Hearing Loss Autosomal Recessive 120

Mendelian MONDO:0859374 Pathograph 11 Show in embeddings browser Autosomal Recessive Nonsyndromic Hearing Loss

DFNB120 is congenital or prelingual, severe-to-profound, nonsyndromic sensorineural hearing loss caused by biallelic loss of MINAR2 (previously the uncharacterised gene KIAA1024L). It was defined in 2022 in thirteen individuals from four families, and the reported literature is still small enough to read in an afternoon. The gene arrived without a function. MINAR2 was named for structural similarity to MINAR1 rather than for anything known about what it does, and the human disease and the animal work were published essentially together. Two independent mechanisms have since been proposed and they are not the same claim. In the mouse, loss of Minar2 depletes the shortest row of outer hair cell stereocilia while leaving ribbon synapses and overall organ of Corti architecture intact at the age when thresholds are already raised, which places the primary defect at the top of the hair cell. In zebrafish, Minar2 sits on apical lysosomes and is required to deliver cholesterol to the hair bundle membrane; mutants have reduced bundle cholesterol, longer and thinner bundles, enlarged apical lysosomes and impaired mechanotransduction, and pharmacologically raising cholesterol rescues them while lowering it makes them worse. These fit together comfortably as a lipid-delivery defect that destabilises the apical hair bundle, but that synthesis is an inference across two species and has not been tested in either. Nobody has measured hair bundle cholesterol in a Minar2 mouse, and nobody has looked at stereocilia row identity in a minar2 zebrafish. The rescue result is the reason this entry is worth curating despite thin evidence. Zebrafish hair cell defects and hearing were restored by drugs that raise cholesterol - a small-molecule, non-genetic intervention in a monogenic deafness. Whether that is meaningful for human DFNB120 is unknown and probably harder than it sounds, since the human phenotype is congenital and profound while the fish phenotype is mild and larval. The gene also has a life outside the ear that human patients do not share. Minar2 knockout mice develop obesity with hypertrophic adipocytes and impaired glucose tolerance through mTORC1 derepression, and a separate study reported parkinsonian motor deficits with nigral dopaminergic loss. Affected humans examined between 4 and 80 years of age had no additional abnormalities, and none had impaired balance on bedside vestibular testing. That dissociation is recorded here as an explicit model mismatch rather than being smoothed over.

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1
Inheritance
6
Pathophys.
3
Phenotypes
2
Gaps
11
Pathograph
1
Genes
2
Medical Actions
3
Models
1
Deep Research
👪

Inheritance

1
Autosomal recessive HP:0000007
Biallelic MINAR2 variants. Reported alleles are a nonsense variant, a frameshift affecting the transmembrane domain, and a variant at the last nucleotide of exon 2 that disrupts a splice donor site; a further homozygous nonsense allele was reported in 2025. Parents are heterozygous carriers with normal pure tone audiograms.
Autosomal recessive inheritance
Show evidence (3 references)
PMID:35727972 SUPPORT Human Clinical
"Here we report on DNA variants in MINAR2, encoding membrane integral NOTCH2-associated receptor 2, in four families underlying autosomal recessive nonsyndromic deafness."
The founding report and its inheritance mode.
PMID:35727972 SUPPORT Human Clinical
"Pure tone audiograms in parents showed normal thresholds"
Heterozygous carriers are unaffected, as recessive inheritance requires.
PMID:41130944 SUPPORT Human Clinical
"Trio whole-exome sequencing of the index and his parents revealed a homozygous nonsense variant in MINAR2"
Independent replication of the recessive gene-disease relationship in a fifth family.
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Discussions and Knowledge Gaps

2
Minar2 knockout mice are obese, glucose intolerant and parkinsonian; humans with biallelic MINAR2 loss examined between 4 and 80 years of age have isolated deafness. Is DFNB120 genuinely nonsyndromic, or are metabolic and motor phenotypes present and simply not looked for in a cohort ascertained through an audiology clinic?
HUMAN MODEL MISMATCH minar2_syndromic_mouse_nonsyndromic_human
Attached to
pathophysiology#Derepression of NOTCH2 and mTORC1 Signalling animal_models#Minar2 knockout mouse metabolic and motor phenotype
The mismatch is stark and it runs in the direction that is easiest to miss. Two independent mouse studies of Minar2 nulls report substantial extra-auditory disease, one metabolic and one neurodegenerative with nigral cell loss. The human series explicitly examined affected individuals neurologically across a wide age range and found nothing additional, and bedside vestibular testing was normal. Taken at face value this says the mouse over-reports, which would be a species difference in what mTORC1 restraint by MINAR2 actually controls. But the human ascertainment is not neutral. These families were found by sequencing for deafness. Obesity and impaired glucose tolerance are common enough in the general population that a handful of affected individuals could carry them without anyone connecting the two, and the neurological evaluation reported is a clinical examination rather than dopaminergic imaging or structured metabolic phenotyping. The oldest reported patient is 80, which does argue against a strongly penetrant parkinsonian phenotype, but eight decades of a normal neurological examination is not the same measurement as a substantia nigra count. What follows practically is that MINAR2 should not yet be described to families as causing isolated deafness with the confidence that phrase usually implies. Body mass index, fasting glucose and a structured motor assessment in the known cohort would settle it cheaply, and would also decide whether the mTORC1 node in this entry belongs to the disease or only to the mouse.
Proposed experiments
Metabolic and motor phenotyping of the known MINAR2 cohort
exp_dfnb120_systemic_phenotyping_of_known_cohort
Recall the reported MINAR2-biallelic individuals for body mass index, fasting glucose and oral glucose tolerance, and a structured motor examination with dopaminergic imaging in the older participants, compared against heterozygous relatives from the same families. Heterozygous relatives are the right comparator because they share household and ancestry while carrying one functional allele.
Would support
pathophysiology#Derepression of NOTCH2 and mTORC1 Signalling
Would refute
pathophysiology#Derepression of NOTCH2 and mTORC1 Signalling
Supporting outcome
  • Affected individuals show higher body mass index, impaired glucose handling, or subclinical motor findings relative to heterozygous relatives, which would make the mTORC1 node part of the human disease and reclassify DFNB120 as oligosymptomatic rather than nonsyndromic.
Refuting outcome
  • Affected individuals are metabolically and neurologically indistinguishable from heterozygous relatives, which would confine the mTORC1 and NOTCH2 arm to the mouse and support removing it from the human pathograph.
Show evidence (6 references)
PMID:35727972 SUPPORT Human Clinical
"Neurologic evaluation of affected individuals at ages ranging from 4 to 80 y old does not show additional abnormalities."
The human side of the mismatch, with its age range.
PMID:35727972 SUPPORT Human Clinical
"None of the affected individuals showed impaired balance on tandem walking and Romberg test."
Normal bedside vestibular and balance testing, which also distinguishes DFNB120 from the recessive deafness genes that carry vestibular involvement.
PMID:37245847 SUPPORT Model Organism
"Minar2 KO mice on a high-fat diet develop obesity and impaired glucose tolerance and metabolism."
The metabolic phenotype absent from the human description.
+ 3 more references
Does the cholesterol-delivery mechanism established in zebrafish operate in the mammalian cochlea, and is the mouse shortest-row stereocilia lesion the same defect seen through a different species?
KNOWLEDGE GAP minar2_cholesterol_mechanism_species_gap
Attached to
pathophysiology#Loss of Cholesterol Delivery to the Hair Bundle pathophysiology#Depletion of the Shortest Row of Outer Hair Cell Stereocilia
These two nodes are the whole mechanistic content of DFNB120 and they come from different animals, with no experiment joining them. The fish work explains what MINAR2 does at a molecular level and the mouse work shows what breaks in a mammalian cochlea, and the tempting move is to assume the second is caused by the first. There is a specific reason to hold back. The two structural phenotypes point in opposite directions: fish hair bundles are longer and thinner while mouse stereocilia in the affected row are shorter and fewer. A membrane lipid defect could plausibly produce either, but a mechanism that produces both in the same way needs to be demonstrated, not asserted. There is also no zebrafish equivalent of row identity, since fish hair bundles are not organised into the mammalian graded staircase of outer hair cells, so the most distinctive feature of the mouse lesion has no counterpart in the system where the mechanism was worked out. The measurement that would close this is a direct one: cholesterol in mouse cochlear hair bundles, wild type against Minar2 null, with the shortest row resolved. If bundle cholesterol is reduced and the reduction is greatest where stereocilia are lost, the two literatures become one mechanism. If it is not, DFNB120 has two candidate mechanisms rather than one, and this entry should be split accordingly.
Show evidence (3 references)
PMID:36317962 SUPPORT Model Organism
"Consistent with this model, loss of minar2 markedly reduces cholesterol distribution in the hair bundles, causes longer and thinner hair bundles, and gives rise to enlarged and aggregated apical lysosomes."
The fish structural phenotype, longer and thinner, stated alongside the cholesterol deficit.
PMID:35727972 SUPPORT Model Organism
"However, when we examined the stereocilia bundles of outer hair cells, we saw the shortest row was depleted, with reduced numbers and abnormally short stereocilia"
The mouse structural phenotype, shorter and fewer, which is the opposite direction and the reason the two are not yet one mechanism.
PMID:36317962 SUPPORT Model Organism
"The degree of hearing loss in mutant minar2fs139 zebrafish larvae is not as severe as it was in the adult knockout mouse."
Supports this knowledge gap: the authors' own statement of the severity gap between the two models is a further reason not to treat the fish result as directly transferable to the mouse lesion.
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Pathophysiology

6
MINAR2 Loss of Function
Biallelic null or near-null MINAR2 alleles. The reported spectrum is a nonsense variant, a frameshift affecting the transmembrane domain, and a variant substituting the last nucleotide of exon 2 that abolishes a splice donor site rather than acting as the missense change it superficially resembles. A later homozygous nonsense allele is predicted to be removed by nonsense-mediated decay. The allelic spectrum is therefore uniformly loss of function, which is why this entry does not attempt a genotype-phenotype correlation. MINAR2 is a small membrane protein with an intrinsically disordered region, named for its similarity to MINAR1 rather than for a demonstrated function, and it was still formally uncharacterised when the deafness families were sequenced.
MINAR2 hgnc:33914 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MINAR2 (hgnc:33914). hgnc:33914 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Loss of Cholesterol Delivery to the Hair Bundle
Depletion of the Shortest Row of Outer Hair Cell Stereocilia
Derepression of NOTCH2 and mTORC1 Signalling
Show evidence (4 references)
PMID:35727972 SUPPORT Human Clinical
"We detected three MINAR2 variants, c.144G > A (p.Trp48*), c.412_419delCGGTTTTG (p.Arg138Valfs*10), and c.393G > T, in 13 individuals with congenital- or prelingual-onset severe-to-profound sensorineural hearing loss (HL)."
The founding allelic series and the phenotype it produces.
PMID:35727972 SUPPORT In Vitro
"The c.393G > T variant is shown to disrupt a splice donor site."
Why the one apparently missense allele belongs in the loss-of-function class; the functional consequence is splicing, not amino acid substitution.
PMID:41130944 SUPPORT Human Clinical
"This variant introduces an early stop codon and probably results in a loss of function because of the predicted nonsense-mediated decay."
The predicted molecular consequence of the 2025 allele, consistent with the earlier ones.
+ 1 more reference
Loss of Cholesterol Delivery to the Hair Bundle
The proposed molecular job of MINAR2. In cultured cells the protein localises mainly to lysosomes and recruits cholesterol; in zebrafish hair cells, cholesterol is concentrated in the hair bundle membrane and this enrichment is lost in minar2 mutants, whose apical lysosomes become enlarged and aggregated. Hair bundles become longer and thinner rather than shorter, which is the opposite of what a simple structural-protein loss would give and is consistent with a membrane-property defect. The causal direction was tested pharmacologically rather than only inferred: lowering cholesterol worsens the mutant and raising it rescues hair cell defects and hearing. That is the strongest single result in the DFNB120 literature. The caveat is species. Every element of this node is zebrafish or cell culture. No cholesterol measurement has been made in a mammalian Minar2 hair bundle, so its application to human DFNB120 is an extrapolation.
cochlea auditory hair cell CL:4023120 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlea auditory hair cell (CL:4023120). CL:4023120 is a cell type from the Cell Ontology.
intracellular cholesterol transport GO:0032367 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased intracellular cholesterol transport (GO:0032367). GO:0032367 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
minar2 frameshift zebrafish Zebrafish recapitulates The only system in which the proposed molecular function of MINAR2 has been tested. Bundle cholesterol was measured with a genetically encoded sensor, and the causal role established by moving cholesterol in both directions pharmacologically.
Downstream
Impaired Hair Cell Mechanotransduction
Show evidence (7 references)
PMID:36317962 SUPPORT Model Organism
"Strikingly, cholesterol is highly enriched in the hair bundle membrane, and loss of kiaa1024L/minar2 reduces cholesterol localization to the hair bundles."
The central measurement, showing that bundle cholesterol enrichment depends on Minar2.
PMID:36317962 SUPPORT Model Organism
"Lowering cholesterol levels aggravates, while increasing cholesterol levels rescues the hair cell defects in the kiaa1024L/minar2 mutant."
Bidirectional pharmacological manipulation, which is what makes this causal rather than correlative.
PMID:36317962 SUPPORT In Vitro
"In cultured cells, Kiaa1024L/Minar2 is mainly localized to lysosomes, and its overexpression recruits cholesterol and increases cholesterol labeling."
The subcellular localisation and cholesterol-recruiting activity, in cells.
+ 4 more references
Depletion of the Shortest Row of Outer Hair Cell Stereocilia
The mammalian structural lesion. In Minar2 null mice the shortest row of outer hair cell stereocilia is depleted, with fewer and abnormally short stereocilia, while inner hair cells are close to normal. This is not secondary to hair cell death: at postnatal day 14, when thresholds are already raised, the organ of Corti is organised normally and very few bundles are missing, and ribbon synapse numbers are not different from controls. Hair cell degeneration appears later. The shortest row is where the mechanotransduction channel complexes sit, which is why the authors read this as a defect at the top of the hair cell rather than a synaptopathy or a neural problem.
cochlear outer hair cell CL:0000601 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlear outer hair cell (CL:0000601). CL:0000601 is a cell type from the Cell Ontology.
auditory receptor cell stereocilium organization GO:0060088 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased auditory receptor cell stereocilium organization (GO:0060088). GO:0060088 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Minar2 tm1b null mouse Mouse recapitulates This is the model in which the mammalian lesion is defined. Cochlear stereocilia cannot be examined in living patients, so the mouse is not merely corroborating the human phenotype - it is the only place the structural mechanism has been observed at all.
Downstream
Impaired Hair Cell Mechanotransduction
Progressive Hair Cell Degeneration
Show evidence (3 references)
PMID:35727972 SUPPORT Model Organism
"However, when we examined the stereocilia bundles of outer hair cells, we saw the shortest row was depleted, with reduced numbers and abnormally short stereocilia"
The row-selective structural measurement in the mouse.
PMID:35727972 SUPPORT Model Organism
"The reduced number of stereocilia in the shortest row on outer hair cells would be expected to have a severe impact upon the number of transduction channel complexes available and suggests that the primary defect in these mutant mice is located at the top of the hair cell."
The authors' localisation of the primary defect and its functional rationale.
PMID:35727972 SUPPORT Model Organism
"The organization of the organ of Corti appeared normal and there were very few missing stereocilia bundles in mutants, suggesting that hair cell degeneration cannot explain the raised ABR thresholds at this age"
Excludes degeneration as the cause of the early threshold shift, which is what makes the stereocilia lesion primary rather than a late consequence.
Impaired Hair Cell Mechanotransduction
The convergence point of both proposed mechanisms. In zebrafish minar2 mutants, mechanotransduction dye labelling falls by about half while hair cell number falls by only about a fifth, so the loss of function exceeds the loss of cells. In mice, distortion product otoacoustic emissions are raised in threshold at two weeks and mostly absent by four weeks, and hair cells still take up transduction-channel dye while failing to produce normal responses - present but not working.
cochlear outer hair cell CL:0000601 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlear outer hair cell (CL:0000601). CL:0000601 is a cell type from the Cell Ontology. cochlear inner hair cell CL:0000589 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlear inner hair cell (CL:0000589). CL:0000589 is a cell type from the Cell Ontology.
detection of mechanical stimulus involved in sensory perception of sound GO:0050910 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased detection of mechanical stimulus involved in sensory perception of sound (GO:0050910). GO:0050910 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Minar2 tm1b null mouse Mouse recapitulates The mouse shows hair cells that are present, take up transduction-channel dye, and still fail to transduce, which is the functional claim of this node.
minar2 frameshift zebrafish Zebrafish recapitulates Transduction is impaired out of proportion to hair cell loss, which is the specific claim this node makes.
Downstream
Congenital Severe-to-Profound Sensorineural Hearing Impairment
Show evidence (4 references)
PMID:36317962 SUPPORT Model Organism
"Because the decreases in hair cell numbers (~18% reduction) are smaller than those reductions of AM1-43 labeling intensities (~50% reduction), these results suggest that loss of minar2 function mainly affects hair cell mechanotransduction in the zebrafish larvae."
The quantitative argument separating a transduction defect from simple hair cell loss.
PMID:35727972 SUPPORT Model Organism
"It is notable that although the sensory hair cells are present up to 4 wk old and are able to take up fn1-43 dye through transduction channels, they do not appear to be functioning normally as shown by the raised ABR and DPOAE thresholds."
The mammalian counterpart: hair cells present, channels open to dye, function nevertheless lost.
PMID:35727972 SUPPORT Model Organism
"Otoacoustic emissions can be detected in the mutant mice but at raised thresholds at 2 wk old, and these responses are mostly absent by 4 wk old, implicating outer hair cells in the pathology."
The outer hair cell functional readout and its rapid decline.
+ 1 more reference
Progressive Hair Cell Degeneration
A later consequence rather than the initiating event. Hair cell degeneration is reported in Minar2 null mice at a later age than the threshold elevation, and the relative preservation of hair cells during the interval is what the founding authors identify as a therapeutic opportunity.
cochlea auditory hair cell CL:4023120 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlea auditory hair cell (CL:4023120). CL:4023120 is a cell type from the Cell Ontology.
Downstream
Congenital Severe-to-Profound Sensorineural Hearing Impairment
Show evidence (2 references)
PMID:35727972 SUPPORT Model Organism
"Mice with loss of function of the Minar2 protein (Minar2tm1b/tm1b) present with rapidly progressive sensorineural HL associated with a reduction in outer hair cell stereocilia in the shortest row and degeneration of hair cells at a later age."
Places degeneration after the stereocilia lesion in the mouse time course.
PMID:35727972 SUPPORT DIRECT Model Organism
"Progressive HL observed in mice and in some affected individuals and as well as relative preservation of hair cells provides an opportunity to interfere with HL using genetic therapies."
Direct against this node: the sentence asserts progressive hearing loss with relative preservation of hair cells, which is the degeneration claim itself. The therapeutic window the authors draw from it is a further inference beyond this node, and no rescue experiment has been done in this model.
Derepression of NOTCH2 and mTORC1 Signalling
MINAR2 restrains two signalling systems in cultured cells: overexpression reduces NOTCH2 abundance and silencing raises it, and silencing increases mTORC1 activity as read out by S6 phosphorylation without affecting mTORC2. In adipose tissue of Minar2 knockout mice the same derepression is seen, and it is the mechanism proposed for the metabolic phenotype. This node is deliberately drawn as a consequence of MINAR2 loss with no edge into the hearing phenotypes. No experiment has connected NOTCH2 or mTORC1 derepression to any cochlear phenotype in any species; the founding authors put it no more strongly than that Notch signalling might play a role. Drawing the arrow would state something the literature does not.
TOR signaling GO:0031929 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased TOR signaling (GO:0031929). GO:0031929 is a biological process from the Gene Ontology. ↑ INCREASED Notch signaling pathway GO:0007219 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Notch signaling pathway (GO:0007219). GO:0007219 is a biological process from the Gene Ontology. ↑ INCREASED
Animal models
Minar2 knockout mouse metabolic and motor phenotype Mouse recapitulates Establishes in vivo that losing Minar2 derepresses mTORC1, and identifies the molecular route through Raptor binding. That is exactly the node, and the model supports it well.
Show evidence (3 references)
PMID:35727972 SUPPORT DIRECT In Vitro
"Finally, via in vitro studies we demonstrated that MINAR2 suppresses NOTCH2, suggesting that notch signaling might play a role in pathogenesis."
Direct against this node: "MINAR2 suppresses NOTCH2" is the derepression claim itself, and it is asserted as a demonstrated result. The hedge in the same sentence is about onward relevance to deafness, which this node does not claim.
PMID:35727972 SUPPORT In Vitro
"Silencing of MINAR2 in PC12 cells, which endogenously express MINAR2, leads to an increase in NOTCH2 and confirms the suppressor effect of MINAR2 on NOTCH2 abundance"
The loss-of-function direction of the NOTCH2 effect, which is the disease-relevant one.
PMID:37245847 SUPPORT Model Organism
"Mechanistically, Minar2 interacts with Raptor, a specific and essential component of mammalian TOR complex 1 (mTORC1) and inhibits mTOR activation."
The molecular basis of the mTORC1 arm, established in mouse tissue and cells.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Hearing Loss Autosomal Recessive 120 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

3
Congenital Severe-to-Profound Sensorineural Hearing Impairment OBLIGATE Auditory HP:0008527 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital severe to profound sensorineural hearing impairment, annotated with Congenital sensorineural hearing impairment (HP:0008527). HP:0008527 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:35727972 SUPPORT Human Clinical
"We detected three MINAR2 variants, c.144G > A (p.Trp48*), c.412_419delCGGTTTTG (p.Arg138Valfs*10), and c.393G > T, in 13 individuals with congenital- or prelingual-onset severe-to-profound sensorineural hearing loss (HL)."
Onset and severity across the founding series.
PMID:35727972 SUPPORT Human Clinical
"Individual II:3 in family 1 was diagnosed with profound sensorineural HL after failing the newborn hearing screening test."
Detection by newborn screening, which distinguishes DFNB120 from the progressive recessive forms that can pass screening.
PMID:41130944 SUPPORT Human Clinical
"We report a patient with bilateral, nonsyndromic severe to profound hearing loss, along with a family history of a sibling presenting with the same phenotype and disease severity."
Independent replication of severity and bilaterality in a later family.
Progressive Sensorineural Hearing Impairment OCCASIONAL Auditory HP:0000408 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive sensorineural hearing impairment (HP:0000408). HP:0000408 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35727972 SUPPORT Human Clinical
"A progressive HL reaching a severe-to-profound degree during childhood was noted in four affected individuals."
The size of the progressive subgroup within the founding series.
PMID:35727972 SUPPORT Human Clinical
"Parents of family 1 stated that in individuals II:1 and II:2, HL was milder in younger ages and progressed to a severe or profound degree by around age 10."
The reported time course of progression in one family.
Absent Otoacoustic Emissions FREQUENT Auditory HP:6000182 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absent otoacoustic emissions (HP:6000182). HP:6000182 is a phenotype from the Human Phenotype Ontology.
Frequency is FREQUENT rather than higher because emissions were tested in only three of the thirteen affected individuals; the denominator, not the result, is what limits the claim.
Show evidence (1 reference)
PMID:35727972 SUPPORT Human Clinical
"In addition to ABR thresholds showing sensorineural HL, otoacoustic emissions were absent in three children tested, suggesting dysfunction of both inner hair cell/acoustic nerve and outer hair cells."
The measurement and the interpretation the authors place on it.
🧬

Genetic Associations

1
MINAR2
Gene: MINAR2 hgnc:33914 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MINAR2 (hgnc:33914). hgnc:33914 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (3 references)
PMID:35727972 SUPPORT Human Clinical
"We conclude that MINAR2 is essential for hearing in humans and mice and its disruption leads to sensorineural HL."
The gene-disease conclusion, drawn from human genetics plus a mouse null.
PMID:35727972 SUPPORT Model Organism
"We show that Minar2 is expressed in the mouse inner ear, with the protein localizing mainly in the hair cells, spiral ganglia, the spiral limbus, and the stria vascularis."
The expression pattern, which is worth recording because it is wider than the observed lesion and leaves room for contributions this entry does not yet model.
PMID:35727972 SUPPORT Other
"MINAR2 (previously known as uncharacterized protein KIAA1024L and mouse gene A730017C20Rik) has recently been identified, and based on its structural similarity to MINAR1, named as major intrinsically disordered NOTCH2-associated receptor 2 or membrane integral NOTCH2-associated receptor 2"
The gene's aliases, needed because the zebrafish literature calls it kiaa1024L and a reader searching only for MINAR2 will miss the cholesterol work.
🗃️

External Assertions

1
OMIM deafness, autosomal recessive 120 record
OMIM disease record OMIM:620238
OMIM entry for DFNB120, the MINAR2-related autosomal recessive nonsyndromic hearing loss phenotype curated here.
💊

Medical Actions

2
Genetic Counselling and Confirmatory Testing
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Platform: Other
Counselling for a recessive condition with a 25 percent sibling recurrence risk, and confirmatory testing of at-risk siblings. In the founding series a sibling pair was identified in the same family, and in the 2025 report the proband's affected sibling had the same phenotype and severity, so the sibling recurrence is not theoretical.
Show evidence (2 references)
PMID:41130944 SUPPORT Human Clinical
"We report a patient with bilateral, nonsyndromic severe to profound hearing loss, along with a family history of a sibling presenting with the same phenotype and disease severity."
An affected sibling in the most recent family, the recurrence counselling is about.
PMID:41130944 SUPPORT Human Clinical
"The parents were carriers of the same variant."
Confirmed carrier status in both parents, which is what makes the recurrence risk quantifiable.
Cochlear Implantation
Action: cochlear implantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cochlear implantation, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Device
The intervention actually used in this disorder. Three molecularly confirmed individuals from the founding Turkish family received unilateral cochlear implants, and in all three oral communication was the reported outcome. The ages are the informative part. Two siblings whose hearing was milder in early childhood and reached severe or profound by about age 10 were implanted at 12 and 10; their younger brother, who failed the newborn hearing screen and was profound from the start, was implanted at 1. So implantation timing in DFNB120 tracks the individual course rather than the diagnosis, and the progressive minority reach candidacy years later than the congenitally profound majority.
Show evidence (2 references)
PMID:35727972 SUPPORT Human Clinical
"These siblings received unilateral cochlear implants at ages 12 and 10, respectively, which improved their oral communication."
Implantation and its functional outcome in the two siblings with the progressive course.
PMID:35727972 SUPPORT Human Clinical
"He received a unilateral cochlear implant at age 1 and communicates orally."
Implantation in infancy in their brother, who was profound from birth. Together the two items show the same family spanning an eleven-year range in age at implantation.
🔬

Diagnosis

1
Gene panel or exome sequencing after a failed newborn screen
DFNB120 presents as congenital severe-to-profound nonsyndromic sensorineural hearing loss with no distinguishing clinical feature, so it is not diagnosable without sequencing and is not distinguishable from GJB2-related deafness on phenotype. In reported families the route was whole exome sequencing after variants in previously recognised deafness genes had been excluded. MINAR2 is recent enough that older targeted panels may not contain it.
Show evidence (2 references)
PMID:35727972 SUPPORT Human Clinical
"After excluding variants in previously recognized deafness genes, in family 1 we filtered shared homozygous coding and splice variants"
The diagnostic sequence that identified the founding family.
PMID:41130944 SUPPORT Human Clinical
"WES revealed a homozygous novel LoF variant in MINAR2 that explains the isolated hearing loss phenotype observed in this patient."
Exome sequencing as the diagnostic route in the most recent family.
📊

Prevalence

1
Worldwide, published cases
Cases In Literature Ultra Rare
Thirteen affected individuals in four unrelated families in the founding 2022 report, plus a further family reported in 2025. No population estimate exists. The 2025 report puts the causal allele at two heterozygous carriers among 767,859 individuals in gnomAD.
Show evidence (1 reference)
PMID:41130944 SUPPORT Human Clinical
"Recently, biallelic variants in MINAR2 have been reported to cause SNHL in four unrelated families with nonsyndromic severe to profound SNHL."
The size of the reported literature at the time of the second report.
🐁

Animal Models

3
Minar2 tm1b null mouse
The mammalian model, produced by the knockout-mouse phenotyping pipeline and characterised alongside the human families. Homozygotes have raised auditory brainstem response and distortion product otoacoustic emission thresholds from postnatal day 14, two days after hearing normally begins, and by four weeks show severe elevation or no response. The structural correlate is depletion of the shortest row of outer hair cell stereocilia; ribbon synapse numbers and organ of Corti organisation are normal at the age when thresholds are already abnormal.
Species
Mouse
Genotype
Minar2 tm1b/tm1b, homozygous null
Genes
MINAR2 hgnc:33914 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns MINAR2 (hgnc:33914). hgnc:33914 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:35727972
Pathograph links
Depletion of the Shortest Row of Outer Hair Cell Stereocilia recapitulates fidelity: high This is the model in which the mammalian lesion is defined. Cochlear stereocilia cannot be examined in living patients, so the mouse is not merely corroborating the human phenotype - it is the only place the structural mechanism has been observed at all.
Limitations: A complete null, whereas human alleles are nonsense, frameshift and spliceogenic; those are predicted null but the prediction rests on transcript consequence rather than on measured protein. Onset also differs in kind: mouse thresholds are already raised two days after hearing onset and then worsen rapidly, whereas most human patients are congenitally profound with only a minority showing progression. The mouse therefore models a rapidly progressive course that most patients do not have.
Readouts
Outer hair cell shortest-row stereocilia number and length
Direction: DECREASED
Interpretation: Row-selective loss: the shortest row is depleted and shortened while inner hair cells are close to normal.
Show evidence (1 reference)
PMID:35727972 SUPPORT Model Organism
"However, when we examined the stereocilia bundles of outer hair cells, we saw the shortest row was depleted, with reduced numbers and abnormally short stereocilia"
The scanning electron microscopy measurement behind this readout.
Inner hair cell ribbon synapse count
Direction: UNCHANGED
Interpretation: A real negative result, and the one that makes the stereocilia lesion primary: synapse numbers are normal at the age when thresholds are already raised.
Show evidence (1 reference)
PMID:35727972 SUPPORT Model Organism
"the number of synapses per inner hair cell in homozygous mutants was not significantly different from numbers in heterozygotes or wild-type controls at P14"
The synapse count that excludes synaptopathy as the early mechanism.
Show evidence (1 reference)
PMID:35727972 SUPPORT Model Organism
"We further showed that homozygous Minar2tm1b mutant mice develop rapidly progressive HL associated with changes in outer hair cell stereocilia."
The model's central auditory conclusion, which is the node it supports.
Impaired Hair Cell Mechanotransduction recapitulates fidelity: moderate The mouse shows hair cells that are present, take up transduction-channel dye, and still fail to transduce, which is the functional claim of this node.
Limitations: Mechanotransduction is inferred from threshold measurements and dye uptake rather than measured directly by transduction current recording, so the claim is functional rather than biophysical.
Readouts
Distortion product otoacoustic emission threshold
Direction: INCREASED
Interpretation: Thresholds rise, so the direction is INCREASED even though the underlying function falls: outer hair cell function is already impaired at two weeks and largely gone by four, the mouse counterpart of the absent emissions in patients.
Show evidence (1 reference)
PMID:35727972 SUPPORT Model Organism
"Otoacoustic emissions can be detected in the mutant mice but at raised thresholds at 2 wk old, and these responses are mostly absent by 4 wk old, implicating outer hair cells in the pathology."
The emission time course in the null.
Show evidence (1 reference)
PMID:35727972 SUPPORT Model Organism
"Thresholds for both ABRs and DPOAEs were raised in homozygous mutants compared with wild-type littermates from the earliest age studied, postnatal day (P) 14, only 2 d after the usual onset of hearing"
Establishes that the functional deficit is present essentially from hearing onset, which is what makes it comparable to a congenital human phenotype.
Show evidence (1 reference)
PMID:35727972 SUPPORT Model Organism
"In conclusion, audiological findings both in humans and mice show that loss of MINAR2 function results in early-onset and sensorineural HL that rapidly progresses to severe to profound deafness."
The authors' joint human and mouse conclusion, which is the basis for treating the mouse as informative.
minar2 frameshift zebrafish
Two frameshift alleles of the zebrafish orthologue. Mutant larvae have reduced auditory evoked potentials, reduced mechanotransduction dye labelling, longer and thinner hair bundles, disorganised lateral line kinocilia, and enlarged aggregated lysosomes in the apical region of hair cells. This is the system in which the cholesterol mechanism was established, including the pharmacological rescue.
Species
Zebrafish
Genotype
kiaa1024L/minar2 fs139 and fs140 frameshift, homozygous
Genes
MINAR2 hgnc:33914 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns MINAR2 (hgnc:33914). hgnc:33914 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:36317962
Pathograph links
Loss of Cholesterol Delivery to the Hair Bundle recapitulates fidelity: moderate The only system in which the proposed molecular function of MINAR2 has been tested. Bundle cholesterol was measured with a genetically encoded sensor, and the causal role established by moving cholesterol in both directions pharmacologically.
Limitations: Zebrafish, and the correspondence to the mammalian phenotype is imperfect in a way the authors state: hearing loss in the mutant larvae is not as severe as in the adult knockout mouse. The bundle phenotype also differs in direction - fish bundles are longer and thinner, mouse stereocilia are shorter and fewer - so whether the two species are showing the same lesion is not established. No cholesterol measurement exists in any mammalian Minar2 hair bundle.
Readouts
Hair bundle cholesterol reporter intensity
Direction: DECREASED
Interpretation: Cholesterol available in inner ear stereocilia falls to roughly half of wild type, with transgene expression confirmed unchanged.
Show evidence (2 references)
PMID:36317962 SUPPORT Model Organism
"The results showed the average D4H-mCherry signals of inner ear stereocilia in the minar2fs139 larvae were about half of those in the wild controls"
The quantified sensor measurement in mutant stereocilia.
+ 1 more reference
Mechanotransduction dye labelling after cholesterol restoration
Direction: RESTORED
Interpretation: Raising cholesterol pharmacologically restores both transduction labelling and hearing, which is what makes the cholesterol deficit causal rather than incidental.
Show evidence (1 reference)
PMID:36317962 SUPPORT Model Organism
"Thus, both the mechanotransduction (AM1-43 staining) and the hearing were restored after the decreased cholesterol levels were restored by the treatment with efavirenz."
The rescue result, with the specific drug and the two readouts it restored.
Show evidence (1 reference)
PMID:36317962 SUPPORT Model Organism
"Therefore, cholesterol plays an essential role in hair bundles, and Kiaa1024L/Minar2 regulates cholesterol distribution and homeostasis to ensure normal hearing."
The study's central conclusion, which is the mechanism this node curates.
Impaired Hair Cell Mechanotransduction recapitulates fidelity: moderate Transduction is impaired out of proportion to hair cell loss, which is the specific claim this node makes.
Limitations: Larval lateral line and inner ear hair cells, not cochlear outer hair cells; zebrafish have no cochlea and no outer hair cell electromotility, so the mechanism is being modelled in a cell type that lacks the mammalian amplifier.
Readouts
AM1-43 mechanotransduction labelling
Direction: DECREASED
Interpretation: Roughly half the wild-type labelling against roughly a fifth fewer hair cells, so the deficit is functional rather than a count.
Show evidence (1 reference)
PMID:36317962 SUPPORT Model Organism
"Because the decreases in hair cell numbers (~18% reduction) are smaller than those reductions of AM1-43 labeling intensities (~50% reduction), these results suggest that loss of minar2 function mainly affects hair cell mechanotransduction in the zebrafish larvae."
The quantitative comparison that separates transduction failure from cell loss.
Show evidence (1 reference)
PMID:36317962 SUPPORT Model Organism
"We conclude that minar2 is required for mechanotransduction in the zebrafish larvae, and loss of minar2 reduces the number of inner ear hair cells in the zebrafish adults."
The authors' conclusion for this node, including the adult cell-loss component.
Minar2 knockout mouse metabolic and motor phenotype
The same null line examined outside the ear. Knockouts have three-fold higher adipose mass on a chow diet, hypertrophic adipocytes, accelerated weight gain and impaired glucose tolerance on a high-fat diet, all without increased food intake, driven by mTORC1 derepression through loss of Minar2 binding to Raptor. A separate study on a knockout of the same gene reported rigidity, bradykinesia, gait abnormalities and loss of tyrosine hydroxylase positive neurons in the substantia nigra pars compacta with raised alpha-synuclein.
Species
Mouse
Genotype
Minar2 knockout, homozygous, exon 2 replaced by lacZ
Genes
MINAR2 hgnc:33914 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns MINAR2 (hgnc:33914). hgnc:33914 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:37245847
Pathograph links
Derepression of NOTCH2 and mTORC1 Signalling recapitulates fidelity: high Establishes in vivo that losing Minar2 derepresses mTORC1, and identifies the molecular route through Raptor binding. That is exactly the node, and the model supports it well.
Limitations: The tissue is adipose, not cochlea, and the phenotypes measured are metabolic. The model says nothing about whether mTORC1 derepression occurs in hair cells or contributes to deafness, which is why this entry draws no edge from that node into the auditory phenotypes.
Readouts
mTOR Ser2448 phosphorylation in adipocytes
Direction: INCREASED
Interpretation: Loss of Minar2 raises mTOR activating phosphorylation in vivo.
Show evidence (1 reference)
PMID:37245847 SUPPORT Model Organism
"Our results showed a significant increase in Ser2448 phosphorylation of mTOR in Minar2 KO adipocytes"
The direct measurement of mTOR activation in knockout tissue.
Show evidence (1 reference)
PMID:37245847 SUPPORT Model Organism
"Our findings identified Minar2 as a novel physiological negative regulator of mTORC1 with a key role in obesity and metabolic disorders."
The study conclusion establishing Minar2 as an mTORC1 restraint in vivo.
Show evidence (2 references)
PMID:37245847 SUPPORT Model Organism
"Minar2 KO mice on a high-fat diet develop obesity and impaired glucose tolerance and metabolism."
The extra-auditory phenotype itself, curated because its absence in human patients is a substantive mismatch rather than a footnote.
PMID:32954300 SUPPORT Model Organism
"Analysis of the major intrinsically disordered NOTCH2-associated receptor 2 knockout mice brain revealed significant anomalies in neuronal function and appearance including the loss of tyrosine hydroxylase-positive neurons in the pars compacta, which was accompanied by an up-regulation in..."
The second extra-auditory mouse phenotype, with a neuropathological correlate rather than only a behavioural one.
{ }

Source YAML

click to show 
name: Hearing Loss Autosomal Recessive 120
category: Mendelian
creation_date: "2026-08-28T00:00:00Z"
synonyms:
- DFNB120
- deafness, autosomal recessive 120
- MINAR2-related autosomal recessive hearing loss
- KIAA1024L-related hearing loss
description: >-
  DFNB120 is congenital or prelingual, severe-to-profound, nonsyndromic sensorineural
  hearing loss caused by biallelic loss of MINAR2 (previously the uncharacterised gene
  KIAA1024L). It was defined in 2022 in thirteen individuals from four families, and the
  reported literature is still small enough to read in an afternoon.

  The gene arrived without a function. MINAR2 was named for structural similarity to
  MINAR1 rather than for anything known about what it does, and the human disease and the
  animal work were published essentially together. Two independent mechanisms have since
  been proposed and they are not the same claim. In the mouse, loss of Minar2 depletes the
  shortest row of outer hair cell stereocilia while leaving ribbon synapses and overall
  organ of Corti architecture intact at the age when thresholds are already raised, which
  places the primary defect at the top of the hair cell. In zebrafish, Minar2 sits on
  apical lysosomes and is required to deliver cholesterol to the hair bundle membrane;
  mutants have reduced bundle cholesterol, longer and thinner bundles, enlarged apical
  lysosomes and impaired mechanotransduction, and pharmacologically raising cholesterol
  rescues them while lowering it makes them worse.

  These fit together comfortably as a lipid-delivery defect that destabilises the apical
  hair bundle, but that synthesis is an inference across two species and has not been
  tested in either. Nobody has measured hair bundle cholesterol in a Minar2 mouse, and
  nobody has looked at stereocilia row identity in a minar2 zebrafish.

  The rescue result is the reason this entry is worth curating despite thin evidence.
  Zebrafish hair cell defects and hearing were restored by drugs that raise cholesterol -
  a small-molecule, non-genetic intervention in a monogenic deafness. Whether that is
  meaningful for human DFNB120 is unknown and probably harder than it sounds, since the
  human phenotype is congenital and profound while the fish phenotype is mild and
  larval.

  The gene also has a life outside the ear that human patients do not share. Minar2
  knockout mice develop obesity with hypertrophic adipocytes and impaired glucose
  tolerance through mTORC1 derepression, and a separate study reported parkinsonian motor
  deficits with nigral dopaminergic loss. Affected humans examined between 4 and 80 years
  of age had no additional abnormalities, and none had impaired balance on bedside
  vestibular testing. That dissociation is recorded here as an explicit model mismatch
  rather than being smoothed over.
disease_term:
  preferred_term: hearing loss, autosomal recessive 120
  term:
    id: MONDO:0859374
    label: hearing loss, autosomal recessive 120
parents:
- Autosomal Recessive Nonsyndromic Hearing Loss
external_assertions:
- name: OMIM deafness, autosomal recessive 120 record
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:620238
  description: >-
    OMIM entry for DFNB120, the MINAR2-related autosomal recessive nonsyndromic hearing
    loss phenotype curated here.
inheritance:
- name: Autosomal recessive
  description: >-
    Biallelic MINAR2 variants. Reported alleles are a nonsense variant, a frameshift
    affecting the transmembrane domain, and a variant at the last nucleotide of exon 2
    that disrupts a splice donor site; a further homozygous nonsense allele was reported
    in 2025. Parents are heterozygous carriers with normal pure tone audiograms.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:35727972
    reference_title: "Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report on DNA variants in MINAR2, encoding membrane integral NOTCH2-associated receptor 2, in four families underlying autosomal recessive nonsyndromic deafness."
    explanation: The founding report and its inheritance mode.
  - reference: PMID:35727972
    reference_title: "Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pure tone audiograms in parents showed normal thresholds"
    explanation: Heterozygous carriers are unaffected, as recessive inheritance requires.
  - reference: PMID:41130944
    reference_title: "Biallelic MINAR2 variant is associated with nonsyndromic severe to profound sensorineural hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Trio whole-exome sequencing of the index and his parents revealed a homozygous nonsense variant in MINAR2"
    explanation: Independent replication of the recessive gene-disease relationship in a fifth family.
pathophysiology:
- name: MINAR2 Loss of Function
  description: >-
    Biallelic null or near-null MINAR2 alleles. The reported spectrum is a nonsense
    variant, a frameshift affecting the transmembrane domain, and a variant substituting
    the last nucleotide of exon 2 that abolishes a splice donor site rather than acting as
    the missense change it superficially resembles. A later homozygous nonsense allele is
    predicted to be removed by nonsense-mediated decay. The allelic spectrum is therefore
    uniformly loss of function, which is why this entry does not attempt a
    genotype-phenotype correlation.

    MINAR2 is a small membrane protein with an intrinsically disordered region, named for
    its similarity to MINAR1 rather than for a demonstrated function, and it was still
    formally uncharacterised when the deafness families were sequenced.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: MINAR2
    term:
      id: hgnc:33914
      label: MINAR2
  downstream:
  - target: Loss of Cholesterol Delivery to the Hair Bundle
    causal_link_type: DIRECT
  - target: Depletion of the Shortest Row of Outer Hair Cell Stereocilia
    causal_link_type: DIRECT
  - target: Derepression of NOTCH2 and mTORC1 Signalling
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:35727972
    reference_title: "Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We detected three MINAR2 variants, c.144G > A (p.Trp48*), c.412_419delCGGTTTTG (p.Arg138Valfs*10), and c.393G > T, in 13 individuals with congenital- or prelingual-onset severe-to-profound sensorineural hearing loss (HL)."
    explanation: The founding allelic series and the phenotype it produces.
  - reference: PMID:35727972
    reference_title: "Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The c.393G > T variant is shown to disrupt a splice donor site."
    explanation: >-
      Why the one apparently missense allele belongs in the loss-of-function class; the
      functional consequence is splicing, not amino acid substitution.
  - reference: PMID:41130944
    reference_title: "Biallelic MINAR2 variant is associated with nonsyndromic severe to profound sensorineural hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This variant introduces an early stop codon and probably results in a loss of function because of the predicted nonsense-mediated decay."
    explanation: The predicted molecular consequence of the 2025 allele, consistent with the earlier ones.
  - reference: PMID:35727972
    reference_title: "Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MINAR2 is a recently annotated gene with limited functional understanding."
    explanation: >-
      The state of knowledge when the disease was defined, which is the honest frame for
      how thin the mechanistic evidence below still is.
- name: Loss of Cholesterol Delivery to the Hair Bundle
  description: >-
    The proposed molecular job of MINAR2. In cultured cells the protein localises mainly to
    lysosomes and recruits cholesterol; in zebrafish hair cells, cholesterol is
    concentrated in the hair bundle membrane and this enrichment is lost in minar2 mutants,
    whose apical lysosomes become enlarged and aggregated. Hair bundles become longer and
    thinner rather than shorter, which is the opposite of what a simple structural-protein
    loss would give and is consistent with a membrane-property defect.

    The causal direction was tested pharmacologically rather than only inferred: lowering
    cholesterol worsens the mutant and raising it rescues hair cell defects and hearing.
    That is the strongest single result in the DFNB120 literature.

    The caveat is species. Every element of this node is zebrafish or cell culture. No
    cholesterol measurement has been made in a mammalian Minar2 hair bundle, so its
    application to human DFNB120 is an extrapolation.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: cochlea auditory hair cell
    term:
      id: CL:4023120
      label: cochlea auditory hair cell
  biological_processes:
  - preferred_term: intracellular cholesterol transport
    term:
      id: GO:0032367
      label: intracellular cholesterol transport
    modifier: DECREASED
  downstream:
  - target: Impaired Hair Cell Mechanotransduction
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:36317962
    reference_title: "Kiaa1024L/Minar2 is essential for hearing by regulating cholesterol distribution in hair bundles."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Strikingly, cholesterol is highly enriched in the hair bundle membrane, and loss of kiaa1024L/minar2 reduces cholesterol localization to the hair bundles."
    explanation: The central measurement, showing that bundle cholesterol enrichment depends on Minar2.
  - reference: PMID:36317962
    reference_title: "Kiaa1024L/Minar2 is essential for hearing by regulating cholesterol distribution in hair bundles."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Lowering cholesterol levels aggravates, while increasing cholesterol levels rescues the hair cell defects in the kiaa1024L/minar2 mutant."
    explanation: >-
      Bidirectional pharmacological manipulation, which is what makes this causal rather
      than correlative.
  - reference: PMID:36317962
    reference_title: "Kiaa1024L/Minar2 is essential for hearing by regulating cholesterol distribution in hair bundles."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In cultured cells, Kiaa1024L/Minar2 is mainly localized to lysosomes, and its overexpression recruits cholesterol and increases cholesterol labeling."
    explanation: The subcellular localisation and cholesterol-recruiting activity, in cells.
  - reference: PMID:36317962
    reference_title: "Kiaa1024L/Minar2 is essential for hearing by regulating cholesterol distribution in hair bundles."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Defects in mechanotransduction, longer and thinner hair bundles, and enlarged apical lysosomes are observed in hair cells in kiaa1024L/minar2 mutant."
    explanation: >-
      The three structural and functional consequences together, including the enlarged
      apical lysosomes that tie the phenotype back to the protein's location.
  - reference: PMID:36317962
    reference_title: "Kiaa1024L/Minar2 is essential for hearing by regulating cholesterol distribution in hair bundles."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These results suggested that the sterol synthesis pathway was activated due to a reduction of the accessible cholesterol pool in the minar2fs139 mutant larvae."
    explanation: >-
      Independent confirmation that the accessible cholesterol pool really is reduced,
      arrived at from the opposite direction: the animal's own sterol-synthesis programme
      is switched on, which is a readout that does not depend on the fluorescent reporter
      used for the primary measurement. Curated as evidence on this node rather than as a
      separate compensatory-response node, because nothing links the compensation itself
      to the hearing phenotype.
  - reference: PMID:36317962
    reference_title: "Kiaa1024L/Minar2 is essential for hearing by regulating cholesterol distribution in hair bundles."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These effects were not due to changes in expression levels of the point mutation construct, since it was expressed at a similar level as the wild-type construct (Figure 7C)."
    explanation: >-
      The controlled version of the binding claim. Mutating the critical aromatic residues
      of the predicted cholesterol-recognition motifs to alanine abolishes cholesterol
      recruitment at equal construct expression, so the effect is attributable to the motif
      rather than to how much protein is present.
  - reference: PMID:36317962
    reference_title: "Kiaa1024L/Minar2 is essential for hearing by regulating cholesterol distribution in hair bundles."
    supports: NO_EVIDENCE
    evidence_source: IN_VITRO
    snippet: "Nevertheless, further biochemical studies are required to demonstrate direct binding between the Kiaa1024L/Minar2 protein and cholesterol."
    explanation: >-
      Carried deliberately as a limitation, not as a direction. The authors report no
      experiment here: they state that direct binding has not been demonstrated, which is
      absence of evidence rather than evidence against. The motif analysis, the recruitment
      assay and the docking study are consistent with a cholesterol-binding protein without
      establishing one. This node's claim is cholesterol delivery, which the paper's other
      results support; the sentence is quoted so the binding mechanism is not read as
      settled.
- name: Depletion of the Shortest Row of Outer Hair Cell Stereocilia
  description: >-
    The mammalian structural lesion. In Minar2 null mice the shortest row of outer hair
    cell stereocilia is depleted, with fewer and abnormally short stereocilia, while inner
    hair cells are close to normal. This is not secondary to hair cell death: at postnatal
    day 14, when thresholds are already raised, the organ of Corti is organised normally
    and very few bundles are missing, and ribbon synapse numbers are not different from
    controls. Hair cell degeneration appears later.

    The shortest row is where the mechanotransduction channel complexes sit, which is why
    the authors read this as a defect at the top of the hair cell rather than a
    synaptopathy or a neural problem.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: cochlear outer hair cell
    term:
      id: CL:0000601
      label: cochlear outer hair cell
  biological_processes:
  - preferred_term: auditory receptor cell stereocilium organization
    term:
      id: GO:0060088
      label: auditory receptor cell stereocilium organization
    modifier: DECREASED
  downstream:
  - target: Impaired Hair Cell Mechanotransduction
    causal_link_type: DIRECT
  - target: Progressive Hair Cell Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:35727972
    reference_title: "Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "However, when we examined the stereocilia bundles of outer hair cells, we saw the shortest row was depleted, with reduced numbers and abnormally short stereocilia"
    explanation: The row-selective structural measurement in the mouse.
  - reference: PMID:35727972
    reference_title: "Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The reduced number of stereocilia in the shortest row on outer hair cells would be expected to have a severe impact upon the number of transduction channel complexes available and suggests that the primary defect in these mutant mice is located at the top of the hair cell."
    explanation: The authors' localisation of the primary defect and its functional rationale.
  - reference: PMID:35727972
    reference_title: "Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The organization of the organ of Corti appeared normal and there were very few missing stereocilia bundles in mutants, suggesting that hair cell degeneration cannot explain the raised ABR thresholds at this age"
    explanation: >-
      Excludes degeneration as the cause of the early threshold shift, which is what makes
      the stereocilia lesion primary rather than a late consequence.
- name: Impaired Hair Cell Mechanotransduction
  description: >-
    The convergence point of both proposed mechanisms. In zebrafish minar2 mutants,
    mechanotransduction dye labelling falls by about half while hair cell number falls by
    only about a fifth, so the loss of function exceeds the loss of cells. In mice,
    distortion product otoacoustic emissions are raised in threshold at two weeks and
    mostly absent by four weeks, and hair cells still take up transduction-channel dye
    while failing to produce normal responses - present but not working.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: cochlear outer hair cell
    term:
      id: CL:0000601
      label: cochlear outer hair cell
  - preferred_term: cochlear inner hair cell
    term:
      id: CL:0000589
      label: cochlear inner hair cell
  biological_processes:
  - preferred_term: detection of mechanical stimulus involved in sensory perception of sound
    term:
      id: GO:0050910
      label: detection of mechanical stimulus involved in sensory perception of sound
    modifier: DECREASED
  downstream:
  - target: Congenital Severe-to-Profound Sensorineural Hearing Impairment
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:36317962
    reference_title: "Kiaa1024L/Minar2 is essential for hearing by regulating cholesterol distribution in hair bundles."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Because the decreases in hair cell numbers (~18% reduction) are smaller than those reductions of AM1-43 labeling intensities (~50% reduction), these results suggest that loss of minar2 function mainly affects hair cell mechanotransduction in the zebrafish larvae."
    explanation: >-
      The quantitative argument separating a transduction defect from simple hair cell
      loss.
  - reference: PMID:35727972
    reference_title: "Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "It is notable that although the sensory hair cells are present up to 4 wk old and are able to take up fn1-43 dye through transduction channels, they do not appear to be functioning normally as shown by the raised ABR and DPOAE thresholds."
    explanation: >-
      The mammalian counterpart: hair cells present, channels open to dye, function
      nevertheless lost.
  - reference: PMID:35727972
    reference_title: "Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Otoacoustic emissions can be detected in the mutant mice but at raised thresholds at 2 wk old, and these responses are mostly absent by 4 wk old, implicating outer hair cells in the pathology."
    explanation: The outer hair cell functional readout and its rapid decline.
  - reference: PMID:35727972
    reference_title: "Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Ribbon synapses look qualitatively normal at both ages tested, P14 and P30, and the number of synapses per inner hair cell in homozygous mutants was not significantly different from numbers in heterozygotes or wild-type controls at P14, indicating that the raised ABR thresholds observed at that age in mutants are not due to the loss of ribbon synapses"
    explanation: >-
      Excludes synaptopathy, which matters because otoacoustic emissions are also absent in
      human patients and a purely synaptic lesion would have predicted otherwise.
- name: Progressive Hair Cell Degeneration
  description: >-
    A later consequence rather than the initiating event. Hair cell degeneration is
    reported in Minar2 null mice at a later age than the threshold elevation, and the
    relative preservation of hair cells during the interval is what the founding authors
    identify as a therapeutic opportunity.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: cochlea auditory hair cell
    term:
      id: CL:4023120
      label: cochlea auditory hair cell
  downstream:
  - target: Congenital Severe-to-Profound Sensorineural Hearing Impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:35727972
    reference_title: "Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mice with loss of function of the Minar2 protein (Minar2tm1b/tm1b) present with rapidly progressive sensorineural HL associated with a reduction in outer hair cell stereocilia in the shortest row and degeneration of hair cells at a later age."
    explanation: Places degeneration after the stereocilia lesion in the mouse time course.
  - reference: PMID:35727972
    reference_title: "Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: "Progressive HL observed in mice and in some affected individuals and as well as relative preservation of hair cells provides an opportunity to interfere with HL using genetic therapies."
    explanation: >-
      Direct against this node: the sentence asserts progressive hearing loss with relative
      preservation of hair cells, which is the degeneration claim itself. The therapeutic
      window the authors draw from it is a further inference beyond this node, and no rescue
      experiment has been done in this model.
- name: Derepression of NOTCH2 and mTORC1 Signalling
  description: >-
    MINAR2 restrains two signalling systems in cultured cells: overexpression reduces
    NOTCH2 abundance and silencing raises it, and silencing increases mTORC1 activity as
    read out by S6 phosphorylation without affecting mTORC2. In adipose tissue of Minar2
    knockout mice the same derepression is seen, and it is the mechanism proposed for the
    metabolic phenotype.

    This node is deliberately drawn as a consequence of MINAR2 loss with no edge into the
    hearing phenotypes. No experiment has connected NOTCH2 or mTORC1 derepression to any
    cochlear phenotype in any species; the founding authors put it no more strongly than
    that Notch signalling might play a role. Drawing the arrow would state something the
    literature does not.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: TOR signaling
    term:
      id: GO:0031929
      label: TOR signaling
    modifier: INCREASED
  - preferred_term: Notch signaling pathway
    term:
      id: GO:0007219
      label: Notch signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:35727972
    reference_title: "Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: "Finally, via in vitro studies we demonstrated that MINAR2 suppresses NOTCH2, suggesting that notch signaling might play a role in pathogenesis."
    explanation: >-
      Direct against this node: "MINAR2 suppresses NOTCH2" is the derepression claim itself,
      and it is asserted as a demonstrated result. The hedge in the same sentence is about
      onward relevance to deafness, which this node does not claim.
  - reference: PMID:35727972
    reference_title: "Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Silencing of MINAR2 in PC12 cells, which endogenously express MINAR2, leads to an increase in NOTCH2 and confirms the suppressor effect of MINAR2 on NOTCH2 abundance"
    explanation: The loss-of-function direction of the NOTCH2 effect, which is the disease-relevant one.
  - reference: PMID:37245847
    reference_title: "Inactivation of Minar2 in mice hyperactivates mTOR signaling and results in obesity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mechanistically, Minar2 interacts with Raptor, a specific and essential component of mammalian TOR complex 1 (mTORC1) and inhibits mTOR activation."
    explanation: The molecular basis of the mTORC1 arm, established in mouse tissue and cells.
phenotypes:
- name: Congenital Severe-to-Profound Sensorineural Hearing Impairment
  category: Auditory
  description: >-
    The defining phenotype: bilateral sensorineural hearing loss present at birth or
    prelingual onset, reaching severe to profound levels. Nine of the thirteen individuals
    in the founding series were congenital and four prelingual. At least one was picked up
    by a failed newborn hearing screen.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Congenital severe to profound sensorineural hearing impairment
    term:
      id: HP:0008527
      label: Congenital sensorineural hearing impairment
  evidence:
  - reference: PMID:35727972
    reference_title: "Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We detected three MINAR2 variants, c.144G > A (p.Trp48*), c.412_419delCGGTTTTG (p.Arg138Valfs*10), and c.393G > T, in 13 individuals with congenital- or prelingual-onset severe-to-profound sensorineural hearing loss (HL)."
    explanation: Onset and severity across the founding series.
  - reference: PMID:35727972
    reference_title: "Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individual II:3 in family 1 was diagnosed with profound sensorineural HL after failing the newborn hearing screening test."
    explanation: >-
      Detection by newborn screening, which distinguishes DFNB120 from the progressive
      recessive forms that can pass screening.
  - reference: PMID:41130944
    reference_title: "Biallelic MINAR2 variant is associated with nonsyndromic severe to profound sensorineural hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a patient with bilateral, nonsyndromic severe to profound hearing loss, along with a family history of a sibling presenting with the same phenotype and disease severity."
    explanation: Independent replication of severity and bilaterality in a later family.
- name: Progressive Sensorineural Hearing Impairment
  category: Auditory
  description: >-
    A progressive component in a minority. Four affected individuals were noted to have
    hearing loss that worsened during childhood to a severe-to-profound degree, and in one
    family the parents described loss that was milder in early childhood and reached
    severe or profound by about age 10. Most patients are already at the floor, so
    progression is only visible in those who start above it.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Progressive sensorineural hearing impairment
    term:
      id: HP:0000408
      label: Progressive sensorineural hearing impairment
  evidence:
  - reference: PMID:35727972
    reference_title: "Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A progressive HL reaching a severe-to-profound degree during childhood was noted in four affected individuals."
    explanation: The size of the progressive subgroup within the founding series.
  - reference: PMID:35727972
    reference_title: "Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Parents of family 1 stated that in individuals II:1 and II:2, HL was milder in younger ages and progressed to a severe or profound degree by around age 10."
    explanation: The reported time course of progression in one family.
- name: Absent Otoacoustic Emissions
  category: Auditory
  description: >-
    Otoacoustic emissions were absent in the three children tested. Combined with the
    abnormal auditory brainstem responses, the authors read this as dysfunction of both
    the outer hair cells and the inner hair cell to auditory nerve pathway, which is
    consistent with the mouse finding that emissions disappear over the first month.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Absent otoacoustic emissions
    term:
      id: HP:6000182
      label: Absent otoacoustic emissions
  evidence:
  - reference: PMID:35727972
    reference_title: "Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition to ABR thresholds showing sensorineural HL, otoacoustic emissions were absent in three children tested, suggesting dysfunction of both inner hair cell/acoustic nerve and outer hair cells."
    explanation: The measurement and the interpretation the authors place on it.
  notes: >-
    Frequency is FREQUENT rather than higher because emissions were tested in only three of
    the thirteen affected individuals; the denominator, not the result, is what limits the
    claim.
prevalence:
- population: Worldwide, published cases
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Thirteen affected individuals in four unrelated families in the founding 2022 report,
    plus a further family reported in 2025. No population estimate exists. The 2025 report
    puts the causal allele at two heterozygous carriers among 767,859 individuals in
    gnomAD.
  evidence:
  - reference: PMID:41130944
    reference_title: "Biallelic MINAR2 variant is associated with nonsyndromic severe to profound sensorineural hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recently, biallelic variants in MINAR2 have been reported to cause SNHL in four unrelated families with nonsyndromic severe to profound SNHL."
    explanation: The size of the reported literature at the time of the second report.
genetic:
- name: MINAR2
  notes: >-
    MINAR2, on 5q23.3, encodes membrane integral NOTCH2-associated receptor 2, previously
    the uncharacterised protein KIAA1024L and the mouse gene A730017C20Rik. It was named
    for structural similarity to MINAR1 and for binding NOTCH2 in a coimmunoprecipitation
    assay, not for an established cellular role. In the mouse inner ear the protein is
    found in hair cells, spiral ganglia, the spiral limbus and the stria vascularis, which
    is broader than the outer hair cell lesion the mutant shows.
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: MINAR2
    term:
      id: hgnc:33914
      label: MINAR2
  evidence:
  - reference: PMID:35727972
    reference_title: "Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We conclude that MINAR2 is essential for hearing in humans and mice and its disruption leads to sensorineural HL."
    explanation: The gene-disease conclusion, drawn from human genetics plus a mouse null.
  - reference: PMID:35727972
    reference_title: "Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We show that Minar2 is expressed in the mouse inner ear, with the protein localizing mainly in the hair cells, spiral ganglia, the spiral limbus, and the stria vascularis."
    explanation: >-
      The expression pattern, which is worth recording because it is wider than the
      observed lesion and leaves room for contributions this entry does not yet model.
  - reference: PMID:35727972
    reference_title: "Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MINAR2 (previously known as uncharacterized protein KIAA1024L and mouse gene A730017C20Rik) has recently been identified, and based on its structural similarity to MINAR1, named as major intrinsically disordered NOTCH2-associated receptor 2 or membrane integral NOTCH2-associated receptor 2"
    explanation: >-
      The gene's aliases, needed because the zebrafish literature calls it kiaa1024L and a
      reader searching only for MINAR2 will miss the cholesterol work.
diagnosis:
- name: Gene panel or exome sequencing after a failed newborn screen
  description: >-
    DFNB120 presents as congenital severe-to-profound nonsyndromic sensorineural hearing
    loss with no distinguishing clinical feature, so it is not diagnosable without
    sequencing and is not distinguishable from GJB2-related deafness on phenotype. In
    reported families the route was whole exome sequencing after variants in previously
    recognised deafness genes had been excluded. MINAR2 is recent enough that older
    targeted panels may not contain it.
  evidence:
  - reference: PMID:35727972
    reference_title: "Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After excluding variants in previously recognized deafness genes, in family 1 we filtered shared homozygous coding and splice variants"
    explanation: The diagnostic sequence that identified the founding family.
  - reference: PMID:41130944
    reference_title: "Biallelic MINAR2 variant is associated with nonsyndromic severe to profound sensorineural hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "WES revealed a homozygous novel LoF variant in MINAR2 that explains the isolated hearing loss phenotype observed in this patient."
    explanation: Exome sequencing as the diagnostic route in the most recent family.
treatments:
- name: Genetic Counselling and Confirmatory Testing
  description: >-
    Counselling for a recessive condition with a 25 percent sibling recurrence risk, and
    confirmatory testing of at-risk siblings. In the founding series a sibling pair was
    identified in the same family, and in the 2025 report the proband's affected sibling
    had the same phenotype and severity, so the sibling recurrence is not theoretical.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:41130944
    reference_title: "Biallelic MINAR2 variant is associated with nonsyndromic severe to profound sensorineural hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a patient with bilateral, nonsyndromic severe to profound hearing loss, along with a family history of a sibling presenting with the same phenotype and disease severity."
    explanation: An affected sibling in the most recent family, the recurrence counselling is about.
  - reference: PMID:41130944
    reference_title: "Biallelic MINAR2 variant is associated with nonsyndromic severe to profound sensorineural hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The parents were carriers of the same variant."
    explanation: Confirmed carrier status in both parents, which is what makes the recurrence risk quantifiable.
  notes: >-
    No DFNB120-specific report of hearing amplification or of speech-language
    rehabilitation was found, so neither is curated. Cochlear implantation is curated
    separately below, because it is reported.
- name: Cochlear Implantation
  description: >-
    The intervention actually used in this disorder. Three molecularly confirmed
    individuals from the founding Turkish family received unilateral cochlear implants,
    and in all three oral communication was the reported outcome.

    The ages are the informative part. Two siblings whose hearing was milder in early
    childhood and reached severe or profound by about age 10 were implanted at 12 and 10;
    their younger brother, who failed the newborn hearing screen and was profound from the
    start, was implanted at 1. So implantation timing in DFNB120 tracks the individual
    course rather than the diagnosis, and the progressive minority reach candidacy years
    later than the congenitally profound majority.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: cochlear implantation
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:35727972
    reference_title: "Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These siblings received unilateral cochlear implants at ages 12 and 10, respectively, which improved their oral communication."
    explanation: >-
      Implantation and its functional outcome in the two siblings with the progressive
      course.
  - reference: PMID:35727972
    reference_title: "Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He received a unilateral cochlear implant at age 1 and communicates orally."
    explanation: >-
      Implantation in infancy in their brother, who was profound from birth. Together the
      two items show the same family spanning an eleven-year range in age at implantation.
  notes: >-
    treatment_term is bound to NCIT:C15329 Surgical Procedure. NCIT's cochlear implant
    concepts are device terms and are not reachable from NCIT:C25218 Clinical Intervention
    or Procedure, so they fail TreatmentActionTerm validation; the accurate broader action
    term is used rather than a forced narrower binding. therapeutic_modality is DEVICE
    rather than SURGERY because the therapeutic platform is the implant, with surgery as
    the route of delivery.

    Outcomes are reported as improved or maintained oral communication, without audiometric
    or speech-perception scores, so this entry claims no more than that.
animal_models:
- name: Minar2 tm1b null mouse
  species: Mouse
  genotype: Minar2 tm1b/tm1b, homozygous null
  publication: PMID:35727972
  description: >-
    The mammalian model, produced by the knockout-mouse phenotyping pipeline and
    characterised alongside the human families. Homozygotes have raised auditory brainstem
    response and distortion product otoacoustic emission thresholds from postnatal day 14,
    two days after hearing normally begins, and by four weeks show severe elevation or no
    response. The structural correlate is depletion of the shortest row of outer hair cell
    stereocilia; ribbon synapse numbers and organ of Corti organisation are normal at the
    age when thresholds are already abnormal.
  genes:
  - preferred_term: MINAR2
    term:
      id: hgnc:33914
      label: MINAR2
  modeled_mechanisms:
  - target: Depletion of the Shortest Row of Outer Hair Cell Stereocilia
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      This is the model in which the mammalian lesion is defined. Cochlear stereocilia
      cannot be examined in living patients, so the mouse is not merely corroborating the
      human phenotype - it is the only place the structural mechanism has been observed at
      all.
    limitations: >-
      A complete null, whereas human alleles are nonsense, frameshift and spliceogenic;
      those are predicted null but the prediction rests on transcript consequence rather
      than on measured protein. Onset also differs in kind: mouse thresholds are already
      raised two days after hearing onset and then worsen rapidly, whereas most human
      patients are congenitally profound with only a minority showing progression. The
      mouse therefore models a rapidly progressive course that most patients do not have.
    readouts:
    - name: Outer hair cell shortest-row stereocilia number and length
      target: Depletion of the Shortest Row of Outer Hair Cell Stereocilia
      direction: DECREASED
      interpretation: >-
        Row-selective loss: the shortest row is depleted and shortened while inner hair
        cells are close to normal.
      evidence:
      - reference: PMID:35727972
        reference_title: "Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "However, when we examined the stereocilia bundles of outer hair cells, we saw the shortest row was depleted, with reduced numbers and abnormally short stereocilia"
        explanation: The scanning electron microscopy measurement behind this readout.
    - name: Inner hair cell ribbon synapse count
      target: Depletion of the Shortest Row of Outer Hair Cell Stereocilia
      direction: UNCHANGED
      interpretation: >-
        A real negative result, and the one that makes the stereocilia lesion primary:
        synapse numbers are normal at the age when thresholds are already raised.
      evidence:
      - reference: PMID:35727972
        reference_title: "Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "the number of synapses per inner hair cell in homozygous mutants was not significantly different from numbers in heterozygotes or wild-type controls at P14"
        explanation: The synapse count that excludes synaptopathy as the early mechanism.
    evidence:
    - reference: PMID:35727972
      reference_title: "Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We further showed that homozygous Minar2tm1b mutant mice develop rapidly progressive HL associated with changes in outer hair cell stereocilia."
      explanation: The model's central auditory conclusion, which is the node it supports.
  - target: Impaired Hair Cell Mechanotransduction
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The mouse shows hair cells that are present, take up transduction-channel dye, and
      still fail to transduce, which is the functional claim of this node.
    limitations: >-
      Mechanotransduction is inferred from threshold measurements and dye uptake rather
      than measured directly by transduction current recording, so the claim is functional
      rather than biophysical.
    readouts:
    - name: Distortion product otoacoustic emission threshold
      target: Impaired Hair Cell Mechanotransduction
      direction: INCREASED
      interpretation: >-
        Thresholds rise, so the direction is INCREASED even though the underlying function
        falls: outer hair cell function is already impaired at two weeks and largely gone
        by four, the mouse counterpart of the absent emissions in patients.
      evidence:
      - reference: PMID:35727972
        reference_title: "Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Otoacoustic emissions can be detected in the mutant mice but at raised thresholds at 2 wk old, and these responses are mostly absent by 4 wk old, implicating outer hair cells in the pathology."
        explanation: The emission time course in the null.
    evidence:
    - reference: PMID:35727972
      reference_title: "Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Thresholds for both ABRs and DPOAEs were raised in homozygous mutants compared with wild-type littermates from the earliest age studied, postnatal day (P) 14, only 2 d after the usual onset of hearing"
      explanation: >-
        Establishes that the functional deficit is present essentially from hearing onset,
        which is what makes it comparable to a congenital human phenotype.
  evidence:
  - reference: PMID:35727972
    reference_title: "Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In conclusion, audiological findings both in humans and mice show that loss of MINAR2 function results in early-onset and sensorineural HL that rapidly progresses to severe to profound deafness."
    explanation: The authors' joint human and mouse conclusion, which is the basis for treating the mouse as informative.
- name: minar2 frameshift zebrafish
  species: Zebrafish
  genotype: kiaa1024L/minar2 fs139 and fs140 frameshift, homozygous
  publication: PMID:36317962
  description: >-
    Two frameshift alleles of the zebrafish orthologue. Mutant larvae have reduced auditory
    evoked potentials, reduced mechanotransduction dye labelling, longer and thinner hair
    bundles, disorganised lateral line kinocilia, and enlarged aggregated lysosomes in the
    apical region of hair cells. This is the system in which the cholesterol mechanism was
    established, including the pharmacological rescue.
  genes:
  - preferred_term: MINAR2
    term:
      id: hgnc:33914
      label: MINAR2
  modeled_mechanisms:
  - target: Loss of Cholesterol Delivery to the Hair Bundle
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The only system in which the proposed molecular function of MINAR2 has been tested.
      Bundle cholesterol was measured with a genetically encoded sensor, and the causal
      role established by moving cholesterol in both directions pharmacologically.
    limitations: >-
      Zebrafish, and the correspondence to the mammalian phenotype is imperfect in a way
      the authors state: hearing loss in the mutant larvae is not as severe as in the adult
      knockout mouse. The bundle phenotype also differs in direction - fish bundles are
      longer and thinner, mouse stereocilia are shorter and fewer - so whether the two
      species are showing the same lesion is not established. No cholesterol measurement
      exists in any mammalian Minar2 hair bundle.
    readouts:
    - name: Hair bundle cholesterol reporter intensity
      target: Loss of Cholesterol Delivery to the Hair Bundle
      direction: DECREASED
      interpretation: >-
        Cholesterol available in inner ear stereocilia falls to roughly half of wild type,
        with transgene expression confirmed unchanged.
      evidence:
      - reference: PMID:36317962
        reference_title: "Kiaa1024L/Minar2 is essential for hearing by regulating cholesterol distribution in hair bundles."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "The results showed the average D4H-mCherry signals of inner ear stereocilia in the minar2fs139 larvae were about half of those in the wild controls"
        explanation: The quantified sensor measurement in mutant stereocilia.
      - reference: PMID:36317962
        reference_title: "Kiaa1024L/Minar2 is essential for hearing by regulating cholesterol distribution in hair bundles."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "The decreases were not due to changes in transgene expression either"
        explanation: >-
          The control that makes the measurement interpretable: less signal means less
          accessible cholesterol, not less reporter.
    - name: Mechanotransduction dye labelling after cholesterol restoration
      target: Loss of Cholesterol Delivery to the Hair Bundle
      direction: RESTORED
      interpretation: >-
        Raising cholesterol pharmacologically restores both transduction labelling and
        hearing, which is what makes the cholesterol deficit causal rather than incidental.
      evidence:
      - reference: PMID:36317962
        reference_title: "Kiaa1024L/Minar2 is essential for hearing by regulating cholesterol distribution in hair bundles."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Thus, both the mechanotransduction (AM1-43 staining) and the hearing were restored after the decreased cholesterol levels were restored by the treatment with efavirenz."
        explanation: The rescue result, with the specific drug and the two readouts it restored.
    evidence:
    - reference: PMID:36317962
      reference_title: "Kiaa1024L/Minar2 is essential for hearing by regulating cholesterol distribution in hair bundles."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Therefore, cholesterol plays an essential role in hair bundles, and Kiaa1024L/Minar2 regulates cholesterol distribution and homeostasis to ensure normal hearing."
      explanation: The study's central conclusion, which is the mechanism this node curates.
  - target: Impaired Hair Cell Mechanotransduction
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Transduction is impaired out of proportion to hair cell loss, which is the specific
      claim this node makes.
    limitations: >-
      Larval lateral line and inner ear hair cells, not cochlear outer hair cells; zebrafish
      have no cochlea and no outer hair cell electromotility, so the mechanism is being
      modelled in a cell type that lacks the mammalian amplifier.
    readouts:
    - name: AM1-43 mechanotransduction labelling
      target: Impaired Hair Cell Mechanotransduction
      direction: DECREASED
      interpretation: >-
        Roughly half the wild-type labelling against roughly a fifth fewer hair cells, so
        the deficit is functional rather than a count.
      evidence:
      - reference: PMID:36317962
        reference_title: "Kiaa1024L/Minar2 is essential for hearing by regulating cholesterol distribution in hair bundles."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Because the decreases in hair cell numbers (~18% reduction) are smaller than those reductions of AM1-43 labeling intensities (~50% reduction), these results suggest that loss of minar2 function mainly affects hair cell mechanotransduction in the zebrafish larvae."
        explanation: The quantitative comparison that separates transduction failure from cell loss.
    evidence:
    - reference: PMID:36317962
      reference_title: "Kiaa1024L/Minar2 is essential for hearing by regulating cholesterol distribution in hair bundles."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We conclude that minar2 is required for mechanotransduction in the zebrafish larvae, and loss of minar2 reduces the number of inner ear hair cells in the zebrafish adults."
      explanation: The authors' conclusion for this node, including the adult cell-loss component.
- name: Minar2 knockout mouse metabolic and motor phenotype
  species: Mouse
  genotype: Minar2 knockout, homozygous, exon 2 replaced by lacZ
  publication: PMID:37245847
  description: >-
    The same null line examined outside the ear. Knockouts have three-fold higher adipose
    mass on a chow diet, hypertrophic adipocytes, accelerated weight gain and impaired
    glucose tolerance on a high-fat diet, all without increased food intake, driven by
    mTORC1 derepression through loss of Minar2 binding to Raptor. A separate study on a
    knockout of the same gene reported rigidity, bradykinesia, gait abnormalities and loss
    of tyrosine hydroxylase positive neurons in the substantia nigra pars compacta with
    raised alpha-synuclein.
  genes:
  - preferred_term: MINAR2
    term:
      id: hgnc:33914
      label: MINAR2
  modeled_mechanisms:
  - target: Derepression of NOTCH2 and mTORC1 Signalling
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Establishes in vivo that losing Minar2 derepresses mTORC1, and identifies the
      molecular route through Raptor binding. That is exactly the node, and the model
      supports it well.
    limitations: >-
      The tissue is adipose, not cochlea, and the phenotypes measured are metabolic. The
      model says nothing about whether mTORC1 derepression occurs in hair cells or
      contributes to deafness, which is why this entry draws no edge from that node into
      the auditory phenotypes.
    readouts:
    - name: mTOR Ser2448 phosphorylation in adipocytes
      target: Derepression of NOTCH2 and mTORC1 Signalling
      direction: INCREASED
      interpretation: Loss of Minar2 raises mTOR activating phosphorylation in vivo.
      evidence:
      - reference: PMID:37245847
        reference_title: "Inactivation of Minar2 in mice hyperactivates mTOR signaling and results in obesity."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Our results showed a significant increase in Ser2448 phosphorylation of mTOR in Minar2 KO adipocytes"
        explanation: The direct measurement of mTOR activation in knockout tissue.
    evidence:
    - reference: PMID:37245847
      reference_title: "Inactivation of Minar2 in mice hyperactivates mTOR signaling and results in obesity."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Our findings identified Minar2 as a novel physiological negative regulator of mTORC1 with a key role in obesity and metabolic disorders."
      explanation: The study conclusion establishing Minar2 as an mTORC1 restraint in vivo.
  evidence:
  - reference: PMID:37245847
    reference_title: "Inactivation of Minar2 in mice hyperactivates mTOR signaling and results in obesity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Minar2 KO mice on a high-fat diet develop obesity and impaired glucose tolerance and metabolism."
    explanation: >-
      The extra-auditory phenotype itself, curated because its absence in human patients is
      a substantive mismatch rather than a footnote.
  - reference: PMID:32954300
    reference_title: "Loss of MINAR2 impairs motor function and causes Parkinson's disease-like symptoms in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Analysis of the major intrinsically disordered NOTCH2-associated receptor 2 knockout mice brain revealed significant anomalies in neuronal function and appearance including the loss of tyrosine hydroxylase-positive neurons in the pars compacta, which was accompanied by an up-regulation in α-synuclein protein expression."
    explanation: >-
      The second extra-auditory mouse phenotype, with a neuropathological correlate rather
      than only a behavioural one.
discussions:
- discussion_id: minar2_syndromic_mouse_nonsyndromic_human
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Minar2 knockout mice are obese, glucose intolerant and parkinsonian; humans with
    biallelic MINAR2 loss examined between 4 and 80 years of age have isolated deafness.
    Is DFNB120 genuinely nonsyndromic, or are metabolic and motor phenotypes present and
    simply not looked for in a cohort ascertained through an audiology clinic?
  attaches_to:
  - pathophysiology#Derepression of NOTCH2 and mTORC1 Signalling
  - animal_models#Minar2 knockout mouse metabolic and motor phenotype
  rationale: >-
    The mismatch is stark and it runs in the direction that is easiest to miss. Two
    independent mouse studies of Minar2 nulls report substantial extra-auditory disease,
    one metabolic and one neurodegenerative with nigral cell loss. The human series
    explicitly examined affected individuals neurologically across a wide age range and
    found nothing additional, and bedside vestibular testing was normal. Taken at face
    value this says the mouse over-reports, which would be a species difference in what
    mTORC1 restraint by MINAR2 actually controls.

    But the human ascertainment is not neutral. These families were found by sequencing
    for deafness. Obesity and impaired glucose tolerance are common enough in the general
    population that a handful of affected individuals could carry them without anyone
    connecting the two, and the neurological evaluation reported is a clinical
    examination rather than dopaminergic imaging or structured metabolic phenotyping. The
    oldest reported patient is 80, which does argue against a strongly penetrant
    parkinsonian phenotype, but eight decades of a normal neurological examination is not
    the same measurement as a substantia nigra count.

    What follows practically is that MINAR2 should not yet be described to families as
    causing isolated deafness with the confidence that phrase usually implies. Body mass
    index, fasting glucose and a structured motor assessment in the known cohort would
    settle it cheaply, and would also decide whether the mTORC1 node in this entry belongs
    to the disease or only to the mouse.
  evidence:
  - reference: PMID:35727972
    reference_title: "Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurologic evaluation of affected individuals at ages ranging from 4 to 80 y old does not show additional abnormalities."
    explanation: The human side of the mismatch, with its age range.
  - reference: PMID:35727972
    reference_title: "Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "None of the affected individuals showed impaired balance on tandem walking and Romberg test."
    explanation: >-
      Normal bedside vestibular and balance testing, which also distinguishes DFNB120 from
      the recessive deafness genes that carry vestibular involvement.
  - reference: PMID:37245847
    reference_title: "Inactivation of Minar2 in mice hyperactivates mTOR signaling and results in obesity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Minar2 KO mice on a high-fat diet develop obesity and impaired glucose tolerance and metabolism."
    explanation: The metabolic phenotype absent from the human description.
  - reference: PMID:32954300
    reference_title: "Loss of MINAR2 impairs motor function and causes Parkinson's disease-like symptoms in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We generated major intrinsically disordered NOTCH2-associated receptor 2 knockout mouse and demonstrated that the loss of major intrinsically disordered NOTCH2-associated receptor 2 in mouse results in severe motor deficits such as rigidity and bradykinesia, gait abnormalities, reduced spontaneous locomotor and exploratory behaviour, symptoms that are highly similar to those observed in human Parkinson's spectrum disorders."
    explanation: The motor phenotype absent from the human description.
  - reference: DOI:10.1073/pnas.2211351119
    reference_title: "Emerging complexities of the mouse as a model for human hearing loss"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "These motor deficits were not present in even the oldest humans with comparably severe mutations inMINAR2."
    explanation: >-
      An independent commentary drawing the same mismatch, and specifically addressing the
      objection that the humans might simply be too young. Evidence source is OTHER because
      this is a commentary rather than a study. The quote reproduces the cached text
      exactly, including the missing space before the gene symbol.
  - reference: DOI:10.1073/pnas.2211351119
    reference_title: "Emerging complexities of the mouse as a model for human hearing loss"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "For eight genes, includingMINAR2, both species have hearing loss, but the mutant mouse demonstrates additional syndromic features not found in humans."
    explanation: >-
      Puts this mismatch in context rather than treating it as a one-off. MINAR2 is one of
      eight genes where the mouse is syndromic and the human is not, which makes the
      pattern a known property of mouse deafness models and weakens the reading that
      something specific to MINAR2 is going on.
  proposed_experiments:
  - experiment_id: exp_dfnb120_systemic_phenotyping_of_known_cohort
    name: Metabolic and motor phenotyping of the known MINAR2 cohort
    description: >-
      Recall the reported MINAR2-biallelic individuals for body mass index, fasting
      glucose and oral glucose tolerance, and a structured motor examination with
      dopaminergic imaging in the older participants, compared against heterozygous
      relatives from the same families. Heterozygous relatives are the right comparator
      because they share household and ancestry while carrying one functional allele.
    would_support:
    - pathophysiology#Derepression of NOTCH2 and mTORC1 Signalling
    supporting_outcome:
    - >-
      Affected individuals show higher body mass index, impaired glucose handling, or
      subclinical motor findings relative to heterozygous relatives, which would make the
      mTORC1 node part of the human disease and reclassify DFNB120 as oligosymptomatic
      rather than nonsyndromic.
    would_refute:
    - pathophysiology#Derepression of NOTCH2 and mTORC1 Signalling
    refuting_outcome:
    - >-
      Affected individuals are metabolically and neurologically indistinguishable from
      heterozygous relatives, which would confine the mTORC1 and NOTCH2 arm to the mouse
      and support removing it from the human pathograph.
- discussion_id: minar2_cholesterol_mechanism_species_gap
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does the cholesterol-delivery mechanism established in zebrafish operate in the
    mammalian cochlea, and is the mouse shortest-row stereocilia lesion the same defect
    seen through a different species?
  attaches_to:
  - pathophysiology#Loss of Cholesterol Delivery to the Hair Bundle
  - pathophysiology#Depletion of the Shortest Row of Outer Hair Cell Stereocilia
  rationale: >-
    These two nodes are the whole mechanistic content of DFNB120 and they come from
    different animals, with no experiment joining them. The fish work explains what MINAR2
    does at a molecular level and the mouse work shows what breaks in a mammalian cochlea,
    and the tempting move is to assume the second is caused by the first.

    There is a specific reason to hold back. The two structural phenotypes point in
    opposite directions: fish hair bundles are longer and thinner while mouse stereocilia
    in the affected row are shorter and fewer. A membrane lipid defect could plausibly
    produce either, but a mechanism that produces both in the same way needs to be
    demonstrated, not asserted. There is also no zebrafish equivalent of row identity,
    since fish hair bundles are not organised into the mammalian graded staircase of
    outer hair cells, so the most distinctive feature of the mouse lesion has no
    counterpart in the system where the mechanism was worked out.

    The measurement that would close this is a direct one: cholesterol in mouse cochlear
    hair bundles, wild type against Minar2 null, with the shortest row resolved. If bundle
    cholesterol is reduced and the reduction is greatest where stereocilia are lost, the
    two literatures become one mechanism. If it is not, DFNB120 has two candidate
    mechanisms rather than one, and this entry should be split accordingly.
  evidence:
  - reference: PMID:36317962
    reference_title: "Kiaa1024L/Minar2 is essential for hearing by regulating cholesterol distribution in hair bundles."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Consistent with this model, loss of minar2 markedly reduces cholesterol distribution in the hair bundles, causes longer and thinner hair bundles, and gives rise to enlarged and aggregated apical lysosomes."
    explanation: >-
      The fish structural phenotype, longer and thinner, stated alongside the cholesterol
      deficit.
  - reference: PMID:35727972
    reference_title: "Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "However, when we examined the stereocilia bundles of outer hair cells, we saw the shortest row was depleted, with reduced numbers and abnormally short stereocilia"
    explanation: >-
      The mouse structural phenotype, shorter and fewer, which is the opposite direction
      and the reason the two are not yet one mechanism.
  - reference: PMID:36317962
    reference_title: "Kiaa1024L/Minar2 is essential for hearing by regulating cholesterol distribution in hair bundles."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The degree of hearing loss in mutant minar2fs139 zebrafish larvae is not as severe as it was in the adult knockout mouse."
    explanation: >-
      Supports this knowledge gap: the authors' own statement of the severity gap between
      the two models is a further reason not to treat the fish result as directly
      transferable to the mouse lesion.
📚

References & Deep Research

Deep Research

1

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

Evaluations and curation notes (1)

Create: Hearing Loss Autosomal Recessive 120 (DFNB120, MINAR2) · 2026-08-28T19:01:47Z · View source

De novo curation of DFNB120 (MONDO:0859374, MINAR2 hgnc:33914) from the stub queue. entry_type decided as DISEASE: one causal gene, no MONDO descendants, one pathograph from biallelic MINAR2 loss to impaired hair cell mechanotransduction. Nothing in kb/ previously mentioned MINAR2. The evidence base is genuinely thin, so the entry is built to show where its own claims come from. Two mechanisms have been proposed in two different species and no experiment joins them: the mouse null gives a mammalian structural lesion (shortest row of outer hair cell stereocilia depleted, ribbon synapses and organ of Corti normal at the age thresholds are already raised), and the zebrafish mutant gives the molecular function (Minar2 on apical lysosomes delivering cholesterol to the hair bundle membrane, with bidirectional pharmacological rescue). They are curated as separate nodes with a KNOWLEDGE_GAP discussion recording that the two structural phenotypes point in opposite directions - fish bundles longer and thinner, mouse stereocilia shorter and fewer - so the tempting synthesis is not yet earned. The NOTCH2/mTORC1 arm is curated as a pathophysiology node that is deliberately drawn with no edge into the hearing phenotypes, because no experiment connects it to any cochlear phenotype in any species and the founding authors put it no more strongly than that Notch signalling might play a role. A HUMAN_MODEL_MISMATCH discussion carries the corresponding translational problem: Minar2 knockout mice are obese, glucose intolerant and parkinsonian, while affected humans examined between 4 and 80 years of age had isolated deafness and normal bedside balance testing. The discussion states both readings - a real species difference, or ascertainment through an audiology clinic - and proposes recall phenotyping against heterozygous relatives. Evidence: 5 references cited, all fetched with just fetch-reference; 59/59 snippets verified against the local cache. Two readouts are recorded as UNCHANGED because they are real negative results (ribbon synapse counts in the mouse). No treatment other than genetic counselling is curated: cochlear implantation is standard for congenital severe-to-profound loss but no DFNB120-specific report documents it, and the treatment notes say so explicitly rather than importing general practice. Deep research: falcon report run and preflighted against MONDO:0859374, verdict PASS (MINAR2=30 mentions, next gene at 4; OMIM 620238 matched on both sides). Entry curated from primary sources regardless. Validation: just validate exit 0, just validate-terms exit 0, just validate-disorders exit 0, just check-entity-refs exit 0, just check-duplicate-keys exit 0, and check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading, check-environmental-evidence all exit 0.

Falcon ▸
Hearing Loss, Autosomal Recessive 120 (DFNB120): Research Report
Edison Scientific Literature 11 citations 2026-08-28T11:36:52.292348

Hearing Loss, Autosomal Recessive 120 (DFNB120): Research Report

Executive summary and evidence limits

Hearing loss, autosomal recessive 120 (DFNB120) is an ultra-rare Mendelian, nonsyndromic sensorineural hearing-loss disorder caused by biallelic pathogenic variants in MINAR2. The foundational 2022 study reported 13 affected people from four unrelated families; nine had congenital and four had prelingual severe-to-profound hearing loss, with progression documented in four. A 2025 report added an independently ascertained consanguineous family with two clinically affected brothers and a homozygous nonsense allele in the tested proband. Thus, the published human phenotype remains based on approximately 15 clinically affected individuals from five families, not a population cohort. (almontashiri2025biallelicminar2variant pages 1-2, almontashiri2025biallelicminar2variant pages 2-3)

The strongest mechanistic evidence is from knockout mouse and zebrafish experiments. MINAR2 loss disrupts cholesterol localization in sensory-hair-cell stereocilia, alters hair-bundle morphology and mechanotransduction, and ultimately causes hair-cell loss and progressive sensorineural hearing loss. Direct biochemical binding of MINAR2 to cholesterol remains proposed rather than definitively demonstrated. (gao2022kiaa1024lminar2isessential pages 1-2, gao2022kiaa1024lminar2isessential pages 17-18)

No DFNB120-specific interventional trial, approved molecular therapy, prevalence estimate, prospective natural-history cohort, or validated prognostic biomarker was identified. No disease-specific human paper from 2023–2024 was recovered; the principal 2024 development was recognition of MINAR2/DFNB120 in a review of genetically modified hearing-loss models. (wang2024geneticallymodifiedpigs pages 1-2)

DFNB120 evidence summary Key finding Evidence type Citation
Identifiers / synonyms Hearing loss, autosomal recessive 120; autosomal recessive deafness-120; DFNB120; OMIM 620238; MONDO:0859374 Disease-level curated + primary human report (OpenTargets Search: Hearing loss autosomal recessive 120, almontashiri2025biallelicminar2variant pages 1-2)
Causal gene MINAR2 (membrane integral NOTCH2-associated receptor 2) is the established causal gene Human genetic + curated association (OpenTargets Search: Hearing loss autosomal recessive 120, carlson2022emergingcomplexitiesof pages 1-2, almontashiri2025biallelicminar2variant pages 1-2)
Inheritance Autosomal recessive; biallelic loss-of-function/missense-splice-disrupting variants segregate with disease Human family data (carlson2022emergingcomplexitiesof pages 1-2, almontashiri2025biallelicminar2variant pages 1-2, almontashiri2025biallelicminar2variant pages 2-3)
Known human cohort Original report: 13 patients from 4 unrelated families (2022); independent confirmation: 2 clinically affected siblings (2025) Human clinical genetics (almontashiri2025biallelicminar2variant pages 1-2, carlson2022emergingcomplexitiesof pages 1-2)
Core phenotype Bilateral severe-to-profound nonsyndromic sensorineural hearing loss; original cohort included 9 congenital and 4 prelingual cases Human clinical (almontashiri2025biallelicminar2variant pages 1-2)
Progression Progressive SNHL reported in 4/13 patients in the original cohort; model data also support progressive hearing loss Human + model (almontashiri2025biallelicminar2variant pages 1-2, gao2022kiaa1024lminar2isessential pages 17-18)
Newest reported variant NM_001257308.2:c.319A>T; p.Lys107*, homozygous nonsense, predicted loss-of-function via nonsense-mediated decay; parents heterozygous; classified likely pathogenic Human molecular genetics (almontashiri2025biallelicminar2variant pages 2-3, almontashiri2025biallelicminar2variant pages 1-2)
Population frequency p.Lys107* observed as 2/767,859 heterozygotes in gnomAD v4.1; no homozygotes reported in the cited report Human population genetics (almontashiri2025biallelicminar2variant pages 2-3, almontashiri2025biallelicminar2variant pages 1-2)
Mechanism MINAR2 regulates cholesterol distribution/homeostasis in hair bundles; loss reduces stereociliary cholesterol, impairs mechanotransduction, and is associated with longer/thinner bundles and enlarged apical lysosomes Model/mechanistic (gao2022kiaa1024lminar2isessential pages 1-2, gao2022kiaa1024lminar2isessential pages 17-18)
Models Mouse: loss of Minar2 causes degeneration of hair cells and progressive SNHL; zebrafish: hearing loss with mechanotransduction defects and progressive reduction of inner-ear hair cells (to ~30% in adults) Model organism (gao2022kiaa1024lminar2isessential pages 1-2, gao2022kiaa1024lminar2isessential pages 17-18)
Diagnostics used Trio whole-exome sequencing with average 30× depth, variant calling including SNV/CNV pipelines, and Sanger confirmation in the 2025 family; phenotype-driven interpretation under ACMG/ClinGen guidance Human diagnostic evidence (almontashiri2025biallelicminar2variant pages 1-2, almontashiri2025biallelicminar2variant pages 2-3)
Treatments / trials No DFNB120-specific approved molecular therapy identified in cited evidence; no disease-specific trials found in the tool search; current care is inferred from general severe-profound SNHL management rather than disease-specific studies Evidence gap / clinical practice extrapolation (wang2024geneticallymodifiedpigs pages 1-2)
Epidemiology Disease-specific prevalence/incidence are not available; currently documented human evidence is limited to 4 families/13 patients in 2022 plus 1 additional family with 2 affected siblings in 2025 Human evidence summary (almontashiri2025biallelicminar2variant pages 1-2)
Key evidence gaps Missing/limited: robust prevalence, penetrance, founder effects, standardized natural history, genotype-phenotype correlations, long-term outcomes, and disease-specific therapeutic studies Evidence gap (almontashiri2025biallelicminar2variant pages 1-2, wang2024geneticallymodifiedpigs pages 1-2, carlson2022emergingcomplexitiesof pages 1-2)

Table: This table condenses the core human, molecular, and model-organism evidence for hearing loss autosomal recessive 120 (DFNB120). It highlights what is established versus what remains unknown, which is useful for rapid knowledge-base population.

1. Disease information

Definition

DFNB120 is a bilateral, usually congenital or prelingual, severe-to-profound nonsyndromic sensorineural hearing loss (SNHL) inherited in an autosomal-recessive manner. “Nonsyndromic” currently means that the reported human patients lacked consistent neurologic, visual, growth, dysmorphic, or systemic abnormalities; it does not exclude subtle manifestations that could emerge through longer surveillance. (carlson2022emergingcomplexitiesof pages 1-2, almontashiri2025biallelicminar2variant pages 1-2)

Identifiers and synonyms

  • MONDO: MONDO:0859374
  • OMIM phenotype: 620238
  • Preferred/synonymous names: hearing loss, autosomal recessive 120; deafness, autosomal recessive 120; autosomal recessive deafness-120; DFNB120; MINAR2-related nonsyndromic sensorineural hearing loss.
  • Causal target: MINAR2, Ensembl ENSG00000186367, approved name membrane integral NOTCH2 associated receptor 2. Open Targets associates both MINAR2 and OBSCN with this MONDO entry, but the disease-defining human segregation and functional evidence supports MINAR2; the lower-scoring OBSCN association should not be treated as an established second DFNB120 cause without independent disease-specific validation. (OpenTargets Search: Hearing loss autosomal recessive 120)
  • ICD-10/ICD-11 and MeSH: no gene-specific DFNB120 code was found. Use broader congenital/hereditary or sensorineural hearing-loss coding, with the molecular diagnosis represented separately.
  • Orphanet: no disease-specific Orpha code was established from the retrieved evidence.

The report is synthesized from aggregated disease resources plus published family-level research, not individual EHR records. The 2022 and 2025 papers contain patient-level pedigree and clinical data, while MONDO/Open Targets supply aggregated disease-level mappings. (OpenTargets Search: Hearing loss autosomal recessive 120, almontashiri2025biallelicminar2variant pages 1-2)

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

The primary cause is germline biallelic MINAR2 dysfunction. Reported disease alleles include loss-of-function variants and a missense change shown to disrupt a donor splice site; they segregated with recessive hearing loss. The causal model is therefore deficient functional MINAR2 rather than infection, autoimmunity, trauma, or a recognized environmental exposure. (carlson2022emergingcomplexitiesof pages 1-2, almontashiri2025biallelicminar2variant pages 1-2)

The principal risk factors are:

  1. Two pathogenic/likely pathogenic MINAR2 alleles in trans or homozygously.
  2. An affected sibling or known carrier parents.
  3. Consanguinity, which increases the chance that both parents carry the same rare allele; the 2025 parents were first cousins. (almontashiri2025biallelicminar2variant pages 1-2, almontashiri2025biallelicminar2variant pages 2-3)

No sex-specific susceptibility, modifier gene, protective human allele, founder effect, or environmental protective factor has been demonstrated. Noise, ototoxic drugs, infection, and aging can independently worsen hearing in any person, but no DFNB120-specific interaction has been quantified. Experimental zebrafish data suggest a biologically plausible cholesterol interaction: lowering cholesterol worsened, whereas experimentally increasing it rescued hair-cell defects. This is model-organism evidence and not a recommendation for dietary, statin, or cholesterol supplementation therapy in humans. (gao2022kiaa1024lminar2isessential pages 1-2)

3. Phenotypes

Core phenotype

  • Bilateral sensorineural hearing loss — clinical sign/functional deficit; suggested HPO HP:0000407.
  • Congenital hearing impairment — onset descriptor; HP:0008527.
  • Prelingual hearing loss — suggested HPO HP:0012715.
  • Severe hearing impairment — HP:0012714.
  • Profound hearing impairment — HP:0012717.
  • Progressive hearing impairment, where documented — HP:0001730.
  • Nonsyndromic phenotype: absence of a reproducible extra-auditory syndrome is a disease characterization, not a positive HPO phenotype.

In the original 13 patients, onset was congenital in 9/13 (69%) and prelingual in 4/13 (31%); all had severe-to-profound SNHL, while progression was reported in 4/13 (31%). Ages ranged from 4 to 80 years, and none had neurologic features. (almontashiri2025biallelicminar2variant pages 1-2)

The 2025 proband was a 10-year-old boy with congenital bilateral severe-to-profound SNHL; his 20-year-old brother had the same clinical phenotype. Both had age-appropriate cognition/neurodevelopment, normal growth, no dysmorphism, and unremarkable systemic examinations; the proband had no seizures or visual abnormality. (almontashiri2025biallelicminar2variant pages 1-2)

Quality of life: no DFNB120-specific EQ-5D, SF-36, PROMIS, speech-perception, educational, or employment data exist. Severe/profound early hearing loss is expected to affect auditory communication and language access without timely intervention, but that inference should not be stored as a measured DFNB120 outcome. A 2024 review notes that hereditary hearing loss broadly affects communication, cognition, education, and employment and cites a global annual economic burden of approximately US$980 billion for hearing loss overall—not DFNB120. (wang2024geneticallymodifiedpigs pages 1-2)

4. Genetic and molecular information

Gene and alleles

  • Gene: MINAR2; older experimental name KIAA1024L.
  • Protein: membrane integral NOTCH2-associated receptor 2.
  • Inheritance/origin: constitutional germline, autosomal recessive; no somatic disease mechanism is implicated.
  • Likely molecular effect: loss of function through nonsense-mediated decay, frameshift/truncation, or splice disruption.

The original families carried multiple biallelic variants: two families shared a homozygous missense allele within the NOTCH receptor intracellular domain that disrupted donor splicing; the other families carried a nonsense allele in that domain and a frameshift affecting the transmembrane domain. Exact HGVS strings for these original alleles were not recoverable from the available full text and should be imported directly from the foundational paper/ClinVar rather than reconstructed. (almontashiri2025biallelicminar2variant pages 1-2)

The independently reported 2025 allele was NM_001257308.2:c.319A>T; p.(Lys107*), a homozygous exon-2 nonsense variant predicted to trigger nonsense-mediated decay. The proband was homozygous, both parents were heterozygous, and Sanger sequencing confirmed the finding. It was classified likely pathogenic under ACMG/AMP criteria PVS1 + PM2. The affected brother was not genetically tested, so his genotype is inferred from phenotype and pedigree rather than confirmed. (almontashiri2025biallelicminar2variant pages 1-2, almontashiri2025biallelicminar2variant pages 2-3)

In gnomAD v4.1, c.319A>T was observed heterozygously in 2/767,859 individuals (reported minor-allele frequency approximately 0.0001%) and not homozygously. This is allele-specific evidence, not an estimate of DFNB120 carrier frequency. (almontashiri2025biallelicminar2variant pages 2-3, almontashiri2025biallelicminar2variant pages 1-2)

No validated modifier genes, disease-specific methylation signature, chromatin abnormality, recurrent copy-number variant, translocation, inversion, or aneuploidy has been reported. Large deletions involving MINAR2 remain diagnostically possible in principle and require CNV-sensitive analysis.

5. Environmental, lifestyle, and infectious information

DFNB120 is not known to be caused by toxins, radiation, pollution, diet, smoking, alcohol, occupation, or infection. These exposures remain alternative or additive causes of hearing loss rather than established causes of the Mendelian disorder. There is no evidence of zoonotic transmission or communicability. Because hair-bundle cholesterol homeostasis is implicated experimentally, systemic lipid-modifying exposures deserve research attention, but no human exposure-response data exist. (gao2022kiaa1024lminar2isessential pages 1-2, gao2022kiaa1024lminar2isessential pages 17-18)

6. Mechanism and pathophysiology

Causal chain

Upstream: biallelic MINAR2 loss → deficient MINAR2 at apical endomembranes/lysosomes and stereociliary membranes → impaired localization and homeostasis of accessible cholesterol in the hair bundle. (gao2022kiaa1024lminar2isessential pages 1-2, gao2022kiaa1024lminar2isessential pages 17-18)

Intermediate: reduced stereociliary cholesterol and altered membrane properties/trafficking → longer, thinner, structurally abnormal hair bundles; enlarged apical lysosomes; impaired mechanoelectrical transduction. Reduced accessible cholesterol also induces downstream SREBP2-responsive genes, consistent with compensatory cholesterol-homeostasis signaling. (gao2022kiaa1024lminar2isessential pages 17-18)

Downstream: sensory-hair-cell dysfunction and progressive loss → impaired conversion of acoustic vibration into receptor current → severe/profound SNHL. Adult zebrafish mutants had an approximately 30% reduction in inner-ear hair cells. (gao2022kiaa1024lminar2isessential pages 1-2, gao2022kiaa1024lminar2isessential pages 17-18)

MINAR2 contains a conserved sequence resembling the caveolin cholesterol-binding CSD domain; overexpressed protein recruited cholesterol in vitro, mutation of predicted binding residues abolished recruitment, and AlphaFold-based docking gave plausible binding energy. However, the investigators explicitly stated that further biochemical work is needed to establish direct cholesterol binding and that the precise transport mechanism remains unclear. (gao2022kiaa1024lminar2isessential pages 17-18)

Suggested ontology annotations include:

  • GO biological process: sensory perception of sound (GO:0007605); auditory receptor cell stereocilium organization (GO:0060088); mechanosensory transduction (GO:0009582); cholesterol homeostasis (GO:0042632); cholesterol transport (GO:0030301); lysosome organization (GO:0007040).
  • GO cellular component: stereocilium (GO:0032420); stereocilium membrane (GO:0060171); lysosome (GO:0005764); endoplasmic-reticulum membrane (GO:0005789).
  • Cell Ontology: hair cell (CL:0000202), with cochlear inner and outer hair-cell subclasses where supported.
  • CHEBI: cholesterol (CHEBI:16113).

No disease-specific human transcriptomic, proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, or multi-omics signature has been established. The available expression and SREBP2 results are experimental-model findings. Immune activation, fibrosis, ischemia, and autoimmunity are not established mechanisms.

7. Anatomical structures affected

The primary organ is the inner ear, particularly the cochlear sensory epithelium/organ of Corti and its mechanosensory hair cells. At the subcellular level, the critical sites are apical hair bundles, actin-rich stereocilia and their membranes, plus apical endomembrane/lysosomal compartments. Suggested terms are UBERON:0001844 (cochlea), UBERON:0002227 (organ of Corti), UBERON:0001846 (internal ear), and the GO/CL terms above. (gao2022kiaa1024lminar2isessential pages 1-2, gao2022kiaa1024lminar2isessential pages 17-18)

Human disease is consistently bilateral. No reproducible vestibular, auditory-nerve, central nervous-system, retinal, or other-organ involvement has been established. Although MINAR2 is expressed in brain and other tissues, expression alone is not evidence of disease involvement. (carlson2022emergingcomplexitiesof pages 1-2, almontashiri2025biallelicminar2variant pages 1-2)

8. Temporal development

Onset is congenital or prelingual and therefore chronic/lifelong. Some patients already have severe/profound impairment at ascertainment; at least 4/13 original cases showed progression, but no standardized stages or annual threshold-change estimates are available. (almontashiri2025biallelicminar2variant pages 1-2)

There is no evidence of spontaneous remission or a relapsing-remitting course. The critical clinical period is early infancy and childhood because auditory access supports speech and language development. Newborn identification, prompt etiologic work-up, and early rehabilitation are therefore important even though no DFNB120-specific intervention window has been experimentally defined.

9. Inheritance, penetrance, and population

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 an unaffected non-carrier, subject to correct variant classification and parentage. Consanguinity can increase recurrence by increasing shared rare alleles, as illustrated by the first-cousin parents in the 2025 family. (almontashiri2025biallelicminar2variant pages 1-2, almontashiri2025biallelicminar2variant pages 2-3)

Penetrance appears high among reported biallelic individuals, but ascertainment is strongly phenotype-driven and the sample is too small to estimate penetrance or expressivity statistically. Severity is relatively consistent, while onset/progression varies. Genetic anticipation and germline mosaicism have not been reported.

Disease-specific prevalence, incidence, carrier frequency, sex ratio, geographic distribution, and ethnic enrichment are unknown. Published evidence comprises four families/13 patients in 2022 and one additional family/two affected brothers in 2025. Consequently, “15 patients” describes the identified literature, not worldwide prevalence. (almontashiri2025biallelicminar2variant pages 1-2)

10. Diagnostics

Clinical assessment

Evaluation should establish type, laterality, severity, and course using age-appropriate behavioral audiometry and objective testing such as auditory brainstem response and otoacoustic emissions. Tympanometry helps exclude conductive disease. Speech/language assessment documents functional consequences. Imaging is not diagnostic for DFNB120 but CT/MRI may be indicated before cochlear implantation or when anatomy/neurologic disease is suspected.

Molecular confirmation

A practical workflow is:

  1. Comprehensive hereditary hearing-loss panel that includes MINAR2, with deletion/duplication detection.
  2. Exome or genome sequencing when panel testing is negative or the phenotype/pedigree is atypical.
  3. Confirm candidate variants and phase/segregation in parents and affected relatives.
  4. Apply ACMG/AMP/ClinGen criteria and check ClinVar and current population databases.

The 2025 study used trio WES from blood, paired-end Illumina sequencing at mean 30× depth, GRCh37/hg19 and mitochondrial alignment, SNV/CNV calling with DRAGEN, Manta, and internal algorithms, followed by Sanger confirmation. This demonstrates WES utility but not comparative superiority over panels or WGS. (almontashiri2025biallelicminar2variant pages 1-2, almontashiri2025biallelicminar2variant pages 2-3)

WGS can improve coverage of poorly captured exons, intronic splice variants, and structural variants. CMA, karyotyping, FISH, mitochondrial testing, and repeat-expansion assays are not first-line disease-specific tests unless clinical or sequencing findings suggest another diagnosis. RNA analysis may resolve suspected splice variants but is not a validated routine DFNB120 assay.

Differential diagnoses include common recessive nonsyndromic genes such as GJB2, SLC26A4, OTOF, TMC1, MYO15A, congenital CMV, ototoxic exposure, inner-ear malformations, auditory neuropathy, and syndromic hearing-loss disorders. Phenotype alone cannot reliably distinguish DFNB120; molecular confirmation is necessary.

11. Outcome and prognosis

Available evidence suggests lifelong auditory disability but not shortened survival. No mortality signal, life-expectancy reduction, 5-/10-year survival statistic, or disease-specific hospitalization rate has been reported. Neurologic disease was absent even in original patients up to age 80, arguing against simply transferring the Parkinson-like mouse phenotype to humans. (carlson2022emergingcomplexitiesof pages 1-2, almontashiri2025biallelicminar2variant pages 1-2)

The major morbidity is severe/profound hearing impairment and its downstream communication burden. Prognosis depends on baseline severity, progression, age at auditory intervention, rehabilitation access, and response to amplification or implantation, but no DFNB120-specific outcome series exists. Residual hearing may deteriorate in some patients; serial audiometry is therefore appropriate. There are no validated molecular prognostic biomarkers.

12. Treatment

No pharmacologic, gene, RNA, cell, immunologic, or gene-editing therapy is approved specifically for DFNB120. No DFNB120/MINAR2 interventional trial was identified in the targeted ClinicalTrials.gov search.

Current care follows severe/profound pediatric SNHL practice:

  • hearing aids where usable residual hearing exists;
  • cochlear-implant evaluation when amplification provides insufficient benefit;
  • speech-language/auditory rehabilitation and educational accommodations;
  • sign-language access according to family/patient preferences;
  • serial audiology to document progression;
  • multidisciplinary otology, audiology, genetics, and developmental follow-up.

A 2024 review characterizes hearing aids and cochlear implants as traditional interventions for hereditary deafness and notes that they do not restore natural biologic hearing. It identifies inner-ear gene therapy as promising but still requiring improved vectors, editing strategies, delivery, and surgery. These are field-level observations, not DFNB120 treatment evidence. (wang2024geneticallymodifiedpigs pages 1-2)

Suggested NCIt concepts include Hearing Aid (C157197), Cochlear Implantation/cochlear implant concepts, Genetic Counseling, Speech Therapy, and Gene Therapy for experimental annotation; local NCIt release identifiers should be verified before database import. Cholesterol manipulation rescued zebrafish cellular defects, but translation is premature because systemic cholesterol alteration could have unrelated risks and the necessary cochlear exposure is unknown. (gao2022kiaa1024lminar2isessential pages 1-2)

13. Prevention

The genotype cannot presently be prevented through lifestyle modification. Primary reproductive options after identifying familial variants include genetic counseling, partner/carrier testing, prenatal diagnosis, and preimplantation genetic testing. Cascade testing can identify carrier relatives. Secondary prevention comprises newborn hearing screening, rapid diagnostic audiology, and early molecular testing. Tertiary prevention comprises prompt auditory rehabilitation, language access, educational support, hearing conservation, and avoidance of unnecessary ototoxic exposure.

No vaccine, medication, dietary regimen, or prophylactic procedure prevents DFNB120. Standard vaccination and congenital-infection prevention may reduce other causes of hearing loss but do not prevent MINAR2-related disease.

14. Other species and natural disease

Experimental orthologues are established in Mus musculus (NCBI Taxon 10090) and Danio rerio (Taxon 7955). Minar2-null mice develop progressive SNHL with hair-cell degeneration; they also show bradykinesia, rigidity, loss of tyrosine-hydroxylase-positive neurons, and α-synuclein upregulation—features not observed in reported humans. This interspecies discordance limits direct syndromic extrapolation. (carlson2022emergingcomplexitiesof pages 1-2, almontashiri2025biallelicminar2variant pages 1-2)

The zebrafish minar2fs139 mutant has impaired mechanotransduction, abnormal hair bundles and enlarged apical lysosomes, with progressive adult hair-cell reduction. Its phenotype is milder than the mouse phenotype, plausibly because zebrafish continue generating hair cells into adulthood and may exhibit genetic compensation. (gao2022kiaa1024lminar2isessential pages 17-18)

No naturally occurring veterinary DFNB120-equivalent disease, breed predisposition, VBO identifier, or zoonotic potential was identified. These are engineered or laboratory genetic models, not transmissible disease.

15. Model organisms and research applications

Mouse

The knockout mouse recapitulates progressive SNHL and hair-cell degeneration and supports mammalian cochlear causality. It is useful for longitudinal ABR, cochlear histology, delivery studies, and eventual MINAR2 replacement experiments. Its limitation is additional Parkinson-like motor/neural pathology absent in humans; model phenotypes therefore cannot automatically populate the human disease entry. (carlson2022emergingcomplexitiesof pages 1-2)

Zebrafish

The minar2fs139 model recapitulates defective auditory/vestibular hair-cell mechanotransduction, stereociliary cholesterol depletion, abnormal bundle morphology, lysosomal enlargement, and progressive hair-cell loss. Pharmacologic cholesterol lowering worsened and cholesterol elevation rescued defects, making the model useful for pathway dissection and compound screening. Continuous adult hair-cell regeneration and possible genetic compensation limit quantitative translation to human cochlear disease. (gao2022kiaa1024lminar2isessential pages 1-2, gao2022kiaa1024lminar2isessential pages 17-18)

Cellular and computational systems

Cultured-cell overexpression localized MINAR2 mainly to lysosomes and recruited cholesterol. Tagged protein in hair cells localized to apical endomembranes and stereociliary membranes. AlphaFold-based docking supports, but does not prove, a cholesterol-binding interface. No patient-derived iPSC hair-cell model, human cochlear organoid, porcine MINAR2 model, CRISPR therapeutic screen, or disease-specific spatial/single-cell atlas was identified. (gao2022kiaa1024lminar2isessential pages 1-2, gao2022kiaa1024lminar2isessential pages 17-18)

Key primary sources and dates

  1. Bademci G, et al. “Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice.” PNAS. Published June 2022. PMID: 35727972. DOI/URL: https://doi.org/10.1073/pnas.2204084119. The central human conclusion is summarized by the exact statement that the variants “led to loss of function of the gene and were perfectly coinherited with autosomal recessive hearing loss.” (carlson2022emergingcomplexitiesof pages 1-2)
  2. Gao G, et al. “Kiaa1024L/Minar2 is essential for hearing by regulating cholesterol distribution in hair bundles.” eLife 11:e80865. Published 1 November 2022. DOI/URL: https://doi.org/10.7554/eLife.80865. Exact abstract statement: “Lowering cholesterol levels aggravates, while increasing cholesterol levels rescues the hair cell defects in the kiaa1024L/minar2 mutant.” (gao2022kiaa1024lminar2isessential pages 1-2)
  3. Carlson RJ, Avraham KB. “Emerging complexities of the mouse as a model for human hearing loss.” PNAS. Published 12 August 2022. DOI/URL: https://doi.org/10.1073/pnas.2211351119. This authoritative commentary emphasizes that mouse motor deficits “were not present in even the oldest humans with comparably severe mutations in MINAR2.” (carlson2022emergingcomplexitiesof pages 1-2)
  4. Wang X, et al. “Genetically modified pigs: Emerging animal models for hereditary hearing loss.” Zoological Research 45:284–291. Published online 6 December 2023; issue March 2024. DOI/URL: https://doi.org/10.24272/j.issn.2095-8137.2023.231. This is a recent field review, not a new DFNB120 human cohort. (wang2024geneticallymodifiedpigs pages 1-2)
  5. Almontashiri NAM. “Biallelic MINAR2 variant is associated with nonsyndromic severe to profound sensorineural hearing loss.” Human Genome Variation 12. Published online 23 October 2025. DOI/URL: https://doi.org/10.1038/s41439-025-00328-w. Exact abstract conclusion: “Our study provides the first independent confirmation of the MINAR2-related SNHL.” (almontashiri2025biallelicminar2variant pages 1-2)

Knowledge-base confidence assessment

High confidence: MINAR2 causality; autosomal-recessive inheritance; bilateral congenital/prelingual severe-to-profound nonsyndromic SNHL; stereociliary/hair-cell involvement; cholesterol-homeostasis mechanism in experimental models.

Moderate confidence: progressive human course, because it was documented in only 4/13 original patients; high penetrance, because all reported biallelic subjects were ascertained through hearing-loss families.

Low or unavailable: disease prevalence/incidence, carrier frequency, founder variants, sex effects, environmental modifiers, exact longitudinal prognosis, human biochemical biomarkers, extra-auditory risk, treatment-response rates, and efficacy of cholesterol-directed or gene therapies. These fields should be recorded as unknown, not inferred from general hearing-loss literature or animal models.

References

  1. (almontashiri2025biallelicminar2variant pages 1-2): Naif A. M. Almontashiri. Biallelic minar2 variant is associated with nonsyndromic severe to profound sensorineural hearing loss. Human Genome Variation, Oct 2025. URL: https://doi.org/10.1038/s41439-025-00328-w, doi:10.1038/s41439-025-00328-w. This article has 0 citations.

  2. (almontashiri2025biallelicminar2variant pages 2-3): Naif A. M. Almontashiri. Biallelic minar2 variant is associated with nonsyndromic severe to profound sensorineural hearing loss. Human Genome Variation, Oct 2025. URL: https://doi.org/10.1038/s41439-025-00328-w, doi:10.1038/s41439-025-00328-w. This article has 0 citations.

  3. (gao2022kiaa1024lminar2isessential pages 1-2): Ge Gao, Shuyu Guo, Quan Zhang, Hefei Zhang, Cuizhen Zhang, and Gang Peng. Kiaa1024l/minar2 is essential for hearing by regulating cholesterol distribution in hair bundles. Nov 2022. URL: https://doi.org/10.7554/elife.80865, doi:10.7554/elife.80865. This article has 8 citations and is from a domain leading peer-reviewed journal.

  4. (gao2022kiaa1024lminar2isessential pages 17-18): Ge Gao, Shuyu Guo, Quan Zhang, Hefei Zhang, Cuizhen Zhang, and Gang Peng. Kiaa1024l/minar2 is essential for hearing by regulating cholesterol distribution in hair bundles. Nov 2022. URL: https://doi.org/10.7554/elife.80865, doi:10.7554/elife.80865. This article has 8 citations and is from a domain leading peer-reviewed journal.

  5. (wang2024geneticallymodifiedpigs pages 1-2): Xiao Wang, Tian-Xia Liu, Ying Zhang, Liang-Wei Xu, Shuo-Long Yuan, A-Long Cui, Wei-Wei Guo, Yan-Fang Wang, Shi-Ming Yang, and Jian-Guo Zhao. Genetically modified pigs: emerging animal models for hereditary hearing loss. Zoological Research, 45:284-291, Mar 2024. URL: https://doi.org/10.24272/j.issn.2095-8137.2023.231, doi:10.24272/j.issn.2095-8137.2023.231. This article has 6 citations.

  6. (OpenTargets Search: Hearing loss autosomal recessive 120): Open Targets Query (Hearing loss autosomal recessive 120, 16 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  7. (carlson2022emergingcomplexitiesof pages 1-2): Ryan J. Carlson and Karen B. Avraham. Emerging complexities of the mouse as a model for human hearing loss. Proceedings of the National Academy of Sciences of the United States of America, Aug 2022. URL: https://doi.org/10.1073/pnas.2211351119, doi:10.1073/pnas.2211351119. This article has 19 citations and is from a highest quality peer-reviewed journal.

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