| 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. (pqac-00000000, pqac-00000014, pqac-00000015) | 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). (pqac-00000000, pqac-00000014, pqac-00000015) | 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. (pqac-00000001, pqac-00000003, pqac-00000008) | 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. (pqac-00000001, pqac-00000002, pqac-00000004, pqac-00000014) | 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. (pqac-00000003, pqac-00000006, pqac-00000008, pqac-00000015) | 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. (pqac-00000001, pqac-00000002, pqac-00000008, pqac-00000014) | 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. (pqac-00000001, pqac-00000008, pqac-00000014) | 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. (pqac-00000001, pqac-00000008, pqac-00000014) | 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. (pqac-00000011, pqac-00000013, pqac-00000016) | 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. (pqac-00000005, pqac-00000009, pqac-00000011) | 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. (pqac-00000005, pqac-00000007, pqac-00000011, pqac-00000013) | 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. (pqac-00000002, pqac-00000003, pqac-00000006, pqac-00000007) | 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. (pqac-00000001, pqac-00000003, pqac-00000015, pqac-00000016) | 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. (pqac-00000008, pqac-00000016) | 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. (pqac-00000016) | 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. (pqac-00000002, pqac-00000003) | 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. (pqac-00000003, pqac-00000013, pqac-00000014) | 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. (pqac-00000007, pqac-00000011, pqac-00000013) | 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. (pqac-00000013, pqac-00000016) | 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.*