hearing Loss recapitulates fidelity: moderate Developmental inactivation of the receptor produces profound hearing loss in young adult mice, matching the severity and the developmental timing of the human phenotype.

Limitations: The mouse loss is described as profound and the human families are severe, and the mouse is a conditional null where the patients carry missense alleles - so the model probably sits at a more severe point on the allelic range than the disease does. Onset is "young adult" in mouse against prelingual in humans, which are not directly comparable developmental stages.

Readouts

Hearing threshold after developmental inactivation

Direction: DECREASED

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.

{ }

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 is severe, prelingual, isolated sensorineural hearing loss attributed to biallelic
  missense variants in MET, the receptor tyrosine kinase for hepatocyte growth factor. Two
  families have been published: a large consanguineous Pakistani kindred mapped in 2015, and
  a single Moroccan girl in 2019.

  The mechanism, unlike the gene, is not about cancer. HGF is expressed in the developing
  cochlear epithelium at the future stria vascularis, and MET is expressed both there and on
  the neural-crest-derived melanocytes that migrate in to form the intermediate cell layer.
  That layer is what makes the stria vascularis able to hold the endolymph's potassium
  concentration and generate the endocochlear potential - the battery that drives hair cell
  transduction. Inactivating MET in mouse stops the melanocytes incorporating, and the
  animals are profoundly deaf as young adults. So DFNB97 is a developmental disease of a
  nonsensory structure, and the hair cells are downstream bystanders.

  Two things about this entry need stating before it is read. First, the gene. MET is an
  oncogene and its literature is overwhelmingly tumour biology; none of that is relevant
  here, and the affected Pakistani family was explicitly free of cancer. Second, the
  strength of the claim. The ClinGen Hearing Loss Gene Curation Expert Panel classifies
  MET-nonsyndromic hearing loss as Limited - not disputed, but not established either, and
  the panel's stated reason is that the evidence is case-level with only one variant scoring.
  The entry is curated to that standard rather than above it.

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 classifies the autosomal recessive
    MET-nonsyndromic hearing loss relationship as Limited. This sits above Disputed and below
    Definitive: the panel found no contradicting evidence, but the supporting evidence is
    case-level, and of the three reported missense variants only one scored - the other
    probands had phenotypes inconsistent with nonsyndromic hearing loss or an allele
    frequency too high to be pathogenic. The mouse work is what the panel credits as
    experimental support.
  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 expert-panel classification row. Graded PARTIAL because Limited neither supports
      nor refutes the relationship - it says the evidence is real but insufficient.
  - 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 panel's summary sentence, which is the calibration this entry is written to.
  - 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: >-
      The half of the classification that distinguishes Limited from Disputed, and the reason
      this entry asserts a mechanism where the TSPEAR entry curated alongside it does not.
  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: >-
    Two families. The 2019 Moroccan report describes itself as the second family in the world.
    No prevalence estimate exists.

    There is one measurement of how rare this is, and it is a negative result worth keeping:
    after mapping DFNB97, the discovering group screened a further 100 Pakistani families
    whose hearing loss was unexplained by known deafness genes and found no additional
    families at this locus.
  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.
    explanation: >-
      The screening effort that establishes DFNB97 as a rare cause even in the population
      where it was found.
  - 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: >-
      Fixes the published family count at two as of 2019.

pathophysiology:

- name: Biallelic MET Missense Variant
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    Both published alleles are homozygous missense variants and both are private to their
    family.

    The Pakistani allele c.2521T>G, p.Phe841Val, was found after homozygosity mapping placed
    the locus on 7q31.2 with a LOD of 4.8. It cosegregated with hearing loss in the family
    and was absent from 800 ethnically matched control chromosomes and from 136,602
    chromosomes in public variant databases.

    The Moroccan allele c.948A>G, p.Ile316Met, lies in the SEMA domain - the ligand-binding
    region of the receptor - and molecular dynamics simulation predicted that it costs the
    domain flexibility.

    Neither allele has been characterised functionally at the bench. That absence is what the
    ClinGen review means by case-level evidence only, and it is why the receptor-signalling
    node below is inferred rather than measured in a patient allele.
  genetic_context:
    gene:
      preferred_term: MET
      term:
        id: hgnc:7029
        label: MET
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    description: >-
      Homozygous in both consanguineous families. functional_impact_category is deliberately
      omitted: the alleles are missense, no functional assay has been performed on either,
      and the only mechanistic prediction available is an in silico structural one. Asserting
      LOSS_OF_FUNCTION here would be inferring the very thing the evidence base does not
      supply.
  downstream:
  - target: Reduced HGF/MET Signalling in the Developing Cochlea
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The inference from a missense receptor allele to reduced signalling. It is plausible
      for a SEMA-domain variant and it has not been measured for either allele.
  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: >-
      Whole-exome sequencing revealed a novel missense mutation c.2521T>G (p.F841V) in MET
      (mesenchymal epithelial transition factor), which encodes the receptor for hepatocyte
      growth factor.
    explanation: >-
      The founding allele.
  - 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 mutation cosegregated with the hearing loss phenotype in the family and was absent
      from 800 chromosomes of ethnically matched control individuals as well as from 136
    explanation: >-
      Cosegregation plus population absence, which is the strongest genetic evidence this
      entity has. The quote stops before the control-chromosome count because the source
      separates its digits with a thin space.
  - 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: >-
      The second family's allele.
  - reference: PMID:31801140
    reference_title: Further Evidence for the Implication of the MET Gene in Non-Syndromic Autosomal Recessive Deafness.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      The results of the MDS approach show that an Ile316Met mutation in the SEMA domain
      leads to protein flexibility loss.
    explanation: >-
      A molecular dynamics prediction, not a measurement. Graded COMPUTATIONAL and PARTIAL
      because a simulated flexibility change is a hypothesis about the allele's consequence
      rather than evidence of it.

- name: Reduced HGF/MET Signalling in the Developing Cochlea
  role: central_effector
  biological_scale: MOLECULAR
  description: >-
    HGF is expressed in the cochlear epithelium at the site that will become the stria
    vascularis, and its receptor MET is expressed both in that epithelium and on the
    melanocyte-derived intermediate cells. The signalling is therefore local, developmental
    and reciprocal, which is what makes an otherwise ubiquitous growth-factor pathway produce
    a phenotype confined to the ear.
  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: >-
      Places the receptor on both partners, which is what makes this a local signalling
      relationship rather than a systemic one.

- name: Failed Melanocyte Incorporation into the Stria Vascularis
  role: central_effector
  biological_scale: TISSUE
  description: >-
    In normal development a subpopulation of neural-crest-derived melanocytes migrates into
    a subregion of the cochlear epithelium and becomes the intermediate cell layer of the
    stria vascularis. Removing c-MET signalling stops that incorporation.

    This is the step that makes DFNB97 a neurocristopathy in the ear - a migration failure of
    a neural crest derivative - even though nothing outside the cochlea is affected.
  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: >-
      The intermediate cell layer is what the stria vascularis needs in order to do its ion
      transport job; without it, the job is not done.
  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: >-
    The stria vascularis is a nonsensory structure whose function is to maintain the
    potassium concentration of the scala media and, with it, the endocochlear potential -
    the standing voltage across the endolymph that supplies the driving force for hair cell
    transduction.

    Two clinical observations in the founding family fit a lesion confined to this structure
    and are recorded here rather than as phenotypes. Vestibular function was spared: the
    affected individuals walked independently at 12 to 13 months and had normal tandem gait
    and Romberg testing, which is what a defect of the stria vascularis of the cochlear duct
    predicts and a general inner-ear defect would not. The testing was clinical rather than
    VEMP or video head-impulse, so mild dysfunction would not have been detected, and the
    authors hedge to "intact, or at least residual".

    A caveat about provenance. The endocochlear potential itself has been measured in the
    HGF arm of this pathway, not the MET arm: a mouse carrying a noncoding Hgf deletion has
    neural crest cells failing to enter the strial intermediate layer and a significantly
    reduced endocochlear potential. That animal models DFNB39, the paired locus, not DFNB97.
    It is cited here because it measures the step, and the reader should know the measurement
    comes from the ligand side.
  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:0006813
      label: potassium ion transport
    modifier: DECREASED
  downstream:
  - target: Severe Prelingual Sensorineural Hearing Loss
    causal_link_type: DIRECT
    description: >-
      Hair cells that are structurally intact cannot transduce without the endocochlear
      potential to drive current through them.
  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: >-
      The only direct measurement of the endocochlear potential in this pathway. Graded
      PARTIAL because it is the HGF ligand arm, modelling DFNB39 rather than DFNB97; it
      supports the shared downstream step and is not evidence about MET.
  - 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 results of tandem gait and Romberg tests were normal, suggesting intact, or at least
      residual, peripheral vestibular function.
    explanation: >-
      Preserved vestibular function in the affected family, which localises the lesion to the
      cochlear duct rather than the inner ear generally. A positive argument for this node
      built from an examined-and-negative clinical finding, which is why it sits here rather
      than as an absent phenotype.

- name: Severe Prelingual Sensorineural Hearing Loss
  role: consequence
  biological_scale: ORGANISM
  description: >-
    The clinical endpoint, and it is confined to hearing. In the Pakistani family the affected
    individuals walked at 12 to 13 months, had normal tandem gait and Romberg testing, and
    had normal blood counts, serum chemistry, liver function and fundoscopy. In mouse,
    developmental inactivation of either the ligand or the receptor produced profound hearing
    loss in young adults.
  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.

phenotypes:

- category: Otologic
  name: Severe Prelingual Sensorineural Hearing Loss
  frequency: OBLIGATE
  severity: SEVERE
  description: >-
    Bilateral and severe. In the Pakistani family, pure tone averages across 500 Hz to 4000 Hz
    ran from 74 to 89 dB HL with variation between affected relatives, and onset was at or
    before two years of age, noticed as delayed speech. The Moroccan child had total
    bilateral loss.
  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: >-
      Confirms bilateral involvement in the second family.

- category: Otologic
  name: Prelingual Onset
  frequency: OBLIGATE
  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.

genetic:

- name: MET
  gene_term:
    preferred_term: MET
    term:
      id: hgnc:7029
      label: MET
  relationship_type: CAUSATIVE
  notes: >-
    Typed CAUSATIVE rather than DISPUTED, matching ClinGen's Limited classification - the
    panel found no contradicting evidence, only insufficient supporting evidence. The
    knowledge gap recorded in the discussions section carries the uncertainty; the
    relationship type should not double-count it.

    MET encodes the receptor tyrosine kinase for hepatocyte growth factor. Its dominant
    identity in the literature is oncological - somatic amplification, exon 14 skipping and
    kinase-domain activation across lung, gastric and renal cancers, and a germline
    relationship with hereditary papillary renal cell carcinoma that ClinGen separately rates
    Definitive. None of that is this disease. DFNB97 is caused by recessive germline missense
    alleles producing a developmental deficit in one nonsensory cochlear structure, in
    families without cancer.

    Three missense variants have been reported across three publications. Only one was
    scored by the ClinGen review; of the others, one proband had a phenotype inconsistent
    with nonsyndromic hearing loss and one variant was too common in the population to be
    pathogenic.
  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: >-
      Mutations in the mesenchymal epithelial transition factor (MET) gene are frequently
      associated with multiple human cancers but can also lead to human non-syndromic
      autosomal recessive deafness (DFNB97).
    explanation: >-
      States the two-identity problem explicitly and separates the deafness relationship from
      the cancer one.
  - 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.

inheritance:

- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Both families are consanguineous and both probands are homozygous. In the Pakistani
    kindred the allele cosegregated across nine affected individuals spanning ages 5 to 60,
    with heterozygous relatives unaffected - the deepest segregation evidence this entity has.
  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 inactivation of c-Met (and, in parallel arms, of Hgf) in the developing inner ear
  publication: PMID:27488639
  description: >-
    The source of the entire mechanism. It establishes where the ligand and receptor are
    expressed in the developing cochlea, shows by genetic dissection that melanocyte
    incorporation into the future stria vascularis requires c-MET signalling, and shows that
    developmental inactivation produces profound hearing loss in young adults. The paper
    names DFNB97 as one of the human diseases its mechanism may underlie.
  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: >-
      This is a conditional inactivation, not a knock-in of either human missense allele.
      Whether p.Phe841Val or p.Ile316Met reduces signalling enough to reproduce the
      developmental failure is exactly what has not been tested, and it is the reason
      ClinGen rates the human relationship Limited. Human cochlear histology in DFNB97 does
      not exist and will not, so the strial defect in patients is inferred from the mouse
      rather than observed.
    readouts:
    - name: Melanocyte incorporation into the strial intermediate cell layer
      target: Failed Melanocyte Incorporation into the Stria Vascularis
      direction: DECREASED
      interpretation: >-
        Incorporation fails without c-MET signalling, which is the developmental defect this
        node describes.
      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: >-
        Our findings reveal a novel mechanism that may underlie human deafness DFNB39 and
        DFNB97.
      explanation: >-
        The authors' statement that this model is offered as the mechanism for DFNB97.
  - target: Severe Prelingual Sensorineural Hearing Loss
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Developmental inactivation of the receptor produces profound hearing loss in young adult
      mice, matching the severity and the developmental timing of the human phenotype.
    limitations: >-
      The mouse loss is described as profound and the human families are severe, and the mouse
      is a conditional null where the patients carry missense alleles - so the model probably
      sits at a more severe point on the allelic range than the disease does. Onset is
      "young adult" in mouse against prelingual in humans, which are not directly comparable
      developmental stages.
    readouts:
    - name: Hearing threshold after developmental inactivation
      target: Severe Prelingual Sensorineural Hearing Loss
      direction: DECREASED
      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.

treatments:

- name: Cochlear Implantation
  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
  description: >-
    The standard intervention for severe prelingual sensorineural hearing loss, and the
    mechanism of this disease argues for it more directly than most. The lesion is in the
    stria vascularis: it removes the endocochlear potential that drives current through the
    hair cells, but the hair cells and the spiral ganglion are not themselves the target of
    the defect, and no cochlear structural malformation has been described in either family.
    An implant stimulates the auditory nerve directly and so does not need the missing
    battery.

    No outcome data exist for DFNB97 patients specifically - there are two families - and
    this is recorded without an evidence item rather than with a quote from the general
    cochlear-implant literature, which would not be about this disease.
  target_mechanisms:
  - target: Failure of Endolymphatic Potassium Homeostasis
    treatment_effect: BYPASSES
    description: >-
      Electrical stimulation of the spiral ganglion substitutes for the transduction current
      the endocochlear potential is no longer there to drive, so the implant works downstream
      of the node that fails.
  notes: >-
    Carries no evidence item deliberately. The rationale above is this entry's inference from
    the strial mechanism and is labelled as such; the published DFNB97 literature reports no
    implant outcomes.

    NCIT:C157820 Cochlear Implant names the device rather than a clinical action and is not
    reachable from NCIT:C25218, so it cannot be the term: of a TreatmentTerm; the specificity
    is carried by preferred_term and by the NCIT:C16830 -> NCIT:C157820 qualifier pair. The
    generic action bound here is the surgical one, which is what implantation is. An earlier
    version bound NCIT:C15315 Rehabilitation and cited
    Autosomal_Recessive_Nonsyndromic_Hearing_Loss_104.yaml as the convention; that entry
    binds NCIT:C15329.

- name: Early Identification and Habilitation
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: auditory habilitation
    term:
      id: NCIT:C15315
      label: Rehabilitation
  description: >-
    The loss is prelingual and severe, so the modifiable outcome is spoken-language
    development and the modifier is how early the loss is found and habilitated. In the
    Pakistani family it was noticed through delayed speech rather than by screening, which is
    late. As with implantation, there are no disease-specific data.
  notes: >-
    No evidence item, for the same reason as above. This is general practice for prelingual
    severe deafness, not a DFNB97 finding.

diagnosis:
- name: Exome or comprehensive panel sequencing after excluding common causes
  description: >-
    DFNB97 has no distinguishing clinical feature; severe prelingual nonsyndromic hearing
    loss looks the same whatever causes it. Both published families reached the diagnosis the
    same way - by excluding GJB2 and the other established recessive deafness genes first,
    then sequencing. Given a Limited gene-disease classification and two families worldwide,
    a MET finding should be treated as a candidate that requires the common causes to have
    been ruled out, not as a first-line result.
  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.

differential_diagnoses:
- name: HGF-related nonsyndromic hearing loss (DFNB39)
  description: >-
    The paired locus, and a genuinely different disease. DFNB39 is caused by noncoding
    variants in HGF - two deletions in a conserved part of the 3' untranslated region of a
    short HGF isoform, and a silent substitution that alters splicing - rather than by coding
    variants in the receptor. It is common in Pakistani families where DFNB97 is not: 40
    consanguineous families mapped to the locus, against the single family that defines
    DFNB97 after 100 more were screened.

    The two converge downstream. Both disable HGF/MET signalling at the developing stria
    vascularis, and the mouse modelling the DFNB39 noncoding deletion is the animal in which
    the endocochlear potential reduction was actually measured. They are curated as separate
    entities because the gene, the variant class and the population frequency all differ,
    and evidence from the HGF side is graded PARTIAL wherever it appears in this entry.
  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: >-
      The family count, which is the practical reason DFNB39 is the likelier diagnosis in the
      population where both were found.
  - 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.

- name: Hereditary papillary renal cell carcinoma (MET-related)
  description: >-
    The other germline MET disease, and the one a MET-focused literature search will surface
    first. It is dominant, caused by activating kinase-domain missense variants, presents as
    renal tumours in adulthood, and ClinGen rates it Definitive. It has no auditory
    phenotype and DFNB97 has no neoplastic one - the affected family was screened and had
    neither tumours nor organ disease. Listed here so the separation is explicit in the entry
    rather than assumed.
  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: >-
      Medical conditions including those related to liver, kidney and heart were not reported
      and there was no history of cancers in the family.
    explanation: >-
      The clinical evidence that the DFNB97 family carried no renal or neoplastic phenotype,
      which is what separates the two germline MET diseases at the bedside.

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: >-
    Neither allele has been assayed. p.Phe841Val was called damaging by prediction programs;
    p.Ile316Met was run through a molecular dynamics simulation that reported loss of
    flexibility in the SEMA domain. Both are computational, and neither has been followed by
    a binding, phosphorylation or downstream-signalling measurement in any system.

    This is the specific gap that keeps the gene-disease classification at Limited. The mouse
    supplies a complete developmental mechanism, but it does so by removing the receptor
    entirely; the human alleles are missense and might be hypomorphic, or might be neutral in
    a consanguineous genome full of other homozygous variants. Nothing published distinguishes
    those.

    It is also tractable. MET signalling assays are routine because of the oncology
    literature, so the reagents to test a germline missense allele already exist - the
    experiment has simply not been done for these two.
  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:
    - >-
      Both alleles reduce HGF-dependent receptor activation relative to wild type, which would
      supply the variant-level functional evidence ClinGen names as missing and would connect
      the human genotype to the mouse mechanism.
    refuting_outcome:
    - >-
      The alleles signal normally, which would leave the two families' hearing loss without a
      mechanistic account through MET and would push the gene-disease relationship toward
      Disputed rather than Limited.

- discussion_id: mismatch_endocochlear_potential_measured_in_hgf_arm
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Failure of Endolymphatic Potassium Homeostasis
  - animal_models#Conditional c-Met inner ear inactivation mouse
  prompt: >-
    Is the endocochlear potential actually reduced in MET-deficient cochleae, or is that
    inferred from the HGF arm of the same pathway?
  rationale: >-
    It is inferred. The endocochlear potential has been measured in a mouse carrying a
    noncoding Hgf deletion, where it is significantly reduced alongside failed neural crest
    infiltration of the strial intermediate layer. That mouse models DFNB39. The c-Met
    inactivation study reports failed melanocyte incorporation and profound hearing loss but
    does not report an endocochlear potential.

    The inference is a good one - the two manipulations disable the same ligand-receptor pair
    at the same structure - but it is an inference, and the entry marks it by grading the HGF
    measurement PARTIAL wherever it appears. The gap matters because the endocochlear
    potential is the step that converts a developmental defect into a functional one, and
    because a reduced-but-present potential and an abolished one imply different residual
    hearing and different windows for intervention.
  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#Failure of Endolymphatic Potassium Homeostasis
    supporting_outcome:
    - >-
      The potential is reduced in the receptor arm to a comparable degree, which would let the
      HGF measurement be retired from this entry and the node stand on MET evidence alone.
    refuting_outcome:
    - >-
      The potential is preserved despite failed melanocyte incorporation, which would mean the
      deafness in the receptor arm runs through some other consequence of the strial defect
      and this node is wrong as written.

notes: >-
  Named entity check, and it is the reason this entry was flagged. MET is an oncogene and its
  literature is overwhelmingly tumour biology, so a gene-frequency preflight on any MET
  retrieval passes trivially while telling you nothing. Deep-research preflight on the report
  for this disease flagged HGF at 33% of MET mentions - the paired DFNB39 locus bleeding in -
  and every citation used here was checked individually for whether it is about the deafness
  phenotype rather than about MET.

  Nothing from the oncology literature is curated. Somatic amplification, exon 14 skipping,
  kinase-domain activation and hereditary papillary renal cell carcinoma appear only in the
  gene notes and the differential diagnoses, as the things DFNB97 is not. The clinical
  counterpart is curated as a phenotype: the affected family was screened and had no tumours
  and no liver, kidney or heart disease.

  HGF separation. DFNB39 is a different disease with a different gene and a different variant
  class, and it converges with DFNB97 only downstream. The one place HGF evidence is used for
  a DFNB97 node is the endocochlear potential, because that is where the measurement exists;
  it is graded PARTIAL, labelled in the node description, and carries its own
  HUMAN_MODEL_MISMATCH discussion. The 2016 c-MET paper is different: it inactivates ligand
  and receptor in parallel arms and reports the receptor result, so it is MET evidence and is
  graded accordingly.

  Two absent findings, and where they went. Preserved vestibular function and absence of
  neoplasia are both examined-and-negative observations that matter for this disease. They
  were initially curated as phenotypes bound to the HP term for the absent thing with
  evidence graded REFUTE, and that was wrong: src/dismech/export/kgx_export.py builds the
  DiseaseToPhenotypicFeatureAssociation from phenotype_term and frequency alone and never
  reads supports, so those entries would have exported as DFNB97 has_phenotype Neoplasm -
  exactly the MET-oncology contamination this entry exists to avoid. Both were removed. The
  vestibular negative now sits in the endocochlear-potential node description as positive
  evidence that the lesion is confined to the cochlear duct, and the cancer negative is in
  the hereditary papillary renal cell carcinoma differential, which is where it does its
  work. Autosomal_Recessive_Nonsyndromic_Hearing_Loss_104 handles its own vestibular negative
  the same way. There is still no way to assert an examined-and-absent phenotype in this
  schema; the answer is not to fake one.

  Evidence grading. The mechanism is mouse and is graded MODEL_ORGANISM throughout. The
  molecular dynamics analysis of the Moroccan allele is graded COMPUTATIONAL and PARTIAL
  rather than being allowed to stand in for a functional assay - that absence is the subject
  of a knowledge gap.

  What is deliberately absent. No treatments: management is generic hearing habilitation with
  no DFNB97-specific evidence, and a curated treatment implies a curated indication. No
  clinical trials, no datasets, no biochemical markers.

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)

📚

References & Deep Research

References

6

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.

Deep Research

1

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.)

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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)

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

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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
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Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

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

13. Prevention

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

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

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

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

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

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

15. Model Organisms

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

Citation Requirements

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

Output Format

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

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

Autosomal Recessive Nonsyndromic Hearing Loss 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

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)
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

Upstream lesion: biallelic MET missense variation changes the extracellular SEMA or IPT4 domain.
Receptor defect: impaired folding, stability, HGF binding, dimerization, activation, or—specifically for p.Phe841Val—possibly transcript splicing reduces effective HGF–MET signaling.
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.
Tissue dysfunction: abnormal or thinned stria vascularis cannot adequately establish cochlear ionic homeostasis and the endocochlear potential.
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.
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

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.
Establish sensorineural rather than conductive loss and document laterality, frequency configuration, severity, and longitudinal change.
Examine for syndromic findings; assess vestibular function and development. Consider ophthalmology, renal, cardiac, infectious, or other testing only when history or examination indicates it.
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

The disease is supported by only two reported families; phenotype frequencies should not be generalized beyond them.
Progression, penetrance, carrier frequency, prevalence, and implant outcomes are unknown.
The mechanistic link to strial intermediate cells is strong pathway inference, not direct human histopathology.
Transcript-dependent variant-number discrepancies require MANE normalization.
Published pathogenicity labels—especially for p.Ile316Met—should be reconciled with current gnomAD, ClinVar, ClinGen, and ACMG/AMP evidence.
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

(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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

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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

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Term Validation

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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

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

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1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

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Autosomal Recessive Nonsyndromic Hearing Loss 97 (DFNB97; MET-related)

Executive summary

Evidence framework

1. Disease information

Definition and identifiers

Landmark abstract quotation

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

Causal factor

Risk factors

Protective factors and modifiers

3. Phenotypes

Core auditory phenotype

Vestibular and extra-auditory findings

Course and quality of life

4. Genetic and molecular information

Gene

Reported DFNB97 variants

Other molecular categories

5. Environmental information

6. Mechanism and pathophysiology

Proposed causal chain

Suggested ontology annotations

7. Anatomical structures affected

8. Temporal development and natural history

9. Inheritance, penetrance, and population epidemiology

10. Diagnostics

Clinical evaluation

Molecular testing

Differential diagnosis

Screening

11. Outcome and prognosis

12. Treatment and current applications

Standard management

Advanced and experimental therapy

13. Prevention

14. Other species and natural disease

15. Model organisms and research models

2023–2024 developments and expert assessment

Knowledge gaps and curation cautions

Artifacts

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