Autosomal Recessive Nonsyndromic Hearing Loss 88

Mendelian MONDO:0014182 Pathograph 21 Show in embeddings browser Autosomal Recessive Nonsyndromic Hearing Loss Hereditary Hearing Loss

DFNB88 is a recessive ELMOD3-associated hearing disorder defined in the consanguineous Pakistani family PKDF468 by homozygous p.Leu265Ser and prelingual, severe-to-profound mixed hearing loss. The variant markedly reduces recombinant ARL2 GTPase-activating activity and impairs ELMOD3 targeting to stereocilia in cultured mouse cochlear explants. Elmod3-null mice develop cochlear F-actin abnormalities, stereociliary degeneration and progressive hearing impairment. The physiological GTPase substrate in the inner ear and the cause of the human conductive component remain unresolved; the mouse null allele and human missense allele also differ in their reported hearing-loss onset.

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1
Inheritance
12
Pathophys.
3
Phenotypes
2
Gaps
21
Pathograph
1
Genes
1
Variants
4
Medical Actions
4
Models
10
References
1
Deep Research
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Inheritance

1
Autosomal recessive HP:0000007
The defining consanguineous family segregates homozygous c.794T>C (p.Leu265Ser) with hearing loss; heterozygous relatives were reported to hear normally. Linkage used a fully penetrant recessive model and a disease-allele frequency of 0.001, yielding a maximum LOD score of 4.74. Those model inputs are not population allele-frequency or penetrance estimates. A separate homozygous deletion involving ELMOD3, CAPG and SH2D6 supports biallelic gene involvement in hearing loss but is not an isolated DFNB88 family.
Autosomal recessive inheritance
Show evidence (3 references)
PMID:24039609 SUPPORT Human Clinical
"Exome sequencing coupled with homozygosity mapping was used to identify a transition mutation (c.794T>C; p.Leu265Ser) in ELMOD3 at the DFNB88 locus that is associated with nonsyndromic deafness in a large Pakistani family, PKDF468."
The gene, the allele, the locus and the recessive study design in one sentence.
PMID:24039609 SUPPORT Human Clinical
"haplotype analysis revealed a 0.91 Mb linkage interval that was delimited by the markers D2S1387 and D2S2232"
The homozygous interval on 2p11.2 that defines DFNB88, from the genome-wide linkage scan.
PMID:30284680 SUPPORT INDIRECT Human Clinical
"we identified a rare homozygous deletion in 2p11.2 region that affects ELMOD3, CAPG, and SH2D6 genes in a boy with ASD, intellectual disability (ID), and hearing impairment (HI)"
A second, independent biallelic ELMOD3 loss with hearing impairment. Graded INDIRECT because the deletion removes two further genes, so it supports the recessive model for the gene without being a DFNB88 observation.
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Discussions and Knowledge Gaps

2
Why is hearing impairment prelingual in PKDF468, whereas the Elmod3-null mouse has normal measured thresholds at one month and elevated thresholds from two months?
HUMAN MODEL MISMATCH OPEN dfnb88_onset_species_mismatch
Attached to
pathophysiology#Cochlear Sensory Transduction Failure animal_models#Elmod3 constitutive knockout mouse
The human missense allele and mouse constitutive null are different perturbations studied in different species. The mouse has early postnatal F-actin and bundle-development abnormalities, broadly normal day-14 scanning electron microscopy, and subsequent bundle degeneration. The evidence therefore does not establish a purely adult maintenance defect. A p.Leu265Ser knock-in and developmental functional measurements could distinguish allele-specific effects from species or background effects. No conversion of mouse age to human prenatal timing is established, and dominant human p.His171Arg results should not be used as a direct explanation of recessive DFNB88.
Show evidence (2 references)
PMID:31628468 SUPPORT Model Organism
"We found that Elmod3−/− mice exhibited significant HL beginning at the age of 2 months and progressed with age."
The model's hearing phenotype and its timing, which is what this link is cited for and also what diverges from the human course.
PMID:24039609 SUPPORT Human Clinical
"The affected individuals of this family exhibited pre-lingual, severe-to-profound degrees of mixed hearing loss."
The human half of the mismatch.
What produces the conductive component of the DFNB88 audiogram, and is it part of the disease at all?
KNOWLEDGE GAP OPEN dfnb88_conductive_component_unexplained
Attached to
phenotypes#Conductive Hearing Impairment
Mixed audiograms are reported in PKDF468, including a large bilateral conductive component in V:5. CT in V:2 and V:11 showed preserved middle-ear/mastoid aeration, but V:5 was not scanned and functional middle-ear testing was not reported. These findings leave the cause of the air-bone gap unresolved. Neither cochlear localization nor ABR/DPOAE measurements in mice establish the absence of a conductive mechanism. Replication in unrelated families with comprehensive audiological assessment is needed before attributing the gap specifically to ELMOD3.
Proposed experiments
Middle-ear assessment in a new DFNB88 family
dfnb88_middle_ear_assessment
In molecularly established DFNB88, repeat masked air- and bone-conduction audiometry with documented output limits, tympanometry, acoustic reflexes and other indicated assessments. Compare affected and unaffected relatives and, where possible, unrelated families; interpret imaging and functional measurements together.
Would support
phenotypes#Conductive Hearing Impairment
Supporting outcome
  • A reproducible conductive deficit that segregates with biallelic ELMOD3 variants across independent families would support a disease association, while requiring exclusion of other causes.
Refuting outcome
  • Disappearance of the air-bone gap with technically adequate repeat testing would argue against the initial conductive finding. Normal tympanometry or reflexes alone would not prove a measurement artefact.
Show evidence (3 references)
PMID:24039609 SUPPORT Human Clinical
"The audiograms of individual V:5 revealed bilateral severe-to-profound mixed hearing loss, with a large conductive component in both ears."
The observation that the gap exists and is large.
PMID:24039609 SUPPORT Human Clinical
"The middle ear and mastoid appeared well-aerated bilaterally."
The preserved aeration constrains interpretation but does not exclude every conductive disorder.
PMID:24039609 SUPPORT Human Clinical
"To determine the temporal bone malformation, we performed computed tomography (CT) scans of two affected (V:2 and V:11) along with a normal hearing sibling (V:7)."
CT examined V:2 and V:11, not the V:5 patient with the specifically described large bilateral gap.
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Pathophysiology

12
ELMOD3 Biallelic Loss of Function
Mechanism confidence: Established
Homozygous c.794T>C (p.Leu265Ser; NM_032213.4 in the original report) affects a conserved residue in the ELMO domain and segregates with hearing loss in PKDF468. The substitution is predicted in all ELMO-domain-containing isoforms described in that study. Recombinant mutant protein had expression and purification yields similar to wild type; this does not establish its abundance in patient hair cells. Leukocyte cDNA assays found no aberrant splicing in the tested exon intervals.
ELMOD3 hgnc:26158 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ELMOD3 (hgnc:26158). hgnc:26158 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context ELMOD3 hgnc:26158 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns ELMOD3 (hgnc:26158). hgnc:26158 is a gene from the HUGO Gene Nomenclature Committee. allele_type: missense variant in the ELMO/CED12 domain variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Downstream
Loss of ARL2 GTPase-Activating Activity Purified recombinant p.Leu265Ser has at least a tenfold reduction in ARL2 GAP activity, approaching the assay detection limit.
Impaired ELMOD3 Targeting to Stereocilia The patient variant directly changes targeting in transfected cochlear explants.
Reduced Cochlear ARL2 Abundance The constitutive Elmod3 null reduces cochlear ARL2 abundance; the same effect has not been demonstrated for the human missense allele.
Reduced Primary Cilium Formation Gene disruption produces this phenotype in fibroblasts; transfer to the patient missense allele and inner ear remains untested.
Altered Ciliary Cargo Localization Gene disruption produces this phenotype in fibroblasts; transfer to the patient missense allele and inner ear remains untested.
Golgi Accumulation of Ciliary Cargo Gene disruption produces this phenotype in fibroblasts; transfer to the patient missense allele and inner ear remains untested.
Show evidence (1 reference)
PMID:24039609 SUPPORT Human Clinical
"The c.794T>C transition mutation is predicted to result in the substitution of serine for a highly conserved leucine in all of the ELMO domain-containing isoforms of ELMOD3"
The substitution affects the ELMO-domain-containing isoforms examined by sequence annotation; this does not exclude every tissue-specific transcript or establish patient protein abundance.
Loss of ARL2 GTPase-Activating Activity
Mechanism confidence: Established
Recombinant p.Leu265Ser ELMOD3 has at least tenfold lower ARL2 GAP activity than wild type, with residual signal at the assay floor. Complete inactivity cannot be distinguished from very low activity. Biochemical substrate panels also detect weak ELMOD3 activity against other ARF-family GTPases; the relevant inner-ear substrate and tissue GTP/GDP state have not been established.
ARL2 GTPase-activating protein activity GO:0005096 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves ARL2 GTPase-activating protein activity, annotated with GTPase activator activity (GO:0005096), qualified as loss of function. GO:0005096 is a molecular function from the Gene Ontology. ⇓ LOSS OF FUNCTION
Experimental models
Recombinant ELMOD3 GAP and localization assays CELL LINE Purified mutant protein has activity at the assay floor.
Downstream
Disorganized Stereociliary Actin Cytoskeleton An effect of lost GAP activity on hair-bundle actin is proposed, but the intervening GTPase and actin regulator have not been demonstrated.
Show evidence (2 references)
PMID:24039609 SUPPORT In Vitro
"Thus, we can safely conclude that the point mutant has at least a 10-fold lower specific activity than the wild-type protein, but it might be completely inactive as an Arl2 GAP."
The full-text result sets a lower bound on activity loss; mutant activity was at the assay floor and indistinguishable from GST alone.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC4036250/ SUPPORT INDIRECT In Vitro
"the very low activities found for ELMOD3 may lead one even to question whether it acts in cells as an ARF family GAP."
The biochemical study cautions against inferring a physiological substrate or disease severity from weak recombinant GAP activity.
Impaired ELMOD3 Targeting to Stereocilia
Mechanism confidence: Established
Overexpressed GFP-tagged p.Leu265Ser fails to concentrate in stereocilia of P2 mouse cochlear explants and shows weak or absent targeting to espin-elongated CL4 microvilli and MDCK plasma membranes. Wild-type rodent immunolocalization supports a hair-bundle context, but the antibody recognized isoform b rather than all ELMOD3 isoforms. The targeting defect is distinct from loss of direct actin binding: weak F-actin co-sedimentation of recombinant protein was unchanged by the variant.
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. 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.
stereocilium GO:0032420 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves stereocilium (GO:0032420). GO:0032420 is a cellular component from the Gene Ontology.
spiral organ of Corti UBERON:0002227 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in spiral organ of Corti, annotated with spiral organ of cochlea (UBERON:0002227). UBERON:0002227 is an anatomical location from the Uberon multi-species anatomy ontology.
Experimental models
p.Leu265Ser expression in cochlear explants PRIMARY CELL CULTURE Tagged patient-variant protein remains predominantly cytosolic rather than concentrating in stereocilia.
Recombinant ELMOD3 GAP and localization assays CELL LINE CL4 microvilli and MDCK membrane localization are impaired by the patient variant.
Downstream
Disorganized Stereociliary Actin Cytoskeleton Loss of correct subcellular targeting may impair local ELMOD3 function, but no experiment isolates targeting failure as the cause of bundle actin abnormalities.
Show evidence (3 references)
PMID:24039609 SUPPORT In Vitro
"Mouse organ of Corti hair cell that was transfected with GFP-ELMOD3 (p.Leu265Ser). No concentration and only negligible fluorescence is observed in the stereocilia"
Direct variant-specific targeting experiment in cultured mouse cochlear tissue; overexpression is not an in-vivo knock-in.
PMID:24039609 SUPPORT In Vitro
"In vitro, the association of ELMOD3 with F-actin was unaffected by the Leu265Ser mutation in the ELMO domain"
Supports the mechanistic distinction: the localization defect occurs despite preserved weak F-actin association in this recombinant assay.
PMID:24039609 SUPPORT In Vitro
"Our antibodies specifically recognized ELMOD3 isoform b but not murine ELMOD1, ELMOD2, or ELMOD3 isoform a"
Normal-tissue localization with this reagent is isoform-limited; absence of vestibular bundle staining does not establish the cause of clinical vestibular sparing.
Reduced Cochlear ARL2 Abundance
Mechanism confidence: Provisional
Elmod3-null cochleae show reduced ARL2 protein by early postnatal immunoblotting and reduced immunolabeling in cochlear cells. This is a change in protein abundance, not a measurement of ARL2 activation or GTP hydrolysis. Whether restoring ARL2 rescues hearing or bundle structure remains unknown.
Animal models
Elmod3 constitutive knockout mouse Mouse measures Elmod3-null cochleae show reduced ARL2 protein by early postnatal immunoblotting and reduced immunolabeling in cochlear cells. This is a change in protein abundance, not a measurement of ARL2 activation or GTP hydrolysis. Whether restoring ARL2 rescues hearing or bundle structure remains unknown.
Downstream
Disorganized Stereociliary Actin Cytoskeleton Reduced ARL2 abundance is a proposed contributor to F-actin abnormalities, without a demonstrated intermediate or rescue.
Show evidence (1 reference)
PMID:31628468 SUPPORT Model Organism
"Western blotting assays of ARL2 protein expression level in postnatal 7 days mice cochlea of WT mice and Elmod3−/− mice. Expression level of ARL2 protein in Elmod3−/− mice were reduced compared with WT mice"
The figure legend directly reports reduced protein abundance at postnatal day seven, distinct from GAP catalytic activity.
Disorganized Stereociliary Actin Cytoskeleton
Mechanism confidence: Provisional
Elmod3-null mice show weaker cochlear phalloidin staining, involving hair cells, supporting cells, spiral ganglion and spiral ligament. Bundle formation appears delayed at postnatal day 1, although scanning electron microscopy at day 14 shows similar gross morphology to wild type. Later stereociliary shortening and degeneration support disturbed actin organization or maintenance; the precise molecular link to ELMOD3 remains provisional.
sensory hair cell CL:0000855 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves sensory hair cell (CL:0000855). CL:0000855 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
Elmod3 constitutive knockout mouse Mouse recapitulates Phalloidin signal is much weaker throughout the knockout cochlea, most markedly in hair cells, and stereocilia formation and maturation are already delayed at postnatal day 1.
Downstream
Inner Hair Cell Stereocilia Shortening and Fusion The inner hair cell arm of the bundle phenotype.
Outer Hair Cell Stereocilia Degeneration The outer hair cell arm of the bundle phenotype.
Show evidence (2 references)
PMID:31628468 SUPPORT Model Organism
"These results indicated a reduction of F-actin cytoskeleton formation in Elmod3 KO mice and therefore suggested that Elmod3 is required for the proper organization of F-actin networks."
The direct measurement behind this node: less F-actin in the knockout cochlea, and the authors' conclusion from it.
PMID:24039609 SUPPORT INDIRECT In Vitro
"We therefore speculate that ELMOD3 functions as a GAP for Arl2 and perhaps other GTPases that participate in actin organization, polymerization or depolymerization in the cochlear hair bundles"
The proposed route from GAP activity to bundle actin. Quoted with its hedge intact and graded INDIRECT because it is explicitly the authors' speculation, not a result.
Inner Hair Cell Stereocilia Shortening and Fusion
Mechanism confidence: Provisional
In the knockout mouse, inner hair cell stereocilia are significantly shortened by two months - the age at which thresholds first shift - and by five months every inner hair cell shows bundle degeneration, some with no bundle at all. Hair cell bodies themselves are largely preserved, so this is a bundle lesion rather than hair cell death.
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.
Animal models
Elmod3 constitutive knockout mouse Mouse recapitulates Inner hair cell stereocilia are significantly shortened at two months and by five months show noticeable degeneration, with a few inner hair cells lacking bundles entirely.
Downstream
Cochlear Sensory Transduction Failure Bundle shortening and degeneration coincide with hearing-threshold elevation; altered mechanotransduction is inferred because hair-cell transduction currents were not recorded.
Show evidence (1 reference)
PMID:31628468 SUPPORT Model Organism
"stereocilia of IHCs were significantly shortened in Elmod3−/− mice compared with the WT littermates"
Scanning electron microscopy directly documents inner-hair-cell bundle shortening at two months.
Outer Hair Cell Stereocilia Degeneration
Mechanism confidence: Provisional
Elmod3-null mice have more missing outer-hair-cell bundles than age-matched wild-type mice at five months; surviving bundles show looser stereociliary connections. The structural finding is distinguished from the functional inference of impaired cochlear amplification.
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.
Animal models
Elmod3 constitutive knockout mouse Mouse measures Elmod3-null mice have more missing outer-hair-cell bundles than age-matched wild-type mice at five months; surviving bundles show looser stereociliary connections. The structural finding is distinguished from the functional inference of impaired cochlear amplification.
Downstream
Impaired Cochlear Amplification Outer-hair-cell bundle degeneration and DPOAE abnormalities support a structural-functional association; neither intervention nor single-cell force measurement establishes causality.
Show evidence (1 reference)
PMID:31628468 SUPPORT INDIRECT Model Organism
"stereocilia of OHCs were missing in both Elmod3−/− and WT mice with an increased frequency of losses in Elmod3−/− mice compared with WT mice"
The outer hair cell bundle loss, measured against wild-type littermates of the same age so that ordinary age-related loss is controlled for. INDIRECT because it is a mouse.
Impaired Cochlear Amplification
Mechanism confidence: Provisional
DPOAE thresholds rise from two months in Elmod3-null mice and worsen with age, consistent with impaired outer-hair-cell-dependent amplification. DPOAEs also depend on sound transmission through the middle ear; these measurements alone do not exclude a conductive contribution.
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.
Animal models
Elmod3 constitutive knockout mouse Mouse measures DPOAE thresholds rise from two months in Elmod3-null mice and worsen with age, consistent with impaired outer-hair-cell-dependent amplification. DPOAEs also depend on sound transmission through the middle ear; these measurements alone do not exclude a conductive contribution.
Downstream
Cochlear Sensory Transduction Failure Impaired amplification is a proposed contributor to hearing-threshold elevation.
Show evidence (1 reference)
PMID:31628468 SUPPORT INDIRECT Model Organism
"the shifting of DPOAE thresholds indicated the reduction of the force coupled into the cochlear amplifier by OHCs motility"
DPOAE threshold shifts support impaired cochlear amplification, without directly measuring outer-hair-cell force.
Cochlear Sensory Transduction Failure
Mechanism confidence: Provisional
The cochlea can no longer turn sound into a neural signal at normal levels. In the mouse this is progressive and measured as auditory brainstem response threshold shifts from two months of age; in the affected members of family PKDF468 it is already established before speech acquisition, and it is the sensorineural half of their mixed audiograms.
sensory perception of sound GO:0007605 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased sensory perception of sound (GO:0007605). GO:0007605 is a biological process from the Gene Ontology. ↓ DECREASED
cochlea UBERON:0001844 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cochlea (UBERON:0001844). UBERON:0001844 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Elmod3 constitutive knockout mouse Mouse partially recapitulates The mouse goes deaf, which is the right outcome, but on a completely different schedule from the humans: thresholds are normal at one month, shift from two months, and worsen to five months.
Downstream
Prelingual Mixed Hearing Impairment The sensorineural component of the audiogram. The conductive component is not explained by this node and is curated as an open question.
Sensorineural Hearing Impairment The sensorineural component of the human mixed hearing loss is consistent with the cochlear mechanism; the conductive component remains unexplained.
Show evidence (1 reference)
PMID:31628468 SUPPORT INDIRECT Model Organism
"Our finding associates Elmod3 deficiencies with stereocilia dysmorphologies and reveals that they might play roles in the actin cytoskeleton dynamics in cochlear hair cells, and thus relate to hearing impairment."
The knockout paper's own statement of the link between the bundle lesion and hearing. INDIRECT because it is a mouse and the authors hedge the mechanistic claim.
Reduced Primary Cilium Formation
Mechanism confidence: Provisional
CRISPR disruption of Elmod3 in immortalized mouse embryonic fibroblasts reduces the fraction of ciliated cells after serum starvation. Normal CEP164 recruitment and CP110 removal place the observed defect after early ciliogenesis licensing. This is a candidate ELMOD3 function relevant to developing hair-cell kinocilia, not a demonstrated DFNB88 cochlear lesion.
Experimental models
Elmod3-disrupted mouse embryonic fibroblasts CELL LINE CRISPR disruption of Elmod3 in immortalized mouse embryonic fibroblasts reduces the fraction of ciliated cells after serum starvation. Normal CEP164 recruitment and CP110 removal place the observed defect after early ciliogenesis licensing. This is a candidate ELMOD3 function relevant to developing hair-cell kinocilia, not a demonstrated DFNB88 cochlear lesion.
Elmod3-disrupted mouse embryonic fibroblasts CELL LINE Fast-cycling ARL3 or ARL16 restores ciliation toward wild-type levels; ARF1 and ARF5 constructs do not.
Show evidence (1 reference)
PMID:34818063 SUPPORT In Vitro
"We found that ciliation was strongly decreased in Elmod1 and Elmod3 single KO MEFs, with <10% of cells on average having a cilium after 24 hr of serum starvation, compared with >60% in WT controls"
A direct cell-model ciliation measurement; neither human DFNB88 nor cochlear cilia were measured.
Altered Ciliary Cargo Localization
Mechanism confidence: Provisional
Elmod3-deficient fibroblasts show depletion of ARL13B, ARL3 and INPP5E from remaining cilia. IFT88, IFT140 and GLI3 localization is preserved, indicating selective cargo effects rather than a universal transport failure. These results have not been reproduced in DFNB88 patient cells or cochlear hair cells.
Experimental models
Elmod3-disrupted mouse embryonic fibroblasts CELL LINE Elmod3-deficient fibroblasts show depletion of ARL13B, ARL3 and INPP5E from remaining cilia. IFT88, IFT140 and GLI3 localization is preserved, indicating selective cargo effects rather than a universal transport failure. These results have not been reproduced in DFNB88 patient cells or cochlear hair cells.
Show evidence (1 reference)
PMID:34818063 SUPPORT In Vitro
"We also discovered changes in the ciliary content of at least three proteins in cells lacking ELMOD1 and/or ELMOD3: ARL13B, ARL3, and INPP5E."
Selective loss of ciliary cargo is a direct cell-model observation, not evidence of a human multisystem ciliopathy.
Golgi Accumulation of Ciliary Cargo
Mechanism confidence: Provisional
INPP5E and IFT140 accumulate at the Golgi in Elmod3-deficient fibroblasts. INPP5E accumulation is more prominent after 24 than 72 hours of serum starvation, and its detection depends on fixation conditions. Delayed export is proposed; ciliary IFT140 localization remains preserved despite its increased Golgi pool.
Experimental models
Elmod3-disrupted mouse embryonic fibroblasts CELL LINE INPP5E and IFT140 accumulate at the Golgi in Elmod3-deficient fibroblasts. INPP5E accumulation is more prominent after 24 than 72 hours of serum starvation, and its detection depends on fixation conditions. Delayed export is proposed; ciliary IFT140 localization remains preserved despite its increased Golgi pool.
Show evidence (1 reference)
PMID:34818063 SUPPORT In Vitro
"In contrast, the presence of INPP5E at the Golgi is evident in well over half of all Elmod1, Elmod3, and DKO cell lines after 24 h of serum starvation"
Direct Golgi localization result in serum-starved fibroblasts. The effect waned at later times.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Autosomal Recessive Nonsyndromic Hearing Loss 88 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
Prelingual Mixed Hearing Impairment Ear HP:0000410 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mixed hearing impairment (HP:0000410). HP:0000410 is a phenotype from the Human Phenotype Ontology.
Audiograms were published for V:2 and V:5 within one family. Prelingual onset was obtained from family history rather than newborn screening. The available ascertainment does not establish a population frequency for mixed loss or a longitudinal human progression pattern.
Show evidence (2 references)
PMID:24039609 SUPPORT Human Clinical
"The affected individuals of this family exhibited pre-lingual, severe-to-profound degrees of mixed hearing loss."
Onset, severity and audiometric type in one clause.
PMID:24039609 SUPPORT Human Clinical
"The family history revealed that the onset of hearing loss was pre-lingual, with no clear vestibular impairment among the deaf individuals."
The onset statement and its source - family history - together with the negative vestibular finding that accompanies it.
Sensorineural Hearing Impairment Ear HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Elevated bone-conduction thresholds establish a sensorineural component in the published audiograms. The severity of the combined air-conduction loss should not be assigned to the sensorineural component alone.
Show evidence (1 reference)
PMID:24039609 SUPPORT Human Clinical
"Individual V:2 exhibited severe-to-profound mixed hearing loss, with bone conduction thresholds for the right ear displaying a mild downward slope to the severe hearing loss range."
Elevated bone-conduction thresholds in a named individual, which is the audiometric definition of a sensorineural component.
Conductive Hearing Impairment Ear HP:0000405 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Conductive hearing impairment (HP:0000405). HP:0000405 is a phenotype from the Human Phenotype Ontology.
The observation comes from one ascertained family and does not support a disease-wide frequency band. The patient with the specifically described large bilateral gap, V:5, was not one of the two affected individuals examined by CT. Preserved aeration does not exclude all ossicular or other conductive disorders.
Show evidence (1 reference)
PMID:24039609 SUPPORT Human Clinical
"The audiograms of individual V:5 revealed bilateral severe-to-profound mixed hearing loss, with a large conductive component in both ears."
The conductive component, its laterality and its size, in the one individual for whom it is quantified in words.
🧬

Genetic Associations

1
ELMOD3
Gene: ELMOD3 hgnc:26158 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ELMOD3 (hgnc:26158). hgnc:26158 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:24039609 SUPPORT Human Clinical
"To further confirm that the p.Leu265Ser allele of ELMOD3 is the only mutation that was associated with hearing loss at the DFNB88 locus, we sequenced the coding, non-coding, and approximately 75 bp flanking sequences of the exon-intron boundaries of all the known candidate genes present within..."
Sequencing other interval genes supported ELMOD3 prioritization; segregation and variant-specific functional findings together support the association, without excluding every possible linked regulatory change.
PMID:29713870 SUPPORT INDIRECT Human Clinical
"novel missense variant, c.512A>G (p.His171Arg) in exon 8 of the ELMO domain-containing 3 (ELMOD3) gene, was identified as a causative variant in this family affected by late-onset and progressive ADNSHL."
The dominant ELMOD3 entity, recorded so that this entry's recessive scope is explicit. INDIRECT because the finding is about a different disease and bears on DFNB88 only through the shared gene.
Variants (1)
NM_032213.4:c.794T>C (p.Leu265Ser)
Homozygous missense allele segregating with prelingual hearing impairment in PKDF468. The numbering uses the transcript in the original report. Functional assays show markedly reduced ARL2 GAP activity and impaired subcellular targeting, while weak F-actin co-sedimentation is preserved. The fully penetrant recessive linkage model was an analytical assumption, not a measured penetrance estimate.
Show evidence (1 reference)
PMID:24039609 SUPPORT Human Clinical
"Exome sequencing coupled with homozygosity mapping was used to identify a transition mutation (c.794T>C; p.Leu265Ser) in ELMOD3 at the DFNB88 locus that is associated with nonsyndromic deafness in a large Pakistani family, PKDF468."
Segregation, positional evidence and functional experiments support the reported recessive allele; no modern ACMG classification is inferred.
🗃️

External Assertions

1
OMIM deafness, autosomal recessive 88 record
OMIM disease record OMIM:615429
OMIM phenotype record for autosomal recessive deafness 88.
💊

Medical Actions

4
Hearing Aid Amplification
Action: hearing aid amplificationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hearing aid amplification, annotated with Rehabilitation (NCIT:C15315), qualified as medical device hearing aid. NCIT:C15315 is a clinical intervention from the NCI Thesaurus. Ontology label: Rehabilitation NCIT:C15315
Platform: Device
Individualized hearing-aid fitting and audiological follow-up may improve access to sound when residual hearing permits useful benefit. This is general hearing-loss care; the retrieved DFNB88 reports do not establish a disease-specific response rate. The conductive contribution requires assessment alongside the sensorineural component.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/books/NBK1434/ SUPPORT Other
"Hearing aids (sound amplification), ... customized by an audiologist to the degree and frequency of hearing loss, can be used in individuals with mild-to-severe hearing loss."
General hearing-loss care supports individualized amplification; this is indirect guidance for DFNB88 rather than a reported treatment outcome.
Cochlear Implantation
Action: cochlear device implantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cochlear device implantation, annotated with Surgical Procedure (NCIT:C15329), qualified as medical device cochlear implant. NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Device
Cochlear-implant candidacy assessment is appropriate for selected individuals with severe-to-profound sensorineural impairment and insufficient aided benefit. Evaluation should characterize the mixed loss and relevant auditory anatomy. General hearing-loss guidance supports considering implantation; the retrieved DFNB88 literature does not report implant outcomes or establish genotype-specific efficacy.
Mechanism Target:
BYPASSES Cochlear Sensory Transduction Failure — Implantation can bypass impaired hair-cell transduction by stimulating the auditory nerve; individual suitability and outcomes require assessment.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/books/NBK1434/ SUPPORT INDIRECT Other
"Cochlear implantation can be considered in children with severe-to-profound hearing loss who are older than age nine months."
General guidance supports considering implantation after clinical assessment; this is not a DFNB88-specific efficacy claim.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Platform: Behavioral / lifestyle
Counseling addresses recessive inheritance, variant interpretation, segregation testing and reproductive options. When both parents carry the relevant recessive pathogenic allele, each pregnancy has a 25% chance of an affected child. Consanguinity alone does not establish that risk. Dominant ELMOD3-associated alleles require separate interpretation.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/books/NBK1434/ SUPPORT Other
"If both parents are known to be ... heterozygous ... autosomal recessive ... hearing loss-related ... pathogenic variant ... has at conception a 25% chance of having hearing loss"
The recurrence calculation is conditional on confirmed parental carrier genotypes, not merely a consanguineous pedigree.
Speech, Language and Communication Support
Action: speech and language therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is speech and language therapy, annotated with Speech Language Therapy (NCIT:C159273). NCIT:C159273 is a clinical intervention from the NCI Thesaurus. Ontology label: Speech Language Therapy NCIT:C159273
Platform: Behavioral / lifestyle
Early, individualized speech, language, educational and communication support accompanies audiological management. D/deaf and hard-of-hearing community resources should be adapted to the child and family. This is general hearing-loss care, with no DFNB88-specific intervention trial implied.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/books/NBK1434/ SUPPORT Other
"A speech-language therapist as well as a neuropsychologist/psychologist for children with hearing loss provides access to resources within the community to aid in speech and language and D/deaf and hard of hearing (DHH) identity development."
General hearing-loss guidance supports communication services; no disease-specific treatment outcome is asserted.
🔬

Diagnosis

3
Molecular diagnosis and variant interpretation
Molecular evaluation of recessive prelingual hearing loss can include a multigene panel or genomic testing with ELMOD3 analysis. Interpretation requires phenotype, inheritance, segregation and variant-level evidence; a variant of uncertain significance does not confirm DFNB88. The original family was solved by linkage and exome sequencing after excluding known loci. Dominant ELMOD3-associated hearing loss must be distinguished from recessive DFNB88.
Show evidence (4 references)
PMID:24039609 SUPPORT Human Clinical
"We initially observed that deafness in family PKDF468 did not co-segregate with short tandem repeat (STR) markers for 74 of the reported recessive nonsyndromic deafness loci"
The exclusion of the known loci, which is what made a novel locus the working hypothesis.
PMID:24039609 SUPPORT Human Clinical
"Although, ELMOD3 is located outside the reported linkage interval of DFNA43"
The relationship between the recessive and dominant loci at 2p, which is the specific confusion this diagnostic note exists to prevent.
url:https://www.ncbi.nlm.nih.gov/books/NBK1434/ SUPPORT Other
"A multigene hearing loss panel ... can often identify the cause of genetic hearing loss while limiting identification of pathogenic variants and variants of ... uncertain significance ... in genes that are irrelevant to the underlying"
General genetic hearing-loss diagnostic guidance, applied to an ELMOD3 differential.
+ 1 more reference
Temporal-bone computed tomography
Temporal-bone CT in V:2 and V:11, with normal-hearing sibling V:7 as a comparison, showed well-aerated middle ears and mastoids. V:11 had a slightly narrow right internal auditory canal. These findings do not explain the mixed audiograms or exclude every functional or subtle structural cause of an air-bone gap. V:5, whose large bilateral gap is specifically described, was not among those scanned.
Show evidence (4 references)
PMID:24039609 SUPPORT Human Clinical
"CT scan of individual V:2 revealed all three semicircular and internal auditory canals were intact on both sides."
The inner-ear anatomy in the more completely scanned patient.
PMID:24039609 SUPPORT Human Clinical
"Imaging of individual V:11 demonstrated a slightly narrow appearing internal auditory canal on the right side only."
The only positive imaging finding in the series, recorded with its laterality because a unilateral narrow canal cannot explain a bilateral loss.
PMID:24039609 SUPPORT Human Clinical
"To determine the temporal bone malformation, we performed computed tomography (CT) scans of two affected (V:2 and V:11) along with a normal hearing sibling (V:7)."
Identifies the imaged individuals, avoiding conflation with V:5.
+ 1 more reference
Audiological and vestibular assessment
Air- and bone-conduction audiometry establishes the mixed hearing phenotype and distinguishes its conductive and sensorineural components. The defining family had no clear vestibular impairment on history and Romberg/tandem-gait examination; this is not equivalent to a comprehensive vestibular laboratory assessment.
Show evidence (2 references)
PMID:24039609 SUPPORT Human Clinical
"Pure-tone bone and air-conduction audiometry revealed severe-to-profound mixed (conductive and sensorineural) hearing loss in the affected individuals of family PKDF468"
Both audiometric modalities were used.
PMID:24039609 SUPPORT Human Clinical
"The family history revealed that the onset of hearing loss was pre-lingual, with no clear vestibular impairment among the deaf individuals."
The reported absence of clear vestibular symptoms does not establish normality on every vestibular test.
📊

Prevalence

1
Worldwide
Cases In Literature Unknown
The defining 2013 report describes one consanguineous Pakistani family. It does not provide a population denominator or prevalence estimate. The separate homozygous ELMOD3/CAPG/SH2D6 deletion report describes a possible contiguous-gene syndrome and is not pooled with isolated DFNB88.
Show evidence (1 reference)
PMID:24039609 SUPPORT Human Clinical
"Exome sequencing coupled with homozygosity mapping was used to identify a transition mutation (c.794T>C; p.Leu265Ser) in ELMOD3 at the DFNB88 locus that is associated with nonsyndromic deafness in a large Pakistani family, PKDF468."
An ascertained family establishes the clinical association, not population prevalence.
🧫

Experimental Models

3
p.Leu265Ser expression in cochlear explants PRIMARY_CELL_CULTURE
Organotypic cochlear explants transfected with wild-type or p.Leu265Ser GFP-ELMOD3 reveal variant-specific failure of stereociliary targeting.
Cell source
P2 C57BL/6J mouse organ-of-Corti explants
Publication
PMID:24039609
Pathograph links
Impaired ELMOD3 Targeting to Stereocilia measures fidelity: moderate Tagged patient-variant protein remains predominantly cytosolic rather than concentrating in stereocilia.
Limitations: Cultured mouse tissue with overexpressed human protein; not endogenous patient protein, an in-vivo knock-in, or a hearing-rescue experiment.
Show evidence (1 reference)
PMID:24039609 SUPPORT In Vitro
"Mouse organ of Corti hair cell that was transfected with GFP-ELMOD3 (p.Leu265Ser). No concentration and only negligible fluorescence is observed in the stereocilia"
Direct variant-specific targeting experiment in cultured mouse cochlear tissue; overexpression is not an in-vivo knock-in.
Recombinant ELMOD3 GAP and localization assays CELL_LINE
Recombinant wild-type and patient-variant ELMOD3 were compared in ARL2 GAP assays and epithelial-cell localization experiments. Cytochalasin-D disruption and recovery indicate actin-dependent localization; weak F-actin co-sedimentation is not reduced by p.Leu265Ser.
Cell source
HEK293T expression for protein purification; CL4 and MDCK epithelial cells for localization
Publication
PMID:24039609
Pathograph links
Loss of ARL2 GTPase-Activating Activity measures fidelity: moderate Purified mutant protein has activity at the assay floor.
Limitations: Recombinant activity does not identify the physiological inner-ear substrate or quantify mutant activity in patient tissue.
Show evidence (1 reference)
PMID:24039609 SUPPORT In Vitro
"Thus, we can safely conclude that the point mutant has at least a 10-fold lower specific activity than the wild-type protein, but it might be completely inactive as an Arl2 GAP."
The full-text result sets a lower bound on activity loss; mutant activity was at the assay floor and indistinguishable from GST alone.
Impaired ELMOD3 Targeting to Stereocilia measures fidelity: low CL4 microvilli and MDCK membrane localization are impaired by the patient variant.
Limitations: Non-hair-cell overexpression models cannot reproduce the architecture or function of the cochlear bundle.
Show evidence (1 reference)
PMID:24039609 SUPPORT In Vitro
"Fluorescently tagged ELMOD3 co-localized with the actin cytoskeleton in MDCK cells and actin-based microvilli of LLC-PK1-CL4 epithelial cells. The p.Leu265Ser mutation in the ELMO domain impaired each of these activities."
Variant-dependent mislocalization in heterologous epithelial cells.
Elmod3-disrupted mouse embryonic fibroblasts CELL_LINE
Multiple predicted-null clones show reduced ciliation, selective ciliary cargo depletion and Golgi cargo accumulation. Multiple clones and re-expression support specificity, but the authors could not confirm endogenous protein absence with available antibodies. Gross F-actin organization and several other cellular structures were preserved, so the fibroblast results should not be equated with the cochlear actin phenotype.
Cell source
Immortalized mouse embryonic fibroblasts with CRISPR-disrupted Elmod3
Publication
PMID:34818063
Pathograph links
Reduced Primary Cilium Formation measures fidelity: low CRISPR disruption of Elmod3 in immortalized mouse embryonic fibroblasts reduces the fraction of ciliated cells after serum starvation. Normal CEP164 recruitment and CP110 removal place the observed defect after early ciliogenesis licensing. This is a candidate ELMOD3 function relevant to developing hair-cell kinocilia, not a demonstrated DFNB88 cochlear lesion.
Limitations: Fibroblasts with predicted-null alleles, not hair cells carrying p.Leu265Ser. The relation of these findings to human hearing loss is provisional.
Show evidence (1 reference)
PMID:34818063 SUPPORT In Vitro
"We found that ciliation was strongly decreased in Elmod1 and Elmod3 single KO MEFs, with <10% of cells on average having a cilium after 24 hr of serum starvation, compared with >60% in WT controls"
A direct cell-model ciliation measurement; neither human DFNB88 nor cochlear cilia were measured.
Altered Ciliary Cargo Localization measures fidelity: low Elmod3-deficient fibroblasts show depletion of ARL13B, ARL3 and INPP5E from remaining cilia. IFT88, IFT140 and GLI3 localization is preserved, indicating selective cargo effects rather than a universal transport failure. These results have not been reproduced in DFNB88 patient cells or cochlear hair cells.
Limitations: Fibroblasts with predicted-null alleles, not hair cells carrying p.Leu265Ser. The relation of these findings to human hearing loss is provisional.
Show evidence (1 reference)
PMID:34818063 SUPPORT In Vitro
"We also discovered changes in the ciliary content of at least three proteins in cells lacking ELMOD1 and/or ELMOD3: ARL13B, ARL3, and INPP5E."
Selective loss of ciliary cargo is a direct cell-model observation, not evidence of a human multisystem ciliopathy.
Golgi Accumulation of Ciliary Cargo measures fidelity: low INPP5E and IFT140 accumulate at the Golgi in Elmod3-deficient fibroblasts. INPP5E accumulation is more prominent after 24 than 72 hours of serum starvation, and its detection depends on fixation conditions. Delayed export is proposed; ciliary IFT140 localization remains preserved despite its increased Golgi pool.
Limitations: Fibroblasts with predicted-null alleles, not hair cells carrying p.Leu265Ser. The relation of these findings to human hearing loss is provisional.
Show evidence (1 reference)
PMID:34818063 SUPPORT In Vitro
"In contrast, the presence of INPP5E at the Golgi is evident in well over half of all Elmod1, Elmod3, and DKO cell lines after 24 h of serum starvation"
Direct Golgi localization result in serum-starved fibroblasts. The effect waned at later times.
Reduced Primary Cilium Formation rescues fidelity: low Fast-cycling ARL3 or ARL16 restores ciliation toward wild-type levels; ARF1 and ARF5 constructs do not.
Limitations: Overexpression rescue in fibroblasts does not demonstrate direct substrate specificity, rescue of hearing, or clinical efficacy.
Show evidence (1 reference)
PMID:34818063 SUPPORT In Vitro
"Expression of either activated ARL3-myc or ARL16-myc restored ciliation percentages near WT levels"
Fast-cycling ARL3 or ARL16 bypasses the ciliation defect in transfected fibroblasts; this does not identify a direct GAP substrate or establish therapy.
The published correction (PMID:35612986; PMC9561853) replaces duplicated double-knockout images in Figure 4E for the serum-containing condition; text, legend and conclusions were unchanged. The cell-model findings remain separate from the cochlear disease mechanism.
🐁

Animal Models

1
Elmod3 constitutive knockout mouse
A constitutive 277-bp exon-6 deletion introduces a premature stop at residue 149; ELMOD3 protein was undetectable in homozygous cochlea. ABR thresholds were normal at one month and elevated from two months, worsening at five months. Heterozygotes tested at two months had normal thresholds; this does not exclude later effects or model every dominant human allele.
Species
Mouse
Genotype
Elmod3 exon 6 frameshift null allele, homozygous, on C57BL/6
Genes
ELMOD3 hgnc:26158 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns ELMOD3 (hgnc:26158). hgnc:26158 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:31628468
Pathograph links
Disorganized Stereociliary Actin Cytoskeleton recapitulates fidelity: moderate observes: cellular Phalloidin signal is much weaker throughout the knockout cochlea, most markedly in hair cells, and stereocilia formation and maturation are already delayed at postnatal day 1.
Limitations: The mouse null and human missense allele are distinct. Recombinant p.Leu265Ser protein is stable in the tested expression system, but patient hair-cell abundance was not measured. Mouse phalloidin abnormalities do not directly establish human bundle actin pathology.
Readouts
Cochlear F-actin content by phalloidin staining
Direction: DECREASED
Interpretation: Reduced phalloidin signal across hair cells, supporting cells, spiral ganglion and spiral ligament in the knockout compared with wild type.
Show evidence (1 reference)
PMID:31628468 SUPPORT Model Organism
"These results indicated a reduction of F-actin cytoskeleton formation in Elmod3 KO mice and therefore suggested that Elmod3 is required for the proper organization of F-actin networks."
The measurement and the direction of change.
Show evidence (1 reference)
PMID:31628468 SUPPORT Model Organism
"Our finding associates Elmod3 deficiencies with stereocilia dysmorphologies and reveals that they might play roles in the actin cytoskeleton dynamics in cochlear hair cells, and thus relate to hearing impairment."
Why this model is treated as informative for the actin node.
Inner Hair Cell Stereocilia Shortening and Fusion recapitulates fidelity: moderate observes: cellular Inner hair cell stereocilia are significantly shortened at two months and by five months show noticeable degeneration, with a few inner hair cells lacking bundles entirely.
Limitations: The human bundle has never been examined, so the correspondence is between a mouse structural phenotype and a human audiogram. The direction is also the opposite of the paralogue Elmod1 knockout, in which stereocilia elongate, so the bundle consequence of losing an ELMOD protein is not generic and should not be transferred between them.
Show evidence (1 reference)
PMID:31628468 SUPPORT Model Organism
"stereocilia of IHCs were significantly shortened in Elmod3−/− mice compared with the WT littermates"
Scanning electron microscopy directly documents inner-hair-cell bundle shortening at two months.
Cochlear Sensory Transduction Failure partially recapitulates fidelity: low observes: organism The mouse goes deaf, which is the right outcome, but on a completely different schedule from the humans: thresholds are normal at one month, shift from two months, and worsen to five months.
Limitations: PKDF468 has prelingual severe-to-profound mixed hearing impairment, whereas null mice have normal ABR thresholds at one month and elevated thresholds from two months. ABR/DPOAE tests without dedicated middle-ear assessment cannot establish that the mouse phenotype is purely sensorineural.
Divergences from the human mechanism
boundary omission qualifying
The human air-bone gap has not been adequately assessed in the mouse. ABR and DPOAE thresholds were measured, but no dedicated functional middle-ear assessment was reported.
species mismatch qualifying
Reported onset differs between the prelingual human phenotype and threshold elevation from mouse postnatal month two. Species, genetic background and missense-versus-null effects are not separated by this comparison.
Show evidence (1 reference)
PMID:31628468 SUPPORT Model Organism
"We found that Elmod3−/− mice exhibited significant HL beginning at the age of 2 months and progressed with age."
The model's hearing phenotype and its timing, which is what this link is cited for and also what diverges from the human course.
Reduced Cochlear ARL2 Abundance measures fidelity: low Elmod3-null cochleae show reduced ARL2 protein by early postnatal immunoblotting and reduced immunolabeling in cochlear cells. This is a change in protein abundance, not a measurement of ARL2 activation or GTP hydrolysis. Whether restoring ARL2 rescues hearing or bundle structure remains unknown.
Limitations: A mouse null observation; contribution of this specific change to hearing loss and correspondence to human p.Leu265Ser have not been established.
Show evidence (1 reference)
PMID:31628468 SUPPORT Model Organism
"Western blotting assays of ARL2 protein expression level in postnatal 7 days mice cochlea of WT mice and Elmod3−/− mice. Expression level of ARL2 protein in Elmod3−/− mice were reduced compared with WT mice"
The figure legend directly reports reduced protein abundance at postnatal day seven, distinct from GAP catalytic activity.
Outer Hair Cell Stereocilia Degeneration measures fidelity: low Elmod3-null mice have more missing outer-hair-cell bundles than age-matched wild-type mice at five months; surviving bundles show looser stereociliary connections. The structural finding is distinguished from the functional inference of impaired cochlear amplification.
Limitations: A mouse null observation; contribution of this specific change to hearing loss and correspondence to human p.Leu265Ser have not been established.
Show evidence (1 reference)
PMID:31628468 SUPPORT INDIRECT Model Organism
"stereocilia of OHCs were missing in both Elmod3−/− and WT mice with an increased frequency of losses in Elmod3−/− mice compared with WT mice"
The outer hair cell bundle loss, measured against wild-type littermates of the same age so that ordinary age-related loss is controlled for. INDIRECT because it is a mouse.
Impaired Cochlear Amplification measures fidelity: low DPOAE thresholds rise from two months in Elmod3-null mice and worsen with age, consistent with impaired outer-hair-cell-dependent amplification. DPOAEs also depend on sound transmission through the middle ear; these measurements alone do not exclude a conductive contribution.
Limitations: A mouse null observation; contribution of this specific change to hearing loss and correspondence to human p.Leu265Ser have not been established.
Show evidence (1 reference)
PMID:31628468 SUPPORT INDIRECT Model Organism
"the shifting of DPOAE thresholds indicated the reduction of the force coupled into the cochlear amplifier by OHCs motility"
DPOAE threshold shifts support impaired cochlear amplification, without directly measuring outer-hair-cell force.
{ }

Source YAML

click to show 
name: Autosomal Recessive Nonsyndromic Hearing Loss 88
category: Mendelian
creation_date: '2026-09-17T00:00:00Z'
synonyms:
- DFNB88
- deafness, autosomal recessive 88
- autosomal recessive deafness 88
- autosomal recessive nonsyndromic deafness caused by mutation in ELMOD3
- ELMOD3 autosomal recessive nonsyndromic deafness
description: DFNB88 is a recessive ELMOD3-associated hearing disorder defined in the consanguineous Pakistani family PKDF468 by homozygous p.Leu265Ser and prelingual, severe-to-profound mixed hearing loss. The variant markedly reduces recombinant ARL2 GTPase-activating activity and impairs ELMOD3 targeting to stereocilia in cultured mouse cochlear explants. Elmod3-null mice develop cochlear F-actin abnormalities, stereociliary degeneration and progressive hearing impairment. The physiological GTPase substrate in the inner ear and the cause of the human conductive component remain unresolved; the mouse null allele and human missense allele also differ in their reported hearing-loss onset.
disease_term:
  preferred_term: autosomal recessive nonsyndromic hearing loss 88
  term:
    id: MONDO:0014182
    label: autosomal recessive nonsyndromic hearing loss 88
parents:
- Autosomal Recessive Nonsyndromic Hearing Loss
- Hereditary Hearing Loss
references:
- reference: PMID:24039609
  title: An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans.
- reference: PMID:31628468
  title: Elmod3 knockout leads to progressive hearing loss and abnormalities in cochlear hair cell stereocilia.
- reference: PMID:29713870
  title: ELMOD3, a novel causative gene, associated with human autosomal dominant nonsyndromic and progressive hearing loss.
- reference: PMID:30284680
  title: Homozygous 2p11.2 deletion supports the implication of ELMOD3 in hearing loss and reveals the potential association of CAPG with ASD/ID etiology.
- reference: PMID:37708136
  title: Gene regulation analysis of patient-derived iPSCs and its CRISPR-corrected control provides a new tool for studying perturbations of ELMOD3 c.512A>G mutation during the development of inherited hearing loss.
- reference: PMID:34818063
  title: The ARF GAPs ELMOD1 and ELMOD3 act at the Golgi and cilia to regulate ciliogenesis and ciliary protein traffic.
- reference: PMID:24616099
  title: Characterization of recombinant ELMOD (cell engulfment and motility domain) proteins as GTPase-activating proteins (GAPs) for ARF family GTPases.
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC4036250/
  title: Characterization of Recombinant ELMOD (Cell Engulfment and Motility Domain) Proteins as GTPase-activating Proteins (GAPs) for ARF Family GTPases - PMC
- reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1434/
  title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
  tags:
  - GeneReviews
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9561853/
  title: The ARF GAPs ELMOD1 and ELMOD3 act at the Golgi and cilia to regulate ciliogenesis and ciliary protein traffic - PMC
inheritance:
- name: Autosomal recessive
  description: The defining consanguineous family segregates homozygous c.794T>C (p.Leu265Ser) with hearing loss; heterozygous relatives were reported to hear normally. Linkage used a fully penetrant recessive model and a disease-allele frequency of 0.001, yielding a maximum LOD score of 4.74. Those model inputs are not population allele-frequency or penetrance estimates. A separate homozygous deletion involving ELMOD3, CAPG and SH2D6 supports biallelic gene involvement in hearing loss but is not an isolated DFNB88 family.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:24039609
    reference_title: An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Exome sequencing coupled with homozygosity mapping was used to identify a transition mutation (c.794T>C; p.Leu265Ser) in ELMOD3 at the DFNB88 locus that is associated with nonsyndromic deafness in a large Pakistani family, PKDF468.
    explanation: The gene, the allele, the locus and the recessive study design in one sentence.
  - reference: PMID:24039609
    reference_title: An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: haplotype analysis revealed a 0.91 Mb linkage interval that was delimited by the markers D2S1387 and D2S2232
    explanation: The homozygous interval on 2p11.2 that defines DFNB88, from the genome-wide linkage scan.
  - reference: PMID:30284680
    reference_title: Homozygous 2p11.2 deletion supports the implication of ELMOD3 in hearing loss and reveals the potential association of CAPG with ASD/ID etiology.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: we identified a rare homozygous deletion in 2p11.2 region that affects ELMOD3, CAPG, and SH2D6 genes in a boy with ASD, intellectual disability (ID), and hearing impairment (HI)
    explanation: A second, independent biallelic ELMOD3 loss with hearing impairment. Graded INDIRECT because the deletion removes two further genes, so it supports the recessive model for the gene without being a DFNB88 observation.
pathophysiology:
- name: ELMOD3 Biallelic Loss of Function
  biological_scale: MOLECULAR
  role: trigger
  mechanism_confidence: ESTABLISHED
  description: Homozygous c.794T>C (p.Leu265Ser; NM_032213.4 in the original report) affects a conserved residue in the ELMO domain and segregates with hearing loss in PKDF468. The substitution is predicted in all ELMO-domain-containing isoforms described in that study. Recombinant mutant protein had expression and purification yields similar to wild type; this does not establish its abundance in patient hair cells. Leukocyte cDNA assays found no aberrant splicing in the tested exon intervals.
  genes:
  - preferred_term: ELMOD3
    term:
      id: hgnc:26158
      label: ELMOD3
  genetic_context:
    genes:
    - preferred_term: ELMOD3
      term:
        id: hgnc:26158
        label: ELMOD3
    allele_type: missense variant in the ELMO/CED12 domain
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  downstream:
  - target: Loss of ARL2 GTPase-Activating Activity
    causal_link_type: DIRECT
    description: Purified recombinant p.Leu265Ser has at least a tenfold reduction in ARL2 GAP activity, approaching the assay detection limit.
    evidence:
    - reference: PMID:24039609
      reference_title: An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Thus, we can safely conclude that the point mutant has at least a 10-fold lower specific activity than the wild-type protein, but it might be completely inactive as an Arl2 GAP.
      explanation: The full-text result sets a lower bound on activity loss; mutant activity was at the assay floor and indistinguishable from GST alone.
  - target: Impaired ELMOD3 Targeting to Stereocilia
    causal_link_type: DIRECT
    description: The patient variant directly changes targeting in transfected cochlear explants.
    evidence:
    - reference: PMID:24039609
      reference_title: An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Mouse organ of Corti hair cell that was transfected with GFP-ELMOD3 (p.Leu265Ser). No concentration and only negligible fluorescence is observed in the stereocilia
      explanation: Direct variant-specific targeting experiment in cultured mouse cochlear tissue; overexpression is not an in-vivo knock-in.
  - target: Reduced Cochlear ARL2 Abundance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The constitutive Elmod3 null reduces cochlear ARL2 abundance; the same effect has not been demonstrated for the human missense allele.
    evidence:
    - reference: PMID:31628468
      reference_title: Elmod3 knockout leads to progressive hearing loss and abnormalities in cochlear hair cell stereocilia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Western blotting assays of ARL2 protein expression level in postnatal 7 days mice cochlea of WT mice and Elmod3−/− mice. Expression level of ARL2 protein in Elmod3−/− mice were reduced compared with WT mice
      explanation: The figure legend directly reports reduced protein abundance at postnatal day seven, distinct from GAP catalytic activity.
      directness: INDIRECT
  - target: Reduced Primary Cilium Formation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Gene disruption produces this phenotype in fibroblasts; transfer to the patient missense allele and inner ear remains untested.
    evidence:
    - reference: PMID:34818063
      reference_title: The ARF GAPs ELMOD1 and ELMOD3 act at the Golgi and cilia to regulate ciliogenesis and ciliary protein traffic.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: We found that ciliation was strongly decreased in Elmod1 and Elmod3 single KO MEFs, with <10% of cells on average having a cilium after 24 hr of serum starvation, compared with >60% in WT controls
      explanation: A direct cell-model ciliation measurement; neither human DFNB88 nor cochlear cilia were measured.
      directness: INDIRECT
  - target: Altered Ciliary Cargo Localization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Gene disruption produces this phenotype in fibroblasts; transfer to the patient missense allele and inner ear remains untested.
    evidence:
    - reference: PMID:34818063
      reference_title: The ARF GAPs ELMOD1 and ELMOD3 act at the Golgi and cilia to regulate ciliogenesis and ciliary protein traffic.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: 'We also discovered changes in the ciliary content of at least three proteins in cells lacking ELMOD1 and/or ELMOD3: ARL13B, ARL3, and INPP5E.'
      explanation: Selective loss of ciliary cargo is a direct cell-model observation, not evidence of a human multisystem ciliopathy.
  - target: Golgi Accumulation of Ciliary Cargo
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Gene disruption produces this phenotype in fibroblasts; transfer to the patient missense allele and inner ear remains untested.
    evidence:
    - reference: PMID:34818063
      reference_title: The ARF GAPs ELMOD1 and ELMOD3 act at the Golgi and cilia to regulate ciliogenesis and ciliary protein traffic.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: In contrast, the presence of INPP5E at the Golgi is evident in well over half of all Elmod1, Elmod3, and DKO cell lines after 24 h of serum starvation
      explanation: Direct Golgi localization result in serum-starved fibroblasts. The effect waned at later times.
      directness: INDIRECT
  evidence:
  - reference: PMID:24039609
    reference_title: An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The c.794T>C transition mutation is predicted to result in the substitution of serine for a highly conserved leucine in all of the ELMO domain-containing isoforms of ELMOD3
    explanation: The substitution affects the ELMO-domain-containing isoforms examined by sequence annotation; this does not exclude every tissue-specific transcript or establish patient protein abundance.
- name: Loss of ARL2 GTPase-Activating Activity
  biological_scale: MOLECULAR
  role: mediator
  mechanism_confidence: ESTABLISHED
  description: Recombinant p.Leu265Ser ELMOD3 has at least tenfold lower ARL2 GAP activity than wild type, with residual signal at the assay floor. Complete inactivity cannot be distinguished from very low activity. Biochemical substrate panels also detect weak ELMOD3 activity against other ARF-family GTPases; the relevant inner-ear substrate and tissue GTP/GDP state have not been established.
  molecular_functions:
  - preferred_term: ARL2 GTPase-activating protein activity
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0005096
      label: GTPase activator activity
  downstream:
  - target: Disorganized Stereociliary Actin Cytoskeleton
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: An effect of lost GAP activity on hair-bundle actin is proposed, but the intervening GTPase and actin regulator have not been demonstrated.
    evidence:
    - reference: PMID:24039609
      reference_title: An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: We therefore speculate that ELMOD3 functions as a GAP for Arl2 and perhaps other GTPases that participate in actin organization, polymerization or depolymerization in the cochlear hair bundles
      explanation: This is the authors' explicitly speculative mechanistic interpretation.
      directness: INDIRECT
  evidence:
  - reference: PMID:24039609
    reference_title: An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Thus, we can safely conclude that the point mutant has at least a 10-fold lower specific activity than the wild-type protein, but it might be completely inactive as an Arl2 GAP.
    explanation: The full-text result sets a lower bound on activity loss; mutant activity was at the assay floor and indistinguishable from GST alone.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC4036250/
    reference_title: Characterization of Recombinant ELMOD (Cell Engulfment and Motility Domain) Proteins as GTPase-activating Proteins (GAPs) for ARF Family GTPases - PMC
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: the very low activities found for ELMOD3 may lead one even to question whether it acts in cells as an ARF family GAP.
    explanation: The biochemical study cautions against inferring a physiological substrate or disease severity from weak recombinant GAP activity.
    directness: INDIRECT
  notes: ARL2 protein abundance in knockout cochlea is a separate observation, represented in its own node. Sigma-1 receptor bound ELMOD3 in co-immunoprecipitation experiments, but the reported functional inhibition assays tested ELMOD1 and ELMOD2; they do not establish an ELMOD3-directed treatment.
- name: Impaired ELMOD3 Targeting to Stereocilia
  biological_scale: CELLULAR
  role: mediator
  mechanism_confidence: ESTABLISHED
  description: 'Overexpressed GFP-tagged p.Leu265Ser fails to concentrate in stereocilia of P2 mouse cochlear explants and shows weak or absent targeting to espin-elongated CL4 microvilli and MDCK plasma membranes. Wild-type rodent immunolocalization supports a hair-bundle context, but the antibody recognized isoform b rather than all ELMOD3 isoforms. The targeting defect is distinct from loss of direct actin binding: weak F-actin co-sedimentation of recombinant protein was unchanged by the variant.'
  cell_types:
  - preferred_term: cochlear inner hair cell
    term:
      id: CL:0000589
      label: cochlear inner hair cell
  - preferred_term: cochlear outer hair cell
    term:
      id: CL:0000601
      label: cochlear outer hair cell
  cellular_components:
  - preferred_term: stereocilium
    term:
      id: GO:0032420
      label: stereocilium
  locations:
  - preferred_term: spiral organ of Corti
    term:
      id: UBERON:0002227
      label: spiral organ of cochlea
  downstream:
  - target: Disorganized Stereociliary Actin Cytoskeleton
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Loss of correct subcellular targeting may impair local ELMOD3 function, but no experiment isolates targeting failure as the cause of bundle actin abnormalities.
    evidence:
    - reference: PMID:24039609
      reference_title: An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: These results suggest that the localization of ELMOD3 is dependent on the actin cytoskeleton and/or may contribute to a mechanism that supports its maintenance.
      explanation: The source leaves the direction and molecular basis of the actin-localization relationship unresolved.
      directness: INDIRECT
  evidence:
  - reference: PMID:24039609
    reference_title: An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Mouse organ of Corti hair cell that was transfected with GFP-ELMOD3 (p.Leu265Ser). No concentration and only negligible fluorescence is observed in the stereocilia
    explanation: Direct variant-specific targeting experiment in cultured mouse cochlear tissue; overexpression is not an in-vivo knock-in.
  - reference: PMID:24039609
    reference_title: An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: In vitro, the association of ELMOD3 with F-actin was unaffected by the Leu265Ser mutation in the ELMO domain
    explanation: 'Supports the mechanistic distinction: the localization defect occurs despite preserved weak F-actin association in this recombinant assay.'
  - reference: PMID:24039609
    reference_title: An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Our antibodies specifically recognized ELMOD3 isoform b but not murine ELMOD1, ELMOD2, or ELMOD3 isoform a
    explanation: Normal-tissue localization with this reagent is isoform-limited; absence of vestibular bundle staining does not establish the cause of clinical vestibular sparing.
- name: Reduced Cochlear ARL2 Abundance
  biological_scale: MOLECULAR
  role: mediator
  mechanism_confidence: PROVISIONAL
  description: Elmod3-null cochleae show reduced ARL2 protein by early postnatal immunoblotting and reduced immunolabeling in cochlear cells. This is a change in protein abundance, not a measurement of ARL2 activation or GTP hydrolysis. Whether restoring ARL2 rescues hearing or bundle structure remains unknown.
  evidence:
  - reference: PMID:31628468
    reference_title: Elmod3 knockout leads to progressive hearing loss and abnormalities in cochlear hair cell stereocilia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Western blotting assays of ARL2 protein expression level in postnatal 7 days mice cochlea of WT mice and Elmod3−/− mice. Expression level of ARL2 protein in Elmod3−/− mice were reduced compared with WT mice
    explanation: The figure legend directly reports reduced protein abundance at postnatal day seven, distinct from GAP catalytic activity.
  downstream:
  - target: Disorganized Stereociliary Actin Cytoskeleton
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced ARL2 abundance is a proposed contributor to F-actin abnormalities, without a demonstrated intermediate or rescue.
    evidence:
    - reference: PMID:31628468
      reference_title: Elmod3 knockout leads to progressive hearing loss and abnormalities in cochlear hair cell stereocilia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Loss of Elmod3 and reduction in ARL2 expression level are likely responsible for the altered hair bundle morphology observed in Elmod3
      explanation: The authors associate decreased cochlear ARL2 abundance with bundle abnormalities; a causal rescue was not performed.
      directness: INDIRECT
- name: Disorganized Stereociliary Actin Cytoskeleton
  biological_scale: CELLULAR
  role: mediator
  mechanism_confidence: PROVISIONAL
  description: Elmod3-null mice show weaker cochlear phalloidin staining, involving hair cells, supporting cells, spiral ganglion and spiral ligament. Bundle formation appears delayed at postnatal day 1, although scanning electron microscopy at day 14 shows similar gross morphology to wild type. Later stereociliary shortening and degeneration support disturbed actin organization or maintenance; the precise molecular link to ELMOD3 remains provisional.
  biological_processes:
  - preferred_term: auditory receptor cell stereocilium organization
    modifier: DECREASED
    term:
      id: GO:0060088
      label: auditory receptor cell stereocilium organization
  cell_types:
  - preferred_term: sensory hair cell
    term:
      id: CL:0000855
      label: sensory hair cell
  downstream:
  - target: Inner Hair Cell Stereocilia Shortening and Fusion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The inner hair cell arm of the bundle phenotype.
    evidence:
    - reference: PMID:31628468
      reference_title: Elmod3 knockout leads to progressive hearing loss and abnormalities in cochlear hair cell stereocilia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: The deafness associated with the mutation may be caused by cochlear hair cells dysfunction, which manifests with shortening and fusion of inner hair cells stereocilia and progressive degeneration of outer hair cells stereocilia.
      explanation: Both bundle phenotypes in one sentence. INDIRECT because it is a mouse and because the authors state the causal link as a possibility.
  - target: Outer Hair Cell Stereocilia Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The outer hair cell arm of the bundle phenotype.
    evidence:
    - reference: PMID:31628468
      reference_title: Elmod3 knockout leads to progressive hearing loss and abnormalities in cochlear hair cell stereocilia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: stereocilia of OHCs were missing in both Elmod3−/− and WT mice with an increased frequency of losses in Elmod3−/− mice compared with WT mice
      explanation: The outer hair cell bundle loss, measured against wild-type littermates of the same age so that ordinary age-related loss is controlled for. INDIRECT because it is a mouse.
  evidence:
  - reference: PMID:31628468
    reference_title: Elmod3 knockout leads to progressive hearing loss and abnormalities in cochlear hair cell stereocilia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: These results indicated a reduction of F-actin cytoskeleton formation in Elmod3 KO mice and therefore suggested that Elmod3 is required for the proper organization of F-actin networks.
    explanation: 'The direct measurement behind this node: less F-actin in the knockout cochlea, and the authors'' conclusion from it.'
  - reference: PMID:24039609
    reference_title: An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: We therefore speculate that ELMOD3 functions as a GAP for Arl2 and perhaps other GTPases that participate in actin organization, polymerization or depolymerization in the cochlear hair bundles
    explanation: The proposed route from GAP activity to bundle actin. Quoted with its hedge intact and graded INDIRECT because it is explicitly the authors' speculation, not a result.
- name: Inner Hair Cell Stereocilia Shortening and Fusion
  biological_scale: CELLULAR
  role: effector
  mechanism_confidence: PROVISIONAL
  description: In the knockout mouse, inner hair cell stereocilia are significantly shortened by two months - the age at which thresholds first shift - and by five months every inner hair cell shows bundle degeneration, some with no bundle at all. Hair cell bodies themselves are largely preserved, so this is a bundle lesion rather than hair cell death.
  cell_types:
  - preferred_term: cochlear inner hair cell
    term:
      id: CL:0000589
      label: cochlear inner hair cell
  downstream:
  - target: Cochlear Sensory Transduction Failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Bundle shortening and degeneration coincide with hearing-threshold elevation; altered mechanotransduction is inferred because hair-cell transduction currents were not recorded.
    evidence:
    - reference: PMID:31628468
      reference_title: Elmod3 knockout leads to progressive hearing loss and abnormalities in cochlear hair cell stereocilia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: Shortened stereocilia in IHCs of Elmod3−/− mice were discovered at the age of 2 months and found to worsen in the later life of Elmod3−/− mice, which is consistent with the timing of the increased hearing threshold onset
      explanation: 'The bundle lesion and the threshold shift arrive together, which is the observation linking this node to hearing. INDIRECT: it is a mouse, and the link is a temporal coincidence rather than an intervention.'
  evidence:
  - reference: PMID:31628468
    reference_title: Elmod3 knockout leads to progressive hearing loss and abnormalities in cochlear hair cell stereocilia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: stereocilia of IHCs were significantly shortened in Elmod3−/− mice compared with the WT littermates
    explanation: Scanning electron microscopy directly documents inner-hair-cell bundle shortening at two months.
- name: Outer Hair Cell Stereocilia Degeneration
  biological_scale: CELLULAR
  role: effector
  mechanism_confidence: PROVISIONAL
  description: Elmod3-null mice have more missing outer-hair-cell bundles than age-matched wild-type mice at five months; surviving bundles show looser stereociliary connections. The structural finding is distinguished from the functional inference of impaired cochlear amplification.
  cell_types:
  - preferred_term: cochlear outer hair cell
    term:
      id: CL:0000601
      label: cochlear outer hair cell
  downstream:
  - target: Impaired Cochlear Amplification
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Outer-hair-cell bundle degeneration and DPOAE abnormalities support a structural-functional association; neither intervention nor single-cell force measurement establishes causality.
    evidence:
    - reference: PMID:31628468
      reference_title: Elmod3 knockout leads to progressive hearing loss and abnormalities in cochlear hair cell stereocilia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: the shifting of DPOAE thresholds indicated the reduction of the force coupled into the cochlear amplifier by OHCs motility
      explanation: DPOAE threshold shifts support impaired cochlear amplification, without directly measuring outer-hair-cell force.
      directness: INDIRECT
  evidence:
  - reference: PMID:31628468
    reference_title: Elmod3 knockout leads to progressive hearing loss and abnormalities in cochlear hair cell stereocilia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: stereocilia of OHCs were missing in both Elmod3−/− and WT mice with an increased frequency of losses in Elmod3−/− mice compared with WT mice
    explanation: The outer hair cell bundle loss, measured against wild-type littermates of the same age so that ordinary age-related loss is controlled for. INDIRECT because it is a mouse.
- name: Impaired Cochlear Amplification
  biological_scale: TISSUE
  role: effector
  mechanism_confidence: PROVISIONAL
  description: DPOAE thresholds rise from two months in Elmod3-null mice and worsen with age, consistent with impaired outer-hair-cell-dependent amplification. DPOAEs also depend on sound transmission through the middle ear; these measurements alone do not exclude a conductive contribution.
  evidence:
  - reference: PMID:31628468
    reference_title: Elmod3 knockout leads to progressive hearing loss and abnormalities in cochlear hair cell stereocilia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: the shifting of DPOAE thresholds indicated the reduction of the force coupled into the cochlear amplifier by OHCs motility
    explanation: DPOAE threshold shifts support impaired cochlear amplification, without directly measuring outer-hair-cell force.
    directness: INDIRECT
  cell_types:
  - preferred_term: cochlear outer hair cell
    term:
      id: CL:0000601
      label: cochlear outer hair cell
  downstream:
  - target: Cochlear Sensory Transduction Failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Impaired amplification is a proposed contributor to hearing-threshold elevation.
    evidence:
    - reference: PMID:31628468
      reference_title: Elmod3 knockout leads to progressive hearing loss and abnormalities in cochlear hair cell stereocilia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: the shifting of DPOAE thresholds indicated the reduction of the force coupled into the cochlear amplifier by OHCs motility
      explanation: DPOAE threshold shifts support impaired cochlear amplification, without directly measuring outer-hair-cell force.
      directness: INDIRECT
- name: Cochlear Sensory Transduction Failure
  biological_scale: TISSUE
  role: effector
  mechanism_confidence: PROVISIONAL
  description: The cochlea can no longer turn sound into a neural signal at normal levels. In the mouse this is progressive and measured as auditory brainstem response threshold shifts from two months of age; in the affected members of family PKDF468 it is already established before speech acquisition, and it is the sensorineural half of their mixed audiograms.
  biological_processes:
  - preferred_term: sensory perception of sound
    modifier: DECREASED
    term:
      id: GO:0007605
      label: sensory perception of sound
  locations:
  - preferred_term: cochlea
    term:
      id: UBERON:0001844
      label: cochlea
  downstream:
  - target: Prelingual Mixed Hearing Impairment
    causal_link_type: DIRECT
    description: The sensorineural component of the audiogram. The conductive component is not explained by this node and is curated as an open question.
    evidence:
    - reference: PMID:24039609
      reference_title: An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The affected individuals of this family exhibited pre-lingual, severe-to-profound degrees of mixed hearing loss.
      explanation: The clinical outcome of the mechanism in the defining family.
  - target: Sensorineural Hearing Impairment
    causal_link_type: DIRECT
    description: The sensorineural component of the human mixed hearing loss is consistent with the cochlear mechanism; the conductive component remains unexplained.
    evidence:
    - reference: PMID:24039609
      reference_title: An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Pure-tone bone and air-conduction audiometry revealed severe-to-profound mixed (conductive and sensorineural) hearing loss in the affected individuals of family PKDF468
      explanation: Bone-conduction thresholds are elevated, which is what makes part of this loss sensorineural rather than purely conductive.
  evidence:
  - reference: PMID:31628468
    reference_title: Elmod3 knockout leads to progressive hearing loss and abnormalities in cochlear hair cell stereocilia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: Our finding associates Elmod3 deficiencies with stereocilia dysmorphologies and reveals that they might play roles in the actin cytoskeleton dynamics in cochlear hair cells, and thus relate to hearing impairment.
    explanation: The knockout paper's own statement of the link between the bundle lesion and hearing. INDIRECT because it is a mouse and the authors hedge the mechanistic claim.
  notes: The available data do not demonstrate spiral ganglion degeneration or substantial hair-cell death, so conformance to the combined death/degeneration nodes of the sensorineural_hair_cell_loss module is not asserted. Mouse ABR and DPOAE abnormalities support hearing dysfunction but do not by themselves establish a purely sensorineural phenotype.
- name: Reduced Primary Cilium Formation
  biological_scale: CELLULAR
  role: mediator
  mechanism_confidence: PROVISIONAL
  description: CRISPR disruption of Elmod3 in immortalized mouse embryonic fibroblasts reduces the fraction of ciliated cells after serum starvation. Normal CEP164 recruitment and CP110 removal place the observed defect after early ciliogenesis licensing. This is a candidate ELMOD3 function relevant to developing hair-cell kinocilia, not a demonstrated DFNB88 cochlear lesion.
  evidence:
  - reference: PMID:34818063
    reference_title: The ARF GAPs ELMOD1 and ELMOD3 act at the Golgi and cilia to regulate ciliogenesis and ciliary protein traffic.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We found that ciliation was strongly decreased in Elmod1 and Elmod3 single KO MEFs, with <10% of cells on average having a cilium after 24 hr of serum starvation, compared with >60% in WT controls
    explanation: A direct cell-model ciliation measurement; neither human DFNB88 nor cochlear cilia were measured.
- name: Altered Ciliary Cargo Localization
  biological_scale: CELLULAR
  role: mediator
  mechanism_confidence: PROVISIONAL
  description: Elmod3-deficient fibroblasts show depletion of ARL13B, ARL3 and INPP5E from remaining cilia. IFT88, IFT140 and GLI3 localization is preserved, indicating selective cargo effects rather than a universal transport failure. These results have not been reproduced in DFNB88 patient cells or cochlear hair cells.
  evidence:
  - reference: PMID:34818063
    reference_title: The ARF GAPs ELMOD1 and ELMOD3 act at the Golgi and cilia to regulate ciliogenesis and ciliary protein traffic.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: 'We also discovered changes in the ciliary content of at least three proteins in cells lacking ELMOD1 and/or ELMOD3: ARL13B, ARL3, and INPP5E.'
    explanation: Selective loss of ciliary cargo is a direct cell-model observation, not evidence of a human multisystem ciliopathy.
- name: Golgi Accumulation of Ciliary Cargo
  biological_scale: CELLULAR
  role: mediator
  mechanism_confidence: PROVISIONAL
  description: INPP5E and IFT140 accumulate at the Golgi in Elmod3-deficient fibroblasts. INPP5E accumulation is more prominent after 24 than 72 hours of serum starvation, and its detection depends on fixation conditions. Delayed export is proposed; ciliary IFT140 localization remains preserved despite its increased Golgi pool.
  evidence:
  - reference: PMID:34818063
    reference_title: The ARF GAPs ELMOD1 and ELMOD3 act at the Golgi and cilia to regulate ciliogenesis and ciliary protein traffic.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: In contrast, the presence of INPP5E at the Golgi is evident in well over half of all Elmod1, Elmod3, and DKO cell lines after 24 h of serum starvation
    explanation: Direct Golgi localization result in serum-starved fibroblasts. The effect waned at later times.
phenotypes:
- name: Prelingual Mixed Hearing Impairment
  category: Ear
  description: The defining feature. Pure-tone audiometry in family PKDF468 shows severe-to-profound mixed loss - elevated bone conduction thresholds with an additional air-bone gap - present before speech acquisition. Individual V:5 had a large conductive component in both ears.
  phenotype_term:
    preferred_term: Mixed hearing impairment
    term:
      id: HP:0000410
      label: Mixed hearing impairment
  notes: Audiograms were published for V:2 and V:5 within one family. Prelingual onset was obtained from family history rather than newborn screening. The available ascertainment does not establish a population frequency for mixed loss or a longitudinal human progression pattern.
  evidence:
  - reference: PMID:24039609
    reference_title: An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The affected individuals of this family exhibited pre-lingual, severe-to-profound degrees of mixed hearing loss.
    explanation: Onset, severity and audiometric type in one clause.
  - reference: PMID:24039609
    reference_title: An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The family history revealed that the onset of hearing loss was pre-lingual, with no clear vestibular impairment among the deaf individuals.
    explanation: The onset statement and its source - family history - together with the negative vestibular finding that accompanies it.
- name: Sensorineural Hearing Impairment
  category: Ear
  description: The bone-conduction component of the loss, which is what the hair-bundle mechanism explains. In individual V:2 bone conduction thresholds slope from mild down into the severe range on the right and are near-normal at low frequencies on the left.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  notes: Elevated bone-conduction thresholds establish a sensorineural component in the published audiograms. The severity of the combined air-conduction loss should not be assigned to the sensorineural component alone.
  evidence:
  - reference: PMID:24039609
    reference_title: An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Individual V:2 exhibited severe-to-profound mixed hearing loss, with bone conduction thresholds for the right ear displaying a mild downward slope to the severe hearing loss range.
    explanation: Elevated bone-conduction thresholds in a named individual, which is the audiometric definition of a sensorineural component.
- name: Conductive Hearing Impairment
  category: Ear
  description: An air-bone gap accompanies the sensorineural hearing loss; individual V:5 has a large conductive component in both ears. Temporal-bone CT was reported for V:2 and V:11, with well-aerated middle ears and mastoids. Functional middle-ear measurements were not reported, and the conductive contribution is not explained by the proposed hair-bundle mechanism.
  phenotype_term:
    preferred_term: Conductive hearing impairment
    term:
      id: HP:0000405
      label: Conductive hearing impairment
  notes: The observation comes from one ascertained family and does not support a disease-wide frequency band. The patient with the specifically described large bilateral gap, V:5, was not one of the two affected individuals examined by CT. Preserved aeration does not exclude all ossicular or other conductive disorders.
  evidence:
  - reference: PMID:24039609
    reference_title: An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The audiograms of individual V:5 revealed bilateral severe-to-profound mixed hearing loss, with a large conductive component in both ears.
    explanation: The conductive component, its laterality and its size, in the one individual for whom it is quantified in words.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: UNKNOWN
  notes: The defining 2013 report describes one consanguineous Pakistani family. It does not provide a population denominator or prevalence estimate. The separate homozygous ELMOD3/CAPG/SH2D6 deletion report describes a possible contiguous-gene syndrome and is not pooled with isolated DFNB88.
  evidence:
  - reference: PMID:24039609
    reference_title: An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Exome sequencing coupled with homozygosity mapping was used to identify a transition mutation (c.794T>C; p.Leu265Ser) in ELMOD3 at the DFNB88 locus that is associated with nonsyndromic deafness in a large Pakistani family, PKDF468.
    explanation: An ascertained family establishes the clinical association, not population prevalence.
genetic:
- name: ELMOD3
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: ELMOD3
    term:
      id: hgnc:26158
      label: ELMOD3
  notes: The recessive p.Leu265Ser allele affects the ELMO domain. A separate heterozygous p.His171Arg allele was reported with late-onset progressive dominant hearing loss; interpretation of a heterozygous ELMOD3 finding must therefore be variant-specific. The homozygous deletion of ELMOD3 together with CAPG and SH2D6 is supportive gene-level evidence but does not isolate the contribution of ELMOD3 to the additional neurodevelopmental features.
  evidence:
  - reference: PMID:24039609
    reference_title: An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: To further confirm that the p.Leu265Ser allele of ELMOD3 is the only mutation that was associated with hearing loss at the DFNB88 locus, we sequenced the coding, non-coding, and approximately 75 bp flanking sequences of the exon-intron boundaries of all the known candidate genes present within the linkage region in two affected individuals of family PKDF468.
    explanation: Sequencing other interval genes supported ELMOD3 prioritization; segregation and variant-specific functional findings together support the association, without excluding every possible linked regulatory change.
  - reference: PMID:29713870
    reference_title: ELMOD3, a novel causative gene, associated with human autosomal dominant nonsyndromic and progressive hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: novel missense variant, c.512A>G (p.His171Arg) in exon 8 of the ELMO domain-containing 3 (ELMOD3) gene, was identified as a causative variant in this family affected by late-onset and progressive ADNSHL.
    explanation: The dominant ELMOD3 entity, recorded so that this entry's recessive scope is explicit. INDIRECT because the finding is about a different disease and bears on DFNB88 only through the shared gene.
  variants:
  - name: NM_032213.4:c.794T>C (p.Leu265Ser)
    description: Homozygous missense allele segregating with prelingual hearing impairment in PKDF468. The numbering uses the transcript in the original report. Functional assays show markedly reduced ARL2 GAP activity and impaired subcellular targeting, while weak F-actin co-sedimentation is preserved. The fully penetrant recessive linkage model was an analytical assumption, not a measured penetrance estimate.
    evidence:
    - reference: PMID:24039609
      reference_title: An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Exome sequencing coupled with homozygosity mapping was used to identify a transition mutation (c.794T>C; p.Leu265Ser) in ELMOD3 at the DFNB88 locus that is associated with nonsyndromic deafness in a large Pakistani family, PKDF468.
      explanation: Segregation, positional evidence and functional experiments support the reported recessive allele; no modern ACMG classification is inferred.
diagnosis:
- name: Molecular diagnosis and variant interpretation
  description: Molecular evaluation of recessive prelingual hearing loss can include a multigene panel or genomic testing with ELMOD3 analysis. Interpretation requires phenotype, inheritance, segregation and variant-level evidence; a variant of uncertain significance does not confirm DFNB88. The original family was solved by linkage and exome sequencing after excluding known loci. Dominant ELMOD3-associated hearing loss must be distinguished from recessive DFNB88.
  evidence:
  - reference: PMID:24039609
    reference_title: An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We initially observed that deafness in family PKDF468 did not co-segregate with short tandem repeat (STR) markers for 74 of the reported recessive nonsyndromic deafness loci
    explanation: The exclusion of the known loci, which is what made a novel locus the working hypothesis.
  - reference: PMID:24039609
    reference_title: An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Although, ELMOD3 is located outside the reported linkage interval of DFNA43
    explanation: The relationship between the recessive and dominant loci at 2p, which is the specific confusion this diagnostic note exists to prevent.
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1434/
    reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: A multigene hearing loss panel ... can often identify the cause of genetic hearing loss while limiting identification of pathogenic variants and variants of ... uncertain significance ... in genes that are irrelevant to the underlying
    explanation: General genetic hearing-loss diagnostic guidance, applied to an ELMOD3 differential.
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1434/
    reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The identification of variant(s) of ... uncertain significance ... cannot be used to confirm or rule out the diagnosis.
    explanation: A VUS is not a confirmed molecular diagnosis.
- name: Temporal-bone computed tomography
  description: Temporal-bone CT in V:2 and V:11, with normal-hearing sibling V:7 as a comparison, showed well-aerated middle ears and mastoids. V:11 had a slightly narrow right internal auditory canal. These findings do not explain the mixed audiograms or exclude every functional or subtle structural cause of an air-bone gap. V:5, whose large bilateral gap is specifically described, was not among those scanned.
  evidence:
  - reference: PMID:24039609
    reference_title: An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: CT scan of individual V:2 revealed all three semicircular and internal auditory canals were intact on both sides.
    explanation: The inner-ear anatomy in the more completely scanned patient.
  - reference: PMID:24039609
    reference_title: An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Imaging of individual V:11 demonstrated a slightly narrow appearing internal auditory canal on the right side only.
    explanation: The only positive imaging finding in the series, recorded with its laterality because a unilateral narrow canal cannot explain a bilateral loss.
  - reference: PMID:24039609
    reference_title: An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: To determine the temporal bone malformation, we performed computed tomography (CT) scans of two affected (V:2 and V:11) along with a normal hearing sibling (V:7).
    explanation: Identifies the imaged individuals, avoiding conflation with V:5.
  - reference: PMID:24039609
    reference_title: An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The middle ear and mastoid appeared well-aerated bilaterally.
    explanation: Preserved aeration is a limited negative finding, not exclusion of all conductive pathology.
- name: Audiological and vestibular assessment
  description: Air- and bone-conduction audiometry establishes the mixed hearing phenotype and distinguishes its conductive and sensorineural components. The defining family had no clear vestibular impairment on history and Romberg/tandem-gait examination; this is not equivalent to a comprehensive vestibular laboratory assessment.
  evidence:
  - reference: PMID:24039609
    reference_title: An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Pure-tone bone and air-conduction audiometry revealed severe-to-profound mixed (conductive and sensorineural) hearing loss in the affected individuals of family PKDF468
    explanation: Both audiometric modalities were used.
  - reference: PMID:24039609
    reference_title: An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The family history revealed that the onset of hearing loss was pre-lingual, with no clear vestibular impairment among the deaf individuals.
    explanation: The reported absence of clear vestibular symptoms does not establish normality on every vestibular test.
treatments:
- name: Hearing Aid Amplification
  description: Individualized hearing-aid fitting and audiological follow-up may improve access to sound when residual hearing permits useful benefit. This is general hearing-loss care; the retrieved DFNB88 reports do not establish a disease-specific response rate. The conductive contribution requires assessment alongside the sensorineural component.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: hearing aid amplification
    term:
      id: NCIT:C15315
      label: Rehabilitation
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: hearing aid
        term:
          id: NCIT:C183182
          label: Hearing Aid
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1434/
    reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Hearing aids (sound amplification), ... customized by an audiologist to the degree and frequency of hearing loss, can be used in individuals with mild-to-severe hearing loss.
    explanation: General hearing-loss care supports individualized amplification; this is indirect guidance for DFNB88 rather than a reported treatment outcome.
- name: Cochlear Implantation
  description: Cochlear-implant candidacy assessment is appropriate for selected individuals with severe-to-profound sensorineural impairment and insufficient aided benefit. Evaluation should characterize the mixed loss and relevant auditory anatomy. General hearing-loss guidance supports considering implantation; the retrieved DFNB88 literature does not report implant outcomes or establish genotype-specific efficacy.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: cochlear device implantation
    term:
      id: NCIT:C15329
      label: Surgical Procedure
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: cochlear implant
        term:
          id: NCIT:C157820
          label: Cochlear Implant
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1434/
    reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Cochlear implantation can be considered in children with severe-to-profound hearing loss who are older than age nine months.
    explanation: General guidance supports considering implantation after clinical assessment; this is not a DFNB88-specific efficacy claim.
    directness: INDIRECT
  target_mechanisms:
  - target: Cochlear Sensory Transduction Failure
    treatment_effect: BYPASSES
    description: Implantation can bypass impaired hair-cell transduction by stimulating the auditory nerve; individual suitability and outcomes require assessment.
- name: Genetic Counseling
  description: Counseling addresses recessive inheritance, variant interpretation, segregation testing and reproductive options. When both parents carry the relevant recessive pathogenic allele, each pregnancy has a 25% chance of an affected child. Consanguinity alone does not establish that risk. Dominant ELMOD3-associated alleles require separate interpretation.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1434/
    reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: If both parents are known to be ... heterozygous ... autosomal recessive ... hearing loss-related ... pathogenic variant ... has at conception a 25% chance of having hearing loss
    explanation: The recurrence calculation is conditional on confirmed parental carrier genotypes, not merely a consanguineous pedigree.
- name: Speech, Language and Communication Support
  description: Early, individualized speech, language, educational and communication support accompanies audiological management. D/deaf and hard-of-hearing community resources should be adapted to the child and family. This is general hearing-loss care, with no DFNB88-specific intervention trial implied.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: speech and language therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1434/
    reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: A speech-language therapist as well as a neuropsychologist/psychologist for children with hearing loss provides access to resources within the community to aid in speech and language and D/deaf and hard of hearing (DHH) identity development.
    explanation: General hearing-loss guidance supports communication services; no disease-specific treatment outcome is asserted.
animal_models:
- name: Elmod3 constitutive knockout mouse
  species: Mouse
  genotype: Elmod3 exon 6 frameshift null allele, homozygous, on C57BL/6
  publication: PMID:31628468
  genes:
  - preferred_term: ELMOD3
    term:
      id: hgnc:26158
      label: ELMOD3
  description: A constitutive 277-bp exon-6 deletion introduces a premature stop at residue 149; ELMOD3 protein was undetectable in homozygous cochlea. ABR thresholds were normal at one month and elevated from two months, worsening at five months. Heterozygotes tested at two months had normal thresholds; this does not exclude later effects or model every dominant human allele.
  modeled_mechanisms:
  - target: Disorganized Stereociliary Actin Cytoskeleton
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Phalloidin signal is much weaker throughout the knockout cochlea, most markedly in hair cells, and stereocilia formation and maturation are already delayed at postnatal day 1.
    limitations: The mouse null and human missense allele are distinct. Recombinant p.Leu265Ser protein is stable in the tested expression system, but patient hair-cell abundance was not measured. Mouse phalloidin abnormalities do not directly establish human bundle actin pathology.
    readouts:
    - name: Cochlear F-actin content by phalloidin staining
      target: Disorganized Stereociliary Actin Cytoskeleton
      direction: DECREASED
      interpretation: Reduced phalloidin signal across hair cells, supporting cells, spiral ganglion and spiral ligament in the knockout compared with wild type.
      evidence:
      - reference: PMID:31628468
        reference_title: Elmod3 knockout leads to progressive hearing loss and abnormalities in cochlear hair cell stereocilia.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: These results indicated a reduction of F-actin cytoskeleton formation in Elmod3 KO mice and therefore suggested that Elmod3 is required for the proper organization of F-actin networks.
        explanation: The measurement and the direction of change.
    evidence:
    - reference: PMID:31628468
      reference_title: Elmod3 knockout leads to progressive hearing loss and abnormalities in cochlear hair cell stereocilia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Our finding associates Elmod3 deficiencies with stereocilia dysmorphologies and reveals that they might play roles in the actin cytoskeleton dynamics in cochlear hair cells, and thus relate to hearing impairment.
      explanation: Why this model is treated as informative for the actin node.
  - target: Inner Hair Cell Stereocilia Shortening and Fusion
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Inner hair cell stereocilia are significantly shortened at two months and by five months show noticeable degeneration, with a few inner hair cells lacking bundles entirely.
    limitations: The human bundle has never been examined, so the correspondence is between a mouse structural phenotype and a human audiogram. The direction is also the opposite of the paralogue Elmod1 knockout, in which stereocilia elongate, so the bundle consequence of losing an ELMOD protein is not generic and should not be transferred between them.
    evidence:
    - reference: PMID:31628468
      reference_title: Elmod3 knockout leads to progressive hearing loss and abnormalities in cochlear hair cell stereocilia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: stereocilia of IHCs were significantly shortened in Elmod3−/− mice compared with the WT littermates
      explanation: Scanning electron microscopy directly documents inner-hair-cell bundle shortening at two months.
  - target: Cochlear Sensory Transduction Failure
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: 'The mouse goes deaf, which is the right outcome, but on a completely different schedule from the humans: thresholds are normal at one month, shift from two months, and worsen to five months.'
    limitations: PKDF468 has prelingual severe-to-profound mixed hearing impairment, whereas null mice have normal ABR thresholds at one month and elevated thresholds from two months. ABR/DPOAE tests without dedicated middle-ear assessment cannot establish that the mouse phenotype is purely sensorineural.
    divergences:
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: The human air-bone gap has not been adequately assessed in the mouse. ABR and DPOAE thresholds were measured, but no dedicated functional middle-ear assessment was reported.
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: Reported onset differs between the prelingual human phenotype and threshold elevation from mouse postnatal month two. Species, genetic background and missense-versus-null effects are not separated by this comparison.
    evidence:
    - reference: PMID:31628468
      reference_title: Elmod3 knockout leads to progressive hearing loss and abnormalities in cochlear hair cell stereocilia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: We found that Elmod3−/− mice exhibited significant HL beginning at the age of 2 months and progressed with age.
      explanation: The model's hearing phenotype and its timing, which is what this link is cited for and also what diverges from the human course.
  - target: Reduced Cochlear ARL2 Abundance
    relationship: MEASURES
    fidelity: LOW
    description: Elmod3-null cochleae show reduced ARL2 protein by early postnatal immunoblotting and reduced immunolabeling in cochlear cells. This is a change in protein abundance, not a measurement of ARL2 activation or GTP hydrolysis. Whether restoring ARL2 rescues hearing or bundle structure remains unknown.
    limitations: A mouse null observation; contribution of this specific change to hearing loss and correspondence to human p.Leu265Ser have not been established.
    evidence:
    - reference: PMID:31628468
      reference_title: Elmod3 knockout leads to progressive hearing loss and abnormalities in cochlear hair cell stereocilia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Western blotting assays of ARL2 protein expression level in postnatal 7 days mice cochlea of WT mice and Elmod3−/− mice. Expression level of ARL2 protein in Elmod3−/− mice were reduced compared with WT mice
      explanation: The figure legend directly reports reduced protein abundance at postnatal day seven, distinct from GAP catalytic activity.
  - target: Outer Hair Cell Stereocilia Degeneration
    relationship: MEASURES
    fidelity: LOW
    description: Elmod3-null mice have more missing outer-hair-cell bundles than age-matched wild-type mice at five months; surviving bundles show looser stereociliary connections. The structural finding is distinguished from the functional inference of impaired cochlear amplification.
    limitations: A mouse null observation; contribution of this specific change to hearing loss and correspondence to human p.Leu265Ser have not been established.
    evidence:
    - reference: PMID:31628468
      reference_title: Elmod3 knockout leads to progressive hearing loss and abnormalities in cochlear hair cell stereocilia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: stereocilia of OHCs were missing in both Elmod3−/− and WT mice with an increased frequency of losses in Elmod3−/− mice compared with WT mice
      explanation: The outer hair cell bundle loss, measured against wild-type littermates of the same age so that ordinary age-related loss is controlled for. INDIRECT because it is a mouse.
  - target: Impaired Cochlear Amplification
    relationship: MEASURES
    fidelity: LOW
    description: DPOAE thresholds rise from two months in Elmod3-null mice and worsen with age, consistent with impaired outer-hair-cell-dependent amplification. DPOAEs also depend on sound transmission through the middle ear; these measurements alone do not exclude a conductive contribution.
    limitations: A mouse null observation; contribution of this specific change to hearing loss and correspondence to human p.Leu265Ser have not been established.
    evidence:
    - reference: PMID:31628468
      reference_title: Elmod3 knockout leads to progressive hearing loss and abnormalities in cochlear hair cell stereocilia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: the shifting of DPOAE thresholds indicated the reduction of the force coupled into the cochlear amplifier by OHCs motility
      explanation: DPOAE threshold shifts support impaired cochlear amplification, without directly measuring outer-hair-cell force.
      directness: INDIRECT
discussions:
- discussion_id: dfnb88_onset_species_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Cochlear Sensory Transduction Failure
  - animal_models#Elmod3 constitutive knockout mouse
  prompt: Why is hearing impairment prelingual in PKDF468, whereas the Elmod3-null mouse has normal measured thresholds at one month and elevated thresholds from two months?
  rationale: The human missense allele and mouse constitutive null are different perturbations studied in different species. The mouse has early postnatal F-actin and bundle-development abnormalities, broadly normal day-14 scanning electron microscopy, and subsequent bundle degeneration. The evidence therefore does not establish a purely adult maintenance defect. A p.Leu265Ser knock-in and developmental functional measurements could distinguish allele-specific effects from species or background effects. No conversion of mouse age to human prenatal timing is established, and dominant human p.His171Arg results should not be used as a direct explanation of recessive DFNB88.
  evidence:
  - reference: PMID:31628468
    reference_title: Elmod3 knockout leads to progressive hearing loss and abnormalities in cochlear hair cell stereocilia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: We found that Elmod3−/− mice exhibited significant HL beginning at the age of 2 months and progressed with age.
    explanation: The model's hearing phenotype and its timing, which is what this link is cited for and also what diverges from the human course.
  - reference: PMID:24039609
    reference_title: An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The affected individuals of this family exhibited pre-lingual, severe-to-profound degrees of mixed hearing loss.
    explanation: The human half of the mismatch.
- discussion_id: dfnb88_conductive_component_unexplained
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotypes#Conductive Hearing Impairment
  prompt: What produces the conductive component of the DFNB88 audiogram, and is it part of the disease at all?
  rationale: Mixed audiograms are reported in PKDF468, including a large bilateral conductive component in V:5. CT in V:2 and V:11 showed preserved middle-ear/mastoid aeration, but V:5 was not scanned and functional middle-ear testing was not reported. These findings leave the cause of the air-bone gap unresolved. Neither cochlear localization nor ABR/DPOAE measurements in mice establish the absence of a conductive mechanism. Replication in unrelated families with comprehensive audiological assessment is needed before attributing the gap specifically to ELMOD3.
  proposed_experiments:
  - experiment_id: dfnb88_middle_ear_assessment
    name: Middle-ear assessment in a new DFNB88 family
    description: In molecularly established DFNB88, repeat masked air- and bone-conduction audiometry with documented output limits, tympanometry, acoustic reflexes and other indicated assessments. Compare affected and unaffected relatives and, where possible, unrelated families; interpret imaging and functional measurements together.
    would_support:
    - phenotypes#Conductive Hearing Impairment
    supporting_outcome:
    - A reproducible conductive deficit that segregates with biallelic ELMOD3 variants across independent families would support a disease association, while requiring exclusion of other causes.
    refuting_outcome:
    - Disappearance of the air-bone gap with technically adequate repeat testing would argue against the initial conductive finding. Normal tympanometry or reflexes alone would not prove a measurement artefact.
  evidence:
  - reference: PMID:24039609
    reference_title: An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The audiograms of individual V:5 revealed bilateral severe-to-profound mixed hearing loss, with a large conductive component in both ears.
    explanation: The observation that the gap exists and is large.
  - reference: PMID:24039609
    reference_title: An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The middle ear and mastoid appeared well-aerated bilaterally.
    explanation: The preserved aeration constrains interpretation but does not exclude every conductive disorder.
  - reference: PMID:24039609
    reference_title: An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: To determine the temporal bone malformation, we performed computed tomography (CT) scans of two affected (V:2 and V:11) along with a normal hearing sibling (V:7).
    explanation: CT examined V:2 and V:11, not the V:5 patient with the specifically described large bilateral gap.
external_assertions:
- name: OMIM deafness, autosomal recessive 88 record
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:615429
  url: https://omim.org/entry/615429
  description: OMIM phenotype record for autosomal recessive deafness 88.
notes: 'This entry covers recessive DFNB88. Dominant p.His171Arg-associated hearing loss and its patient-derived iPSC study (PMID:37708136) are distinct: the latter analyzed undifferentiated iPSC transcriptomes, not DFNB88 hair cells or physiological ion transport. Its enrichment of sensory-development and potassium-transport transcripts does not establish those mechanisms in recessive disease. The ELMOD3/CAPG/SH2D6 deletion report describes a possible contiguous-gene syndrome; attribution of its neurodevelopmental findings to an individual gene remains uncertain. Fibroblast ciliogenesis and cargo-trafficking findings are included as provisional gene-level mechanisms without asserting a human multisystem ciliopathy or a demonstrated causal link to cochlear injury. No DFNB88-specific treatment efficacy or population prevalence is established by the sources used here.'
experimental_models:
- name: p.Leu265Ser expression in cochlear explants
  experimental_model_type: PRIMARY_CELL_CULTURE
  cell_source: P2 C57BL/6J mouse organ-of-Corti explants
  publication: PMID:24039609
  description: Organotypic cochlear explants transfected with wild-type or p.Leu265Ser GFP-ELMOD3 reveal variant-specific failure of stereociliary targeting.
  modeled_mechanisms:
  - target: Impaired ELMOD3 Targeting to Stereocilia
    relationship: MEASURES
    fidelity: MODERATE
    description: Tagged patient-variant protein remains predominantly cytosolic rather than concentrating in stereocilia.
    limitations: Cultured mouse tissue with overexpressed human protein; not endogenous patient protein, an in-vivo knock-in, or a hearing-rescue experiment.
    evidence:
    - reference: PMID:24039609
      reference_title: An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Mouse organ of Corti hair cell that was transfected with GFP-ELMOD3 (p.Leu265Ser). No concentration and only negligible fluorescence is observed in the stereocilia
      explanation: Direct variant-specific targeting experiment in cultured mouse cochlear tissue; overexpression is not an in-vivo knock-in.
- name: Recombinant ELMOD3 GAP and localization assays
  experimental_model_type: CELL_LINE
  cell_source: HEK293T expression for protein purification; CL4 and MDCK epithelial cells for localization
  publication: PMID:24039609
  description: Recombinant wild-type and patient-variant ELMOD3 were compared in ARL2 GAP assays and epithelial-cell localization experiments. Cytochalasin-D disruption and recovery indicate actin-dependent localization; weak F-actin co-sedimentation is not reduced by p.Leu265Ser.
  modeled_mechanisms:
  - target: Loss of ARL2 GTPase-Activating Activity
    relationship: MEASURES
    fidelity: MODERATE
    description: Purified mutant protein has activity at the assay floor.
    limitations: Recombinant activity does not identify the physiological inner-ear substrate or quantify mutant activity in patient tissue.
    evidence:
    - reference: PMID:24039609
      reference_title: An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Thus, we can safely conclude that the point mutant has at least a 10-fold lower specific activity than the wild-type protein, but it might be completely inactive as an Arl2 GAP.
      explanation: The full-text result sets a lower bound on activity loss; mutant activity was at the assay floor and indistinguishable from GST alone.
  - target: Impaired ELMOD3 Targeting to Stereocilia
    relationship: MEASURES
    fidelity: LOW
    description: CL4 microvilli and MDCK membrane localization are impaired by the patient variant.
    limitations: Non-hair-cell overexpression models cannot reproduce the architecture or function of the cochlear bundle.
    evidence:
    - reference: PMID:24039609
      reference_title: An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Fluorescently tagged ELMOD3 co-localized with the actin cytoskeleton in MDCK cells and actin-based microvilli of LLC-PK1-CL4 epithelial cells. The p.Leu265Ser mutation in the ELMO domain impaired each of these activities.
      explanation: Variant-dependent mislocalization in heterologous epithelial cells.
- name: Elmod3-disrupted mouse embryonic fibroblasts
  experimental_model_type: CELL_LINE
  cell_source: Immortalized mouse embryonic fibroblasts with CRISPR-disrupted Elmod3
  publication: PMID:34818063
  description: Multiple predicted-null clones show reduced ciliation, selective ciliary cargo depletion and Golgi cargo accumulation. Multiple clones and re-expression support specificity, but the authors could not confirm endogenous protein absence with available antibodies. Gross F-actin organization and several other cellular structures were preserved, so the fibroblast results should not be equated with the cochlear actin phenotype.
  modeled_mechanisms:
  - target: Reduced Primary Cilium Formation
    relationship: MEASURES
    fidelity: LOW
    description: CRISPR disruption of Elmod3 in immortalized mouse embryonic fibroblasts reduces the fraction of ciliated cells after serum starvation. Normal CEP164 recruitment and CP110 removal place the observed defect after early ciliogenesis licensing. This is a candidate ELMOD3 function relevant to developing hair-cell kinocilia, not a demonstrated DFNB88 cochlear lesion.
    limitations: Fibroblasts with predicted-null alleles, not hair cells carrying p.Leu265Ser. The relation of these findings to human hearing loss is provisional.
    evidence:
    - reference: PMID:34818063
      reference_title: The ARF GAPs ELMOD1 and ELMOD3 act at the Golgi and cilia to regulate ciliogenesis and ciliary protein traffic.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: We found that ciliation was strongly decreased in Elmod1 and Elmod3 single KO MEFs, with <10% of cells on average having a cilium after 24 hr of serum starvation, compared with >60% in WT controls
      explanation: A direct cell-model ciliation measurement; neither human DFNB88 nor cochlear cilia were measured.
  - target: Altered Ciliary Cargo Localization
    relationship: MEASURES
    fidelity: LOW
    description: Elmod3-deficient fibroblasts show depletion of ARL13B, ARL3 and INPP5E from remaining cilia. IFT88, IFT140 and GLI3 localization is preserved, indicating selective cargo effects rather than a universal transport failure. These results have not been reproduced in DFNB88 patient cells or cochlear hair cells.
    limitations: Fibroblasts with predicted-null alleles, not hair cells carrying p.Leu265Ser. The relation of these findings to human hearing loss is provisional.
    evidence:
    - reference: PMID:34818063
      reference_title: The ARF GAPs ELMOD1 and ELMOD3 act at the Golgi and cilia to regulate ciliogenesis and ciliary protein traffic.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: 'We also discovered changes in the ciliary content of at least three proteins in cells lacking ELMOD1 and/or ELMOD3: ARL13B, ARL3, and INPP5E.'
      explanation: Selective loss of ciliary cargo is a direct cell-model observation, not evidence of a human multisystem ciliopathy.
  - target: Golgi Accumulation of Ciliary Cargo
    relationship: MEASURES
    fidelity: LOW
    description: INPP5E and IFT140 accumulate at the Golgi in Elmod3-deficient fibroblasts. INPP5E accumulation is more prominent after 24 than 72 hours of serum starvation, and its detection depends on fixation conditions. Delayed export is proposed; ciliary IFT140 localization remains preserved despite its increased Golgi pool.
    limitations: Fibroblasts with predicted-null alleles, not hair cells carrying p.Leu265Ser. The relation of these findings to human hearing loss is provisional.
    evidence:
    - reference: PMID:34818063
      reference_title: The ARF GAPs ELMOD1 and ELMOD3 act at the Golgi and cilia to regulate ciliogenesis and ciliary protein traffic.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: In contrast, the presence of INPP5E at the Golgi is evident in well over half of all Elmod1, Elmod3, and DKO cell lines after 24 h of serum starvation
      explanation: Direct Golgi localization result in serum-starved fibroblasts. The effect waned at later times.
  - target: Reduced Primary Cilium Formation
    relationship: RESCUES
    fidelity: LOW
    description: Fast-cycling ARL3 or ARL16 restores ciliation toward wild-type levels; ARF1 and ARF5 constructs do not.
    limitations: Overexpression rescue in fibroblasts does not demonstrate direct substrate specificity, rescue of hearing, or clinical efficacy.
    evidence:
    - reference: PMID:34818063
      reference_title: The ARF GAPs ELMOD1 and ELMOD3 act at the Golgi and cilia to regulate ciliogenesis and ciliary protein traffic.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Expression of either activated ARL3-myc or ARL16-myc restored ciliation percentages near WT levels
      explanation: Fast-cycling ARL3 or ARL16 bypasses the ciliation defect in transfected fibroblasts; this does not identify a direct GAP substrate or establish therapy.
  notes: The published correction (PMID:35612986; PMC9561853) replaces duplicated double-knockout images in Figure 4E for the serum-containing condition; text, legend and conclusions were unchanged. The cell-model findings remain separate from the cochlear disease mechanism.
📚

References & Deep Research

References

10
PMID:24039609
An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans.
No top-level findings curated for this source.
PMID:31628468
Elmod3 knockout leads to progressive hearing loss and abnormalities in cochlear hair cell stereocilia.
No top-level findings curated for this source.
PMID:29713870
ELMOD3, a novel causative gene, associated with human autosomal dominant nonsyndromic and progressive hearing loss.
No top-level findings curated for this source.
PMID:30284680
Homozygous 2p11.2 deletion supports the implication of ELMOD3 in hearing loss and reveals the potential association of CAPG with ASD/ID etiology.
No top-level findings curated for this source.
PMID:37708136
Gene regulation analysis of patient-derived iPSCs and its CRISPR-corrected control provides a new tool for studying perturbations of ELMOD3 c.512A>G mutation during the development of inherited hearing loss.
No top-level findings curated for this source.
PMID:34818063
The ARF GAPs ELMOD1 and ELMOD3 act at the Golgi and cilia to regulate ciliogenesis and ciliary protein traffic.
No top-level findings curated for this source.
PMID:24616099
Characterization of recombinant ELMOD (cell engulfment and motility domain) proteins as GTPase-activating proteins (GAPs) for ARF family GTPases.
No top-level findings curated for this source.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC4036250/
Characterization of Recombinant ELMOD (Cell Engulfment and Motility Domain) Proteins as GTPase-activating Proteins (GAPs) for ARF Family GTPases - PMC
No top-level findings curated for this source.
url:https://www.ncbi.nlm.nih.gov/books/NBK1434/
Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
No top-level findings curated for this source.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9561853/
The ARF GAPs ELMOD1 and ELMOD3 act at the Golgi and cilia to regulate ciliogenesis and ciliary protein traffic - PMC
No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (1)

Create: Autosomal Recessive Nonsyndromic Hearing Loss 88 (DFNB88, ELMOD3) · 2026-09-17T17:01:54Z · View source

Curated DFNB88 (MONDO:0014182, ELMOD3) as a standalone kb/disorders entry. entry_type DISEASE: one gene, one proximal molecular lesion (loss of ARL2 GTPase-activating activity), one clinical picture in one family; the MONDO parent MONDO:0019588 is an ontology grouping of unrelated DFNB loci, not a dismech entry. ELMOD3 was clear across kb/disorders before this change; the gene symbol was confirmed against the HGNC REST API (HGNC:26158 ELMOD3, previous symbols RBM29/RBED1/DFNB88). Seven-node pathograph from the homozygous p.Leu265Ser ELMO-domain allele through loss of ARL2 GAP activity to a disordered stereociliary actin cytoskeleton, separate inner and outer hair cell bundle arms, and cochlear transduction failure; one module conformance, at the terminal node only, against sensorineural_hair_cell_loss. Three phenotypes; Conductive Hearing Impairment is deliberately left unwired and carries an open KNOWLEDGE_GAP discussion because no part of the ELMOD3 mechanism explains the air-bone gap and no middle-ear data have been published. A second open discussion records the HUMAN_MODEL_MISMATCH between the prelingual human onset and the two-month onset of the Elmod3 knockout mouse. A falcon deep-research report is committed alongside; it passed just preflight-dr (ELMOD3 top gene, 53 mentions vs 11 for the next) and just validate-research-reference (7/7 references resolved, confabulation rate 0), and nothing in the entry was taken from it. Validated with just validate (43/43 snippets verified), validate-terms, check-entity-refs, check-causal-targets, check-duplicate-keys, check-qualifier-terms and the whole-KB offline gates.

Falcon ▸
Autosomal Recessive Nonsyndromic Hearing Loss 88 (DFNB88): Research Report
Edison Scientific Literature 29 citations 2026-09-17T10:11:20.312699

Autosomal Recessive Nonsyndromic Hearing Loss 88 (DFNB88): Research Report

Executive summary

Autosomal recessive nonsyndromic hearing loss 88 (DFNB88) is an exceptionally rare Mendelian hearing disorder attributed to biallelic ELMOD3 dysfunction. The disease-defining evidence comes principally from one large consanguineous Pakistani pedigree, PKDF468, in which homozygosity mapping, exome sequencing, segregation analysis, population controls, and functional assays implicated homozygous ELMOD3 c.794T>C (p.Leu265Ser). Affected relatives had bilateral, prelingual, severe-to-profound mixed hearing loss without a consistent extra-auditory syndrome or vestibular deficit. Consequently, the phenotype, penetrance, prevalence, natural history, and variant spectrum remain incompletely defined (jaworek2013analterationin pages 1-2, jaworek2013analterationin pages 2-4, jaworek2013analterationin pages 4-6).

The strongest mechanistic model is impaired regulation of ARL2-family small GTPases and actin-rich cochlear hair-cell stereocilia. The p.Leu265Ser protein lost measurable ARL2 GTPase-activating-protein activity in vitro and localized abnormally to actin-based structures. Homozygous Elmod3-null mice developed progressive cochlear dysfunction, reduced F-actin, shortened/fused inner-hair-cell stereocilia, and progressive outer-hair-cell bundle degeneration (jaworek2013analterationin pages 1-2, li2019elmod3knockoutleads pages 1-2, li2019elmod3knockoutleads pages 2-3, li2019elmod3knockoutleads pages 3-5).

Evidence domain Finding Evidence type Key source/date/DOI/PMID Confidence / limitation
Foundational genetics In consanguineous Pakistani family PKDF468, homozygosity mapping defined DFNB88 at 2p11.2 (maximum two-point LOD 4.74), and exome sequencing identified homozygous ELMOD3 c.794T>C (p.Leu265Ser) segregating with hearing loss. The variant was absent from 524 ethnically matched control chromosomes, 1000 Genomes, and 6,500 NHLBI-ESP individuals. (jaworek2013analterationin pages 2-4, jaworek2013analterationin pages 4-6) Human pedigree, linkage, segregation, exome sequencing Jaworek et al.; published 2013-09-05; DOI 10.1371/journal.pgen.1003774; PMID 24039609 (jaworek2013analterationin pages 1-2, liu2023generegulationanalysis pages 15-16) High for this family and variant. Replication and disease-wide genotype–phenotype data remain sparse; evidence does not establish population-level penetrance or prevalence.
Human phenotype Affected relatives had bilateral, prelingual, severe-to-profound mixed hearing loss, including a substantial conductive component in at least one documented audiogram. No clear vestibular, skin, renal, or retinal abnormalities were identified; temporal-bone CT was largely normal. (jaworek2013analterationin pages 1-2, jaworek2013analterationin pages 2-4) Human clinical and audiologic characterization Jaworek et al.; 2013-09-05; DOI 10.1371/journal.pgen.1003774; PMID 24039609 Moderate. Directly observed but based on one extended family; phenotype frequencies, longitudinal progression, and quality-of-life scores were not reported.
Biochemical mechanism ELMOD3 localized to actin-rich cochlear stereocilia and exhibited GAP activity toward ARL2; p.Leu265Ser impaired localization to actin-based structures and abolished recombinant ELMOD3 ARL2-GAP activity, supporting a loss-of-function mechanism affecting small-GTPase/cytoskeletal regulation. (jaworek2013analterationin pages 1-2, jaworek2013analterationin pages 4-6) Rodent tissue localization, transfected-cell assays, recombinant-protein biochemistry Jaworek et al.; 2013-09-05; DOI 10.1371/journal.pgen.1003774; PMID 24039609 Moderate-to-high mechanistic support. Functional effect was demonstrated in vitro, but the complete causal sequence in human cochlear cells remains partly inferred.
Elmod3-null mouse CRISPR-generated homozygous null mice developed moderate, progressive hearing loss beginning at 2 months; ABR abnormalities involved all tested frequencies, and DPOAE shifts implicated outer-hair-cell dysfunction. Mutants showed reduced cochlear F-actin, shortened/fused inner-hair-cell stereocilia, progressive outer-hair-cell stereocilia degeneration, reduced ARL2 expression, and normal vestibular behavior. (li2019elmod3knockoutleads pages 1-2, li2019elmod3knockoutleads pages 2-3, li2019elmod3knockoutleads pages 3-5, li2019elmod3knockoutleads pages 5-7) In vivo genetic model; ABR, DPOAE, histology, immunostaining, SEM Li et al.; advance publication 2019-10-19; DOI 10.1093/hmg/ddz240 (li2019elmod3knockoutleads pages 1-2) High for mouse phenotype; moderate for human translation. Mouse onset/severity differs from the documented prelingual severe-to-profound human phenotype, and only homozygous mice were affected.
2023 iPSC transcriptomics Patient-derived iPSCs with heterozygous ELMOD3 c.512A>G (p.His171Arg) and an isogenic CRISPR-corrected line showed altered cytoskeletal, ion-transport, ear-morphogenesis, GPCR, PI3K–AKT, cAMP, calcium-signaling, and cell-adhesion programs; 26 downregulated genes related to ion transmembrane transport and 16 to potassium transport were reported. This variant causes autosomal-dominant progressive hearing loss and is not DFNB88-specific evidence. (liu2023generegulationanalysis pages 1-2, liu2023generegulationanalysis pages 10-12) Patient-derived iPSC model, CRISPR correction, bulk RNA-seq, computational enrichment, qRT-PCR Liu et al.; published 2023-09-14; DOI 10.1371/journal.pone.0288640 Supporting ELMOD3 biology only. Undifferentiated iPSCs are not cochlear hair cells; control comparisons were confounded by sex and other genomic differences, and the genotype/inheritance differs from DFNB88.
Population rarity A 2024 review identified 51 ARNSHL genes in Pakistan. Thirteen common genes accounted for more than half of profound hearing-loss cases; other genes, the category containing rare ELMOD3, each contributed <2%. (shadab2024autosomalrecessivenon‐syndromic pages 1-2) Population-focused literature review Shadab et al.; accepted 2024-01-02; DOI 10.1111/jcmm.18119 Low-to-moderate for ELMOD3 frequency. The <2% figure is a category-level estimate, not a DFNB88-specific prevalence or carrier-frequency measurement.
Diagnostics and management Practical diagnosis combines newborn/clinical audiology, air- and bone-conduction testing, tympanometry/OAE/ABR as appropriate, and molecular confirmation of biallelic pathogenic ELMOD3 variants, preferably through a comprehensive hearing-loss panel with CNV analysis or exome/genome sequencing. Current management is phenotype-directed hearing rehabilitation with hearing aids, cochlear-implant assessment, speech-language support, educational accommodations, and genetic counseling. General reviews state that hearing aids and cochlear implants remain the principal corrective options. (petit2023deafnessfromgenetic pages 1-5, zhang2024aav‐mediatedgenetherapy pages 1-2) Clinical application extrapolated from hereditary-hearing-loss standards; disease molecular evidence Petit et al.; 2023; DOI 10.1038/s41576-023-00597-7; Zhang et al.; 2024; DOI 10.1002/advs.202402166 Moderate. No DFNB88-specific diagnostic guideline, validated biomarker, treatment algorithm, or outcome series was identified. Conductive components require independent middle-ear evaluation rather than attribution to ELMOD3 alone.
Trials and disease-modifying therapy No DFNB88/ELMOD3-specific interventional trial or approved pharmacologic, RNA, cell, editing, or gene-replacement therapy was identified. Hereditary-deafness gene therapy has restored hearing in more than 20 mouse models and reached clinical translation for OTOF/DFNB9, but this should not be extrapolated as demonstrated efficacy for DFNB88. (zhang2024aav‐mediatedgenetherapy pages 1-2) Clinical-trial search and contemporary therapeutic review Zhang et al.; 2024; DOI 10.1002/advs.202402166 High confidence that evidence is absent in the searched sources, not proof that no unindexed study exists. ELMOD3 therapy remains preclinical/conceptual, with delivery, target-cell, timing, efficacy, and safety unresolved.

Table: Compact appraisal of the principal human, biochemical, mouse, population, diagnostic, and therapeutic evidence for ELMOD3-associated DFNB88. It separates disease-specific findings from supportive but non-DFNB88 ELMOD3 research.

1. Disease information

Definition and nomenclature

DFNB88 is an autosomal recessive nonsyndromic hearing-loss disorder in which hearing impairment is the primary recognized manifestation. “Nonsyndromic” means that no reproducible pattern of abnormalities in other organs has been established. Synonyms include:

  • autosomal recessive nonsyndromic hearing loss 88;
  • deafness, autosomal recessive 88;
  • DFNB88;
  • ELMOD3-related autosomal recessive hearing loss;
  • ELMOD3-related nonsyndromic deafness.

The supplied identifier is MONDO:0014182. The foundational publication designates the locus DFNB88, mapped to chromosome 2p11.2. Disease-specific OMIM, Orphanet, ICD, and MeSH identifiers were not independently recoverable from the searched full-text literature and should be verified directly against current releases before database ingestion. ICD-10/ICD-11 and MeSH generally classify the hearing-loss phenotype rather than this molecular subtype (jaworek2013analterationin pages 2-4).

The evidence is predominantly aggregated disease-level literature derived from individually phenotyped members of one pedigree, rather than EHR-scale or registry data. Open Targets did not return an ELMOD3–DFNB88-specific association in the retrieved results, illustrating incomplete coverage of ultra-rare subtypes; its returned associations concerned broader recessive hearing loss and other DFNB entities (OpenTargets Search: autosomal recessive nonsyndromic hearing loss 88).

Foundational evidence and direct abstract quotation

Jaworek et al., published 5 September 2013 in PLOS Genetics, DOI 10.1371/journal.pgen.1003774, PMID 24039609, reported: “Exome sequencing coupled with homozygosity mapping was used to identify a transition mutation (c.794T>C; p.Leu265Ser) in ELMOD3 at the DFNB88 locus that is associated with nonsyndromic deafness in a large Pakistani family, PKDF468.” The same abstract states that affected relatives exhibited “pre-lingual, severe-to-profound degrees of mixed hearing loss.” (jaworek2013analterationin pages 1-2, liu2023generegulationanalysis pages 15-16)

2. Etiology

Causal factor

The established cause is a germline, homozygous missense variant in ELMOD3, c.794T>C (p.Leu265Ser), affecting a highly conserved residue in the ELMO domain. The variant segregated with recessive hearing loss, was absent from 524 ancestry-matched control chromosomes, 1000 Genomes, and 6,500 NHLBI-ESP participants, and was predicted deleterious by multiple computational methods (jaworek2013analterationin pages 2-4, jaworek2013analterationin pages 4-6).

Risk factors

  • Genetic: two pathogenic ELMOD3 alleles are the primary risk requirement. For two heterozygous parents, the conventional recurrence probabilities are 25% affected, 50% carrier, and 25% inheriting neither familial allele per pregnancy.
  • Family history/consanguinity: the original family was consanguineous. Consanguinity increases the probability that both parents carry the same rare ancestral allele, but is not mechanistically required for recessive disease. Pakistan has high consanguinity rates, facilitating homozygous recessive-disease discovery (shadab2024autosomalrecessivenon‐syndromic pages 1-2).
  • Sex: no evidence of sex-dependent risk; autosomal inheritance predicts both sexes can be affected.
  • Environmental: no exposure has been shown to cause DFNB88. Noise, congenital infection, and ototoxic medication can independently worsen hearing and should be treated as competing or additive causes, not DFNB88-specific etiologies. Contemporary review evidence identifies noise, TORCH infections, aminoglycosides, platinum agents, and other exposures as general hearing-loss risks (petit2023deafnessfromgenetic pages 1-5).

Protective factors and gene–environment interaction

No DFNB88-specific protective allele, modifier gene, dietary factor, medication, or validated gene–environment interaction has been reported. Avoiding excessive noise and unnecessary ototoxic exposure is prudent for preserving residual hearing but has not been shown to prevent genetically initiated DFNB88. Modifier, epigenetic, and pharmacogenomic evidence is unavailable.

3. Phenotypes

Phenotype Characterization in documented humans Suggested HPO term
Hearing impairment Bilateral, prelingual, severe-to-profound mixed conductive and sensorineural hearing loss Hearing impairment HP:0000365; Prelingual sensorineural hearing impairment HP:0000399; Mixed hearing impairment HP:0000410; Profound hearing impairment HP:0012715
Conductive component A substantial air–bone gap was documented in at least one individual; bone-conduction thresholds ranged from borderline normal to moderately severe by frequency/ear Conductive hearing impairment HP:0000405
Bilaterality Both ears affected in the described audiogram/pedigree phenotype Bilateral hearing impairment HP:0008619
Vestibular function No clear vestibular impairment documented Consider recording absence of Vertigo HP:0002321 and Abnormality of vestibular function HP:0001751 rather than asserting universal absence
Extra-auditory findings No clear skin, renal, or retinal abnormalities in the original assessment Nonsyndromic classification; negative phenotypes should remain family-specific

The original temporal-bone CT assessments showed intact semicircular and internal auditory canals and well-aerated middle ear/mastoid, apart from a slightly narrow right internal auditory canal in one person. Thus, the large conductive component was not explained by a consistent gross malformation in the available imaging (jaworek2013analterationin pages 1-2, jaworek2013analterationin pages 2-4).

Frequency, progression, and quality of life

The hearing phenotype occurred in affected relatives of the linked pedigree, but exact numerator/denominator frequencies for each clinical feature were not available in the retrieved evidence. Human longitudinal progression was not adequately characterized. The prelingual severe-to-profound impairment predicts major risk to spontaneous speech and language acquisition, education, communication, and social participation unless identified and treated early. Contemporary experts note that profound congenital/prelingual loss, conventionally ≥90 dB HL, impedes spontaneous oral-language development; moderate-to-severe loss can also produce school difficulties (petit2023deafnessfromgenetic pages 1-5).

No DFNB88-specific EQ-5D, SF-36, PROMIS, speech-perception, educational, or caregiver-burden statistics have been published in the retrieved literature.

4. Genetic and molecular information

Gene and locus

  • Gene: ELMOD3, ELMO domain containing 3.
  • Location: chromosome 2p11.2; DFNB88 linkage interval was approximately 0.91 Mb, bounded by D2S1387 and D2S2232.
  • Linkage: maximum two-point LOD score 4.74 at D2S2333 (jaworek2013analterationin pages 2-4).
  • Protein: an ELMO-domain protein with GAP activity toward ARF-family small GTPases, especially ARL2 in the foundational assay.
  • Isoforms: at least seven alternatively spliced human isoforms were reported; isoforms B–D encode the same 381-amino-acid protein containing the ELMO domain (jaworek2013analterationin pages 4-6).

HGNC and NCBI Gene numeric identifiers should be imported directly from HGNC/NCBI rather than inferred from literature excerpts.

Pathogenic variant appraisal

NM_001135022.2:c.794T>C, p.(Leu265Ser) is the disease-defining DFNB88 variant. It is a germline missense substitution, homozygous in affected relatives and heterozygous in carriers. Evidence supporting pathogenicity includes phenotype segregation, linkage, extreme rarity in historical controls, conservation, computational predictions, abnormal subcellular association, and complete loss of recombinant ARL2-GAP activity (jaworek2013analterationin pages 2-4, jaworek2013analterationin pages 4-6).

The exact current ClinVar classification and current gnomAD allele frequency were not established from the retrieved documents and must be checked against live records. Historical absence is not equivalent to a contemporary population frequency of zero.

Important allelic distinction

ELMOD3 also has autosomal dominant hearing-loss associations. The heterozygous variants c.512A>G (p.His171Arg) and c.640G>A (p.Gly214Ser) belong to dominant, generally progressive ELMOD3-related hearing-loss literature and should not be annotated as DFNB88 variants without biallelic recessive evidence (yun2025confirmatoryinsightsinto pages 3-7, yun2025confirmatoryinsightsinto pages 21-22, liu2023generegulationanalysis pages 1-2).

No validated DFNB88 modifier genes, protective variants, somatic variants, methylation signatures, repeat expansions, aneuploidies, translocations, or inversions are known. A homozygous 2p11.2 deletion involving ELMOD3 has been discussed elsewhere, but the retrieved evidence was insufficient for detailed pathogenic interpretation.

5. Environmental information

DFNB88 is genetic, not infectious, toxic, occupational, nutritional, or lifestyle-induced. No pathogen, smoking pattern, diet, exercise level, alcohol exposure, pollutant, or radiation exposure has been causally associated with the molecular subtype. General hearing-preservation measures remain appropriate because acquired injury could add to an inherited cochlear deficit. There is no zoonotic or communicable component.

6. Mechanism and pathophysiology

Ordered causal chain

  1. Biallelic ELMOD3 c.794T>C causes p.Leu265Ser substitution in the ELMO domain.
  2. p.Leu265Ser leads to impaired association of ELMOD3 with actin-rich cellular structures and abolishes measurable ARL2-GAP activity in vitro.
  3. Loss of ELMOD3 GAP regulation is inferred to dysregulate ARL2/ARF-family GTPase cycling and associated membrane/cytoskeletal organization.
  4. This dysregulation is inferred to impair development or maintenance of cochlear hair-cell F-actin networks and stereocilia; reduced F-actin and bundle pathology are demonstrated in Elmod3-null mice.
  5. Stereocilia shortening/fusion and outer-hair-cell bundle degeneration lead to defective mechanotransduction and cochlear amplification; elevated DPOAE thresholds in null mice support the outer-hair-cell branch.
  6. Hair-cell dysfunction results in sensorineural hearing loss.
  7. Branch—conductive component: affected humans also had conductive loss, but its connection to ELMOD3 is unresolved because imaging did not reveal a consistent middle-ear or temporal-bone lesion; coincident middle-ear physiology remains possible (jaworek2013analterationin pages 1-2, li2019elmod3knockoutleads pages 2-3, li2019elmod3knockoutleads pages 3-5, li2019elmod3knockoutleads pages 5-7).

Molecular and cellular detail

ELMOD3 was prominent in rodent cochlear stereocilia and was also detected in kinocilia, cuticular plates, hair-cell bodies, and supporting cells. Tagged ELMOD3 colocalized with actin in MDCK cells and actin-based microvilli in LLC-PK1-CL4 epithelial cells. The key direct biochemical result was that recombinant wild-type ELMOD3 had ARL2-GAP activity whereas p.Leu265Ser abolished it (jaworek2013analterationin pages 1-2, jaworek2013analterationin pages 4-6).

Elmod3-null mice showed reduced cochlear ARL2 protein at postnatal day 7, one month, and five months. ARL2 was normally detected in inner and outer hair cells, spiral ganglion, and spiral ligament. Whether reduced ARL2 abundance is causal, compensatory, or downstream remains unresolved (li2019elmod3knockoutleads pages 5-7).

A separate cellular study found that deletion of ELMOD1 or ELMOD3 reduced primary-cilium formation, removed subsets of proteins from cilia, and accumulated some ciliary proteins at the Golgi, consistent with compromised Golgi-to-cilium trafficking. This supports broader ELMOD3 biology but has not been demonstrated as the proximate lesion in DFNB88 cochleae (liu2023generegulationanalysis pages 15-16).

Suggested ontology annotations

  • GO biological process: actin filament organization; regulation of actin cytoskeleton organization; stereocilium organization; sensory perception of sound; auditory receptor-cell development; small GTPase-mediated signal transduction; GTPase-activator activity; cilium assembly; regulation of membrane trafficking; potassium-ion transmembrane transport.
  • GO cellular component: stereocilium; hair-cell stereocilium; actin cytoskeleton; cuticular plate; kinocilium; Golgi apparatus; cilium; plasma membrane.
  • Cell Ontology: inner hair cell (CL:0000589); outer hair cell (CL:0000601); auditory hair cell; cochlear supporting cell; spiral ganglion neuron.

Molecular profiling and 2023 development

Liu et al., published 14 September 2023, DOI 10.1371/journal.pone.0288640, generated iPSCs carrying heterozygous dominant c.512A>G (p.His171Arg), an isogenic CRISPR-corrected line, and a sibling control. Mutant-versus-corrected analysis mapped 382 upregulated and 361 downregulated genes into protein-interaction networks. Twenty-six downregulated genes related to ion transmembrane transport and 16 to potassium transport; altered programs included cytoskeletal organization, sensory-organ/ear development, GPCR, PI3K–AKT, cAMP, calcium, ephrin, chloride transport, and cell adhesion. Examples included KCNB1, KCNC3, KCNH2, KCNK2, KCNN3, KCNN4, TBX1, and ATOH1 (liu2023generegulationanalysis pages 10-12).

This is not DFNB88-specific evidence: the variant and inheritance are dominant, undifferentiated iPSCs are not cochlear hair cells, and sibling comparisons were confounded by sex and other background-genome differences. It nevertheless provides a current experimental platform for studying ELMOD3-regulated networks (liu2023generegulationanalysis pages 1-2, liu2023generegulationanalysis pages 12-13).

No DFNB88-specific single-cell, spatial-transcriptomic, proteomic, metabolomic, lipidomic, or multi-omic dataset was identified.

7. Anatomical structures affected

  • Primary organ/system: inner ear and auditory system.
  • Primary site: cochlea, especially the organ of Corti.
  • Cells: inner and outer sensory hair cells; supporting cells may also express ELMOD3. Spiral ganglion and spiral ligament show ARL2 expression, but direct primary injury there is unproven.
  • Subcellular structures: stereociliary F-actin cores, cuticular plate, kinocilium/cilium, and potentially Golgi-to-cilium trafficking machinery.
  • Laterality: bilateral in the documented human phenotype.
  • Vestibular labyrinth: no clear clinical dysfunction despite vestibular expression; null mice also had normal observed vestibular behavior (jaworek2013analterationin pages 2-4, li2019elmod3knockoutleads pages 2-3).

Suggested anatomy terms include UBERON:0001849 cochlea, UBERON:0002227 organ of Corti, inner ear, spiral ganglion, spiral ligament, and auditory hair-cell stereocilium. Numeric UBERON identifiers other than those confidently known should be validated before production use.

8. Temporal development

The documented human onset is prelingual, implying congenital or early-childhood functional impairment, but newborn-versus-infant onset was not precisely resolved. The severity was already severe-to-profound when characterized. There are no adequate serial audiograms to determine whether DFNB88 is stable or progressive in humans (jaworek2013analterationin pages 1-2).

The mouse null phenotype differs temporally: ABR thresholds were normal at one month, became elevated at two months, and worsened through five months. Stereocilia formation appeared delayed at postnatal day 1; morphology was broadly similar at day 14; inner-hair-cell stereocilia were shortened at two months and markedly degenerated by five months (li2019elmod3knockoutleads pages 2-3, li2019elmod3knockoutleads pages 3-5).

The disease is expected to be lifelong. There is no evidence for episodic attacks, remission, spontaneous recovery, anticipation, or a formal staging system. The key intervention window is early childhood, before language deprivation becomes established; this is a rehabilitation principle rather than a DFNB88 natural-history result.

9. Inheritance and population

Inheritance is autosomal recessive. The original family’s segregation was consistent with affected homozygotes and unaffected carriers. Penetrance appeared high among identified homozygotes in that pedigree, but disease-wide penetrance cannot be quantified. Variable expressivity, germline mosaicism, anticipation, and sex bias have not been demonstrated (jaworek2013analterationin pages 2-4).

No disease-specific prevalence, incidence, carrier frequency, founder age, or geographic distribution has been measured. A 2024 Pakistani review reported 51 ARNSHL genes in that population; 13 common genes accounted for more than half of profound cases, while each remaining gene category contributed <2%. This supports ELMOD3’s rarity but is not a DFNB88 prevalence estimate. The same review noted approximately 14.5 million Pakistanis living with hearing loss, about half presumed genetic, but these figures encompass all hearing loss (shadab2024autosomalrecessivenon‐syndromic pages 1-2).

The apparent Pakistani concentration may reflect consanguinity and ascertainment through gene-mapping programs rather than population specificity. Both sexes should be equally susceptible. No validated founder effect or current carrier rate for p.Leu265Ser is available.

10. Diagnostics

Clinical evaluation

  1. Confirm hearing impairment with age-appropriate behavioral audiometry or ABR.
  2. Determine type and severity using air- and bone-conduction thresholds, tympanometry, acoustic reflexes, and otoscopy.
  3. Assess outer-hair-cell function using otoacoustic emissions where informative.
  4. Evaluate speech detection/perception and functional communication.
  5. Because mixed loss was reported, independently investigate middle-ear disease; do not assume every conductive component is caused by ELMOD3.
  6. Consider temporal-bone CT/MRI when conductive loss, congenital malformation, cochlear implantation, or asymmetric findings warrant it.
  7. Screen clinically for syndromic clues, congenital infection, ototoxic exposure, and common alternative genetic causes.

No blood chemistry, enzyme assay, biopsy, circulating biomarker, or pathology specimen is diagnostic.

Genetic testing

A comprehensive hearing-loss panel including ELMOD3, sequence variants, and copy-number analysis is efficient because inherited hearing loss is highly heterogeneous. If nondiagnostic, trio/family WES or WGS can detect rare coding variants, CNVs, and—particularly with WGS—noncoding or structural lesions. Familial segregation is essential. Single-gene testing is reasonable when the familial ELMOD3 variant is already known. CMA may detect large deletions but is insensitive to the known missense variant; conventional karyotyping and FISH are not first-line. Mitochondrial and repeat-expansion testing should be phenotype- or ancestry-driven rather than routine DFNB88 tests.

Molecular diagnosis requires biallelic pathogenic/likely pathogenic ELMOD3 variants in trans plus a compatible phenotype. A single heterozygous ELMOD3 variant does not establish DFNB88 and may instead raise dominant ELMOD3 disease or carrier status. Current ACMG/AMP classification should use live ClinVar/gnomAD data, segregation, and functional evidence.

Differential diagnosis and screening

Differentials include GJB2-, SLC26A4-, OTOF-, TMC1-, MYO15A-, CDH23-, and other recessive nonsyndromic hearing losses; congenital CMV; structural middle-ear disease; auditory neuropathy; and syndromic deafness. Universal newborn hearing screening detects hearing loss but not etiology. Once a familial variant is established, cascade carrier testing, testing of affected relatives, prenatal diagnosis, and preimplantation genetic testing are technically possible with counseling.

11. Outcome and prognosis

DFNB88 is not known to reduce life expectancy or cause disease-specific mortality. Survival statistics are therefore not applicable. The principal morbidity is communication disability, including impaired spoken-language development, educational difficulty, reduced social participation, and dependence on hearing rehabilitation. Severity at diagnosis, age at amplification or implantation, residual hearing, auditory-nerve integrity, consistency of device use, and access to speech-language/educational services are likely major functional prognostic factors, although none has been quantified specifically for DFNB88.

Recovery of native hearing without intervention has not been reported. Hearing aids and cochlear implants can improve access to sound, but no DFNB88-specific response rate, speech outcome, adverse-event rate, or prognostic biomarker is available. The reported absence of systemic disease suggests normal general medical prognosis, subject to the limited number of characterized families.

12. Treatment

Current clinical management

There is no approved DFNB88-specific pharmacotherapy. Management follows severity- and anatomy-based hearing-loss care:

  • hearing aids when useful residual hearing and the conductive/sensorineural profile permit;
  • cochlear-implant evaluation for bilateral severe-to-profound loss with insufficient aided speech access;
  • management of any independent middle-ear disorder;
  • speech-language therapy, auditory habilitation, sign-language access according to family preference, educational accommodation, and assistive listening technology;
  • serial audiology and device optimization;
  • genetic counseling.

Suggested NCIt concepts include Hearing Aid Device, Cochlear Implant, Cochlear Implantation, Speech Therapy, Auditory Rehabilitation, and Genetic Counseling; identifiers should be resolved in the current NCIt release.

Experimental treatment and recent developments

No ELMOD3/DFNB88-specific gene replacement, editing, RNA therapy, cell therapy, or interventional trial was identified. The 2024 AAV review states: “Clinical treatment options are currently limited to external devices like hearing aids and cochlear implants.” It reports hearing restoration in >20 genetic deafness mouse models and early clinical efficacy for OTOF/DFNB9, but those achievements do not establish efficacy for ELMOD3 disease (zhang2024aav‐mediatedgenetherapy pages 1-2).

ELMOD3 is conceptually amenable to gene augmentation because recessive p.Leu265Ser behaves as loss of biochemical function and cochlear hair cells are the likely target. Major unresolved issues include vector tropism for inner and outer hair cells, dose, expression control, therapeutic timing before irreversible bundle degeneration, durability, immunogenicity, and whether the human conductive component would respond. No treatment-response or adverse-event statistics exist for DFNB88.

13. Prevention

Primary prevention of a de novo molecular lesion through lifestyle measures is impossible. Reproductive risk can be reduced—not eliminated at the population level—through informed carrier testing, cascade testing, prenatal diagnosis, or preimplantation genetic testing after identification of familial variants. Genetic counseling should emphasize autosomal-recessive recurrence risk and preserve reproductive autonomy.

Secondary prevention comprises newborn hearing screening, prompt diagnostic audiology, early molecular diagnosis, and early communication intervention. Tertiary prevention includes optimized amplification/implantation, educational support, avoidance of harmful noise, and careful use or monitoring of ototoxic drugs. Vaccination and infection prevention reduce acquired hearing loss but do not prevent ELMOD3 mutations. No prophylactic medication exists.

14. Other species and natural disease

No naturally occurring veterinary disease conclusively equivalent to human ELMOD3-DFNB88 was identified. ELMOD3 is evolutionarily conserved, and orthologous biology can be studied in mammals. Relevant taxonomy includes Homo sapiens (NCBI Taxon 9606) and Mus musculus (10090). No breed-specific VBO annotation, zoonotic transmission, or cross-species infectious susceptibility applies.

Related ELMOD-family phenotypes in mice support conservation of small-GTPase/actin regulation in sensory hair bundles, but ELMOD1 disease should not be conflated with ELMOD3 deficiency.

15. Model organisms

Mouse model

Li et al., Human Molecular Genetics, advance publication 19 October 2019, DOI 10.1093/hmg/ddz240, generated a C57BL/6 Elmod3−/− line by CRISPR/Cas9. A 277-bp deletion targeting exon 6 produced a frameshift and premature stop at residue 149; cochlear ELMOD3 protein was absent. Genotypes approximated a 1:2:1 Mendelian ratio without sex bias (li2019elmod3knockoutleads pages 1-2, li2019elmod3knockoutleads pages 2-3).

At one month, mutants and wild types had similar ABR and DPOAE thresholds. At two months, mutants showed significant ABR threshold shifts, particularly at 4, 8, and 16 kHz (P<0.001), and elevated DPOAE thresholds at 8, 12, 16, and 24 kHz (P<0.05). At five months, ABR differences remained prominent at 8 and 16 kHz (P<0.001) and DPOAE differences extended across tested frequencies (P<0.01). At least five animals per genotype were used in each age group for physiological testing (li2019elmod3knockoutleads pages 2-3, li2019elmod3knockoutleads pages 7-8).

Histology and microscopy showed reduced F-actin, delayed neonatal bundle maturation, inner-hair-cell stereocilia shortening at two months, marked inner-hair-cell bundle degeneration and looser/missing outer-hair-cell stereocilia at five months, while most hair-cell bodies remained present. Vestibular dysfunction was not observed (li2019elmod3knockoutleads pages 2-3, li2019elmod3knockoutleads pages 3-5).

Strengths: genetically controlled in-vivo system; age series; ABR, DPOAE, histology, immunostaining, and SEM converge on cochlear hair-cell dysfunction. Limitations: mouse disease was moderate and postnatal-progressive rather than prelingual severe-to-profound; only homozygous mice had measurable loss; C57BL/6 background can complicate aging-hearing studies; sample sizes for SEM were limited; and a null allele is not identical to human p.Leu265Ser (li2019elmod3knockoutleads pages 3-5, li2019elmod3knockoutleads pages 5-7, li2019elmod3knockoutleads pages 7-8).

Cellular models

MDCK and LLC-PK1-CL4 epithelial cells established ELMOD3 association with actin-rich structures and the localization defect of p.Leu265Ser. Recombinant-protein assays established loss of ARL2-GAP activity. Patient-derived iPSCs and their CRISPR-corrected isogenic control are available for dominant p.His171Arg biology, but a DFNB88 p.Leu265Ser iPSC-derived hair-cell or cochlear-organoid model was not identified (jaworek2013analterationin pages 1-2, liu2023generegulationanalysis pages 1-2, liu2023generegulationanalysis pages 10-12).

Evidence gaps and expert interpretation

The central limitation is that DFNB88 remains a one-pedigree, one-clearly established recessive missense-variant disorder in the retrieved human literature. Accordingly, assertions of universal progression, complete penetrance, a characteristic conductive mechanism, population prevalence, variant-specific cochlear-implant outcomes, or systemic absence would overstate the evidence. The most defensible knowledge-base representation is: high confidence in the ELMOD3–hearing-loss relationship and p.Leu265Ser functional impairment; moderate confidence in stereocilia/actin–ARL2 pathophysiology; and low confidence in disease-wide frequencies and natural history.

The 2023–2024 literature materially advanced hereditary-deafness therapeutics and ELMOD3 experimental systems, but did not deliver a DFNB88-specific therapy or broader recessive clinical cohort. Expert reviews characterize monogenic inner-ear gene therapy as promising while emphasizing cell-type-specific delivery, safety, durability, and timing challenges. They also continue to regard hearing aids and cochlear implants as the available corrective options (petit2023deafnessfromgenetic pages 1-5, zhang2024aav‐mediatedgenetherapy pages 1-2).

References

  1. (jaworek2013analterationin pages 1-2): Thomas J. Jaworek, Elodie M. Richard, Anna A. Ivanova, Arnaud P. J. Giese, Daniel I. Choo, Shaheen N. Khan, Sheikh Riazuddin, Richard A. Kahn, and Saima Riazuddin. An alteration in elmod3, an arl2 gtpase-activating protein, is associated with hearing impairment in humans. Sep 2013. URL: https://doi.org/10.1371/journal.pgen.1003774, doi:10.1371/journal.pgen.1003774. This article has 60 citations and is from a domain leading peer-reviewed journal.

  2. (jaworek2013analterationin pages 2-4): Thomas J. Jaworek, Elodie M. Richard, Anna A. Ivanova, Arnaud P. J. Giese, Daniel I. Choo, Shaheen N. Khan, Sheikh Riazuddin, Richard A. Kahn, and Saima Riazuddin. An alteration in elmod3, an arl2 gtpase-activating protein, is associated with hearing impairment in humans. Sep 2013. URL: https://doi.org/10.1371/journal.pgen.1003774, doi:10.1371/journal.pgen.1003774. This article has 60 citations and is from a domain leading peer-reviewed journal.

  3. (jaworek2013analterationin pages 4-6): Thomas J. Jaworek, Elodie M. Richard, Anna A. Ivanova, Arnaud P. J. Giese, Daniel I. Choo, Shaheen N. Khan, Sheikh Riazuddin, Richard A. Kahn, and Saima Riazuddin. An alteration in elmod3, an arl2 gtpase-activating protein, is associated with hearing impairment in humans. Sep 2013. URL: https://doi.org/10.1371/journal.pgen.1003774, doi:10.1371/journal.pgen.1003774. This article has 60 citations and is from a domain leading peer-reviewed journal.

  4. (li2019elmod3knockoutleads pages 1-2): Wu Li, Yong Feng, Anhai Chen, Taoxi Li, Sida Huang, Jing Liu, Xianlin Liu, Yalan Liu, Jiangang Gao, Denise Yan, Jie Sun, Lingyun Mei, Xuezhong Liu, and Jie Ling. Elmod3 knockout leads to progressive hearing loss and abnormalities in cochlear hair cell stereocilia. Human molecular genetics, 28:4103-4112, Oct 2019. URL: https://doi.org/10.1093/hmg/ddz240, doi:10.1093/hmg/ddz240. This article has 18 citations and is from a domain leading peer-reviewed journal.

  5. (li2019elmod3knockoutleads pages 2-3): Wu Li, Yong Feng, Anhai Chen, Taoxi Li, Sida Huang, Jing Liu, Xianlin Liu, Yalan Liu, Jiangang Gao, Denise Yan, Jie Sun, Lingyun Mei, Xuezhong Liu, and Jie Ling. Elmod3 knockout leads to progressive hearing loss and abnormalities in cochlear hair cell stereocilia. Human molecular genetics, 28:4103-4112, Oct 2019. URL: https://doi.org/10.1093/hmg/ddz240, doi:10.1093/hmg/ddz240. This article has 18 citations and is from a domain leading peer-reviewed journal.

  6. (li2019elmod3knockoutleads pages 3-5): Wu Li, Yong Feng, Anhai Chen, Taoxi Li, Sida Huang, Jing Liu, Xianlin Liu, Yalan Liu, Jiangang Gao, Denise Yan, Jie Sun, Lingyun Mei, Xuezhong Liu, and Jie Ling. Elmod3 knockout leads to progressive hearing loss and abnormalities in cochlear hair cell stereocilia. Human molecular genetics, 28:4103-4112, Oct 2019. URL: https://doi.org/10.1093/hmg/ddz240, doi:10.1093/hmg/ddz240. This article has 18 citations and is from a domain leading peer-reviewed journal.

  7. (liu2023generegulationanalysis pages 15-16): Xianling Liu, Jie Wen, Xuezhong Liu, Anhai Chen, Sijun Li, Jing Liu, Jie Sun, Wei Gong, Xiaoming Kang, Zhili Feng, Chu-Feng He, Ling-Yun Mei, J. Ling, and Yong Feng. Gene regulation analysis of patient-derived ipscs and its crispr-corrected control provides a new tool for studying perturbations of elmod3 c.512a>g mutation during the development of inherited hearing loss. PLOS ONE, Sep 2023. URL: https://doi.org/10.1371/journal.pone.0288640, doi:10.1371/journal.pone.0288640. This article has 5 citations and is from a peer-reviewed journal.

  8. (li2019elmod3knockoutleads pages 5-7): Wu Li, Yong Feng, Anhai Chen, Taoxi Li, Sida Huang, Jing Liu, Xianlin Liu, Yalan Liu, Jiangang Gao, Denise Yan, Jie Sun, Lingyun Mei, Xuezhong Liu, and Jie Ling. Elmod3 knockout leads to progressive hearing loss and abnormalities in cochlear hair cell stereocilia. Human molecular genetics, 28:4103-4112, Oct 2019. URL: https://doi.org/10.1093/hmg/ddz240, doi:10.1093/hmg/ddz240. This article has 18 citations and is from a domain leading peer-reviewed journal.

  9. (liu2023generegulationanalysis pages 1-2): Xianling Liu, Jie Wen, Xuezhong Liu, Anhai Chen, Sijun Li, Jing Liu, Jie Sun, Wei Gong, Xiaoming Kang, Zhili Feng, Chu-Feng He, Ling-Yun Mei, J. Ling, and Yong Feng. Gene regulation analysis of patient-derived ipscs and its crispr-corrected control provides a new tool for studying perturbations of elmod3 c.512a>g mutation during the development of inherited hearing loss. PLOS ONE, Sep 2023. URL: https://doi.org/10.1371/journal.pone.0288640, doi:10.1371/journal.pone.0288640. This article has 5 citations and is from a peer-reviewed journal.

  10. (liu2023generegulationanalysis pages 10-12): Xianling Liu, Jie Wen, Xuezhong Liu, Anhai Chen, Sijun Li, Jing Liu, Jie Sun, Wei Gong, Xiaoming Kang, Zhili Feng, Chu-Feng He, Ling-Yun Mei, J. Ling, and Yong Feng. Gene regulation analysis of patient-derived ipscs and its crispr-corrected control provides a new tool for studying perturbations of elmod3 c.512a>g mutation during the development of inherited hearing loss. PLOS ONE, Sep 2023. URL: https://doi.org/10.1371/journal.pone.0288640, doi:10.1371/journal.pone.0288640. This article has 5 citations and is from a peer-reviewed journal.

  11. (shadab2024autosomalrecessivenon‐syndromic pages 1-2): Madiha Shadab, Ansar Ahmed Abbasi, Ahsan Ejaz, Afif Ben‐Mahmoud, Vijay Gupta, Hyung‐Goo Kim, and Barbara Vona. Autosomal recessive non‐syndromic hearing loss genes in pakistan during the previous three decades. Journal of Cellular and Molecular Medicine, Mar 2024. URL: https://doi.org/10.1111/jcmm.18119, doi:10.1111/jcmm.18119. This article has 10 citations and is from a peer-reviewed journal.

  12. (petit2023deafnessfromgenetic pages 1-5): Christine Petit, Crystel Bonnet, and Saaïd Safieddine. Deafness: from genetic architecture to gene therapy. Nature Reviews Genetics, 24:665-686, May 2023. URL: https://doi.org/10.1038/s41576-023-00597-7, doi:10.1038/s41576-023-00597-7. This article has 122 citations and is from a domain leading peer-reviewed journal.

  13. (zhang2024aav‐mediatedgenetherapy pages 1-2): Liyan Zhang, Fangzhi Tan, Jieyu Qi, Yicheng Lu, Xiaohan Wang, Xuehan Yang, Xiangyan Chen, Xinru Zhang, Jinyi Fan, Yinyi Zhou, Li Peng, Nianci Li, Lei Xu, Shiming Yang, and Renjie Chai. Aav‐mediated gene therapy for hereditary deafness: progress and perspectives. Advanced Science, Nov 2024. URL: https://doi.org/10.1002/advs.202402166, doi:10.1002/advs.202402166. This article has 43 citations and is from a peer-reviewed journal.

  14. (OpenTargets Search: autosomal recessive nonsyndromic hearing loss 88): Open Targets Query (autosomal recessive nonsyndromic hearing loss 88, 23 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  15. (yun2025confirmatoryinsightsinto pages 3-7): Yejin Yun, Minjae Park, Sohyang Jeong, Sung Ho Jung, and Sang-Yeon Lee. Confirmatory insights into elmod3-associated autosomal dominant non-syndromic hearing loss. MedRxiv, Feb 2025. URL: https://doi.org/10.1101/2025.02.11.25321773, doi:10.1101/2025.02.11.25321773. This article has 0 citations.

  16. (yun2025confirmatoryinsightsinto pages 21-22): Yejin Yun, Minjae Park, Sohyang Jeong, Sung Ho Jung, and Sang-Yeon Lee. Confirmatory insights into elmod3-associated autosomal dominant non-syndromic hearing loss. MedRxiv, Feb 2025. URL: https://doi.org/10.1101/2025.02.11.25321773, doi:10.1101/2025.02.11.25321773. This article has 0 citations.

  17. (liu2023generegulationanalysis pages 12-13): Xianling Liu, Jie Wen, Xuezhong Liu, Anhai Chen, Sijun Li, Jing Liu, Jie Sun, Wei Gong, Xiaoming Kang, Zhili Feng, Chu-Feng He, Ling-Yun Mei, J. Ling, and Yong Feng. Gene regulation analysis of patient-derived ipscs and its crispr-corrected control provides a new tool for studying perturbations of elmod3 c.512a>g mutation during the development of inherited hearing loss. PLOS ONE, Sep 2023. URL: https://doi.org/10.1371/journal.pone.0288640, doi:10.1371/journal.pone.0288640. This article has 5 citations and is from a peer-reviewed journal.

  18. (li2019elmod3knockoutleads pages 7-8): Wu Li, Yong Feng, Anhai Chen, Taoxi Li, Sida Huang, Jing Liu, Xianlin Liu, Yalan Liu, Jiangang Gao, Denise Yan, Jie Sun, Lingyun Mei, Xuezhong Liu, and Jie Ling. Elmod3 knockout leads to progressive hearing loss and abnormalities in cochlear hair cell stereocilia. Human molecular genetics, 28:4103-4112, Oct 2019. URL: https://doi.org/10.1093/hmg/ddz240, doi:10.1093/hmg/ddz240. This article has 18 citations and is from a domain leading peer-reviewed journal.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 7
Resolved 7
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 7
On topic 4
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 13
Resolved 13
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0
Terms whose name was checked 1
Terms named correctly 0
Terms named as a different term 1

Terms the report names something else

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

  • MONDO:0014182 (2 mentions) - the report calls it "if available"; MONDO calls it autosomal recessive nonsyndromic hearing loss 88