DFNB102 is isolated, profound, congenital sensorineural hearing loss caused by biallelic loss of EPS8, the epidermal growth factor receptor pathway substrate 8. It was defined in two siblings of consanguineous Algerian parents who carried a homozygous nonsense allele, p.Gln30*, found by exome sequencing after the common DFNB genes had been excluded. It is very rare: by 2023 only five pathogenic EPS8 variants had been described, in Algerian, Chinese and Iranian families among others, and one of those required copy-number analysis to resolve - an apparently homozygous splice variant turned out to be a splice allele in trans with a 65.9 kb intragenic deletion. **The disease alleles remove the part of the protein that does the work.** EPS8's barbed-end capping activity resides in its conserved carboxy-terminal effector domain, and structural work separates the two activities within it: bundling through a compact four-helix bundle contacting three actin subunits along the filament, capping through an amphipathic helix that inserts into the hydrophobic pocket at the barbed end and blocks monomer addition. Point mutations can dissociate the two. The DFNB102 alleles are truncating or deleting, so both are lost together - which is why this entry has no capping-versus-bundling distinction to make at the level of patients, only at the level of the protein. **EPS8 sets stereocilia length.** Each stereocilium in a hair bundle is a bundle of tightly packed, uniformly polarized actin filaments whose growth is regulated at the barbed ends, at the stereociliary tip. EPS8 has actin binding, bundling and barbed-end capping activities, localizes predominantly to the stereocilia tip, and is required for normal elongation. Eps8 knockout mice are profoundly deaf and have abnormally short hair bundle stereocilia. The link from allele to phenotype is therefore a structural one: the sensory antenna is built too short to detect physiological sound pressures. **There is a second, non-structural arm, and it is confined to inner hair cells.** In Eps8-null mice, inner and outer hair cells both have short stereocilia, but only inner hair cells additionally fail to acquire their mature basolateral ion channel complement, so they do not complete the transition into functional sensory receptors. That is a maturation defect rather than a bundle defect, and it is the reason this entry carries two parallel downstream arms from one molecular lesion rather than one. **Why it is non-syndromic has a mechanistic answer.** EPS8 is expressed in vestibular hair cells too, and those cells also have significantly shorter stereocilia in the null mouse - yet the mice show no vestibular deficit. The difference is that vestibular hair cells keep a normal pattern of basolateral voltage-dependent channels and can still respond to a stimulus, where inner hair cells lose the ability to synchronize their responses. So the restriction of the phenotype to hearing is not "EPS8 is only needed in the cochlea"; it is that the same bundle abnormality is functionally tolerated in one organ and not the other. **EPS8 is one node of a tip complex, not a solo actor.** It works with MYO15A, whirlin and GPSM2-Gai in a tip-complex density that has been reconstituted in vitro and behaves as a phase-separated condensate promoting actin bundling; MYO15A delivers EPS8 to the tip as cargo, and EPS8 in turn is required to localize BAIAP2L2 there. Several of those partners are themselves deafness genes, which is the argument for reading DFNB102 as one lesion in a shared machine.
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name: Autosomal Recessive Nonsyndromic Hearing Loss 102
category: Mendelian
creation_date: "2026-09-22T13:20:00Z"
synonyms:
- DFNB102
- deafness, autosomal recessive 102
- autosomal recessive nonsyndromic deafness 102
- EPS8-related nonsyndromic hearing loss
description: >-
DFNB102 is isolated, profound, congenital sensorineural hearing loss caused by
biallelic loss of EPS8, the epidermal growth factor receptor pathway substrate 8.
It was defined in two siblings of consanguineous Algerian parents who carried a
homozygous nonsense allele, p.Gln30*, found by exome sequencing after the common
DFNB genes had been excluded. It is very rare: by 2023 only five pathogenic EPS8
variants had been described, in Algerian, Chinese and Iranian families among others,
and one of those required copy-number analysis to resolve - an apparently homozygous
splice variant turned out to be a splice allele in trans with a 65.9 kb intragenic
deletion.
**The disease alleles remove the part of the protein that does the work.** EPS8's
barbed-end capping activity resides in its conserved carboxy-terminal effector domain,
and structural work separates the two activities within it: bundling through a compact
four-helix bundle contacting three actin subunits along the filament, capping through
an amphipathic helix that inserts into the hydrophobic pocket at the barbed end and
blocks monomer addition. Point mutations can dissociate the two. The DFNB102 alleles
are truncating or deleting, so both are lost together - which is why this entry has no
capping-versus-bundling distinction to make at the level of patients, only at the level
of the protein.
**EPS8 sets stereocilia length.** Each stereocilium in a hair bundle is a bundle of
tightly packed, uniformly polarized actin filaments whose growth is regulated at the
barbed ends, at the stereociliary tip. EPS8 has actin binding, bundling and
barbed-end capping activities, localizes predominantly to the stereocilia tip, and
is required for normal elongation. Eps8 knockout mice are profoundly deaf and have
abnormally short hair bundle stereocilia. The link from allele to phenotype is
therefore a structural one: the sensory antenna is built too short to detect
physiological sound pressures.
**There is a second, non-structural arm, and it is confined to inner hair cells.**
In Eps8-null mice, inner and outer hair cells both have short stereocilia, but only
inner hair cells additionally fail to acquire their mature basolateral ion channel
complement, so they do not complete the transition into functional sensory
receptors. That is a maturation defect rather than a bundle defect, and it is the
reason this entry carries two parallel downstream arms from one molecular lesion
rather than one.
**Why it is non-syndromic has a mechanistic answer.** EPS8 is expressed in
vestibular hair cells too, and those cells also have significantly shorter
stereocilia in the null mouse - yet the mice show no vestibular deficit. The
difference is that vestibular hair cells keep a normal pattern of basolateral
voltage-dependent channels and can still respond to a stimulus, where inner hair
cells lose the ability to synchronize their responses. So the restriction of the
phenotype to hearing is not "EPS8 is only needed in the cochlea"; it is that the
same bundle abnormality is functionally tolerated in one organ and not the other.
**EPS8 is one node of a tip complex, not a solo actor.** It works with MYO15A,
whirlin and GPSM2-Gai in a tip-complex density that has been reconstituted in vitro
and behaves as a phase-separated condensate promoting actin bundling; MYO15A
delivers EPS8 to the tip as cargo, and EPS8 in turn is required to localize
BAIAP2L2 there. Several of those partners are themselves deafness genes, which is
the argument for reading DFNB102 as one lesion in a shared machine.
disease_term:
preferred_term: autosomal recessive nonsyndromic hearing loss 102
term:
id: MONDO:0014428
label: autosomal recessive nonsyndromic hearing loss 102
parents:
- Autosomal Recessive Nonsyndromic Hearing Loss
references:
- reference: PMID:24741995
title: "EPS8, encoding an actin-binding protein of cochlear hair cell stereocilia, is a new causal gene for autosomal recessive profound deafness."
- reference: PMID:21526224
title: "Eps8 regulates hair bundle length and functional maturation of mammalian auditory hair cells."
- reference: PMID:27132230
title: "Distinct roles of Eps8 in the maturation of cochlear and vestibular hair cells."
- reference: PMID:33151556
title: "Loss of Baiap2l2 destabilizes the transducing stereocilia of cochlear hair cells and leads to deafness."
- reference: PMID:33626355
title: "Phase separation-mediated condensation of Whirlin-Myo15-Eps8 stereocilia tip complex."
- reference: PMID:15558031
title: "Eps8 controls actin-based motility by capping the barbed ends of actin filaments."
- reference: PMID:20532239
title: "Molecular basis for the dual function of Eps8 on actin dynamics: bundling and capping."
- reference: PMID:21236676
title: "Regulation of stereocilia length by myosin XVa and whirlin depends on the actin-regulatory protein Eps8."
- reference: PMID:34637946
title: "Apparent homozygosity for a novel splicing variant in EPS8 causes congenital profound hearing loss."
- reference: PMID:36635257
title: "EPS8 variant causes deafness, autosomal recessive 102 (DFNB102) and literature review."
- reference: PMID:20209148
title: "Loss of the actin remodeler Eps8 causes intestinal defects and improved metabolic status in mice."
- reference: PMID:41895171
title: "Language development after pediatric cochlear implantation: Why outcomes vary and how to optimize clinical management."
- reference: PMID:20301607
title: "Genetic Hearing Loss Overview."
tags:
- GeneReviews
inheritance:
- name: Autosomal recessive
description: >-
Biallelic EPS8 loss of function. In the founding family the nonsense allele was
homozygous in both affected siblings, present heterozygously in both unaffected
parents and in one unaffected sibling, and absent from two other unaffected
siblings - the full segregation pattern for a recessive allele.
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
evidence:
- reference: PMID:24741995
reference_title: "EPS8, encoding an actin-binding protein of cochlear hair cell stereocilia, is a new causal gene for autosomal recessive profound deafness."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The mutation was also present, in the heterozygous state, in one clinically unaffected sibling and in both unaffected parents, and was absent from the other two unaffected siblings."
explanation: >-
The segregation data. Heterozygous carriers are unaffected, which is what
establishes the recessive mode rather than merely being consistent with it.
genetic:
- name: EPS8
notes: >-
EPS8 encodes an 822 amino-acid actin regulator with F-actin capping and bundling
activity. In hair cells it is a component of the hair bundle, concentrated at the
stereocilia tip, and is delivered there by the myosin motor MYO15A.
relationship_type: CAUSATIVE
gene_term:
preferred_term: EPS8
term:
id: hgnc:3420
label: EPS8
evidence:
- reference: PMID:24741995
reference_title: "EPS8, encoding an actin-binding protein of cochlear hair cell stereocilia, is a new causal gene for autosomal recessive profound deafness."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A biallelic nonsense mutation, c.88C > T (p.Gln30*), was identified in EPS8 that encodes epidermal growth factor receptor pathway substrate 8, a 822 amino-acid protein involved in actin dynamics."
explanation: >-
The gene-disease assertion and the founding allele, from the exome study that
established DFNB102.
- reference: PMID:36635257
reference_title: "EPS8 variant causes deafness, autosomal recessive 102 (DFNB102) and literature review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we report the fifth pathogenic variant in the EPS8 gene in an Iranian patient with DFNB102"
explanation: >-
Sizes the allelic series - five pathogenic variants reported by 2023 - which is
the basis for the rarity statement in the description and for not calling this a
single-family disease.
variants:
- name: EPS8 c.88C>T p.Gln30*
description: >-
The founding DFNB102 allele, homozygous in two Algerian siblings. A nonsense codon
at residue 30 of an 822 residue protein, so essentially the whole coding sequence
is lost. It was absent from 120 Algerian normal-hearing controls and from the Exome
Variant Server.
variant_type: single nucleotide variant
clinical_significance: PATHOGENIC
evidence:
- reference: PMID:24741995
reference_title: "EPS8, encoding an actin-binding protein of cochlear hair cell stereocilia, is a new causal gene for autosomal recessive profound deafness."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This mutation predicts a truncated inactive protein or no protein at all."
explanation: >-
The authors' reading of the allele's consequence, which is what licenses treating
the mouse null as the relevant model.
- reference: PMID:24741995
reference_title: "EPS8, encoding an actin-binding protein of cochlear hair cell stereocilia, is a new causal gene for autosomal recessive profound deafness."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "It was not found in 120 Algerian normal hearing control individuals or in the Exome Variant Server database."
explanation: >-
Population absence, the frequency argument for pathogenicity in a consanguineous
family study.
- name: EPS8 c.1435-2A>T in trans with a 65.9 kb intragenic deletion
description: >-
A compound-heterozygous genotype in a non-consanguineous Chinese infant that trio
exome sequencing first read as homozygous for the splice variant. Copy-number
analysis found a 65.9 kb intragenic deletion covering intron 14 on the maternal
allele, which explained the apparent homozygosity.
Recorded because of what it implies for diagnosis rather than for mechanism: a
DFNB102 genotype can be missed, or mis-assigned as homozygous, by sequencing alone.
variant_type: deletion
clinical_significance: PATHOGENIC
evidence:
- reference: PMID:34637946
reference_title: "Apparent homozygosity for a novel splicing variant in EPS8 causes congenital profound hearing loss."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The deletion is covering intron 14 that could account for the apparent homozygosity of the patient."
explanation: >-
The copy-number finding and its diagnostic consequence, in the report that made it.
pathophysiology:
- name: EPS8 Loss of Function
description: >-
A biallelic nonsense allele near the start of the coding sequence removes EPS8.
EPS8 is an F-actin capping and bundling protein present in the hair bundle, so the
loss is of a regulator of actin dynamics at the site where stereocilia grow.
biological_scale: MOLECULAR
mechanism_confidence: ESTABLISHED
genes:
- preferred_term: EPS8
term:
id: hgnc:3420
label: EPS8
cellular_components:
- preferred_term: stereocilium tip
term:
id: GO:0032426
label: stereocilium tip
biological_processes:
- preferred_term: barbed-end actin filament capping
modifier: DECREASED
term:
id: GO:0051016
label: barbed-end actin filament capping
- preferred_term: actin filament bundle assembly
modifier: DECREASED
term:
id: GO:0051017
label: actin filament bundle assembly
downstream:
- target: Loss of the C-Terminal Effector Domain
causal_link_type: DIRECT
- target: Failure of Stereocilia Elongation
causal_link_type: DIRECT
- target: Arrested Functional Maturation of Inner Hair Cells
causal_link_type: DIRECT
description: >-
A second, separable consequence. Eps8-null inner hair cells fail to acquire the
mature basolateral ion channel complement, which is not a consequence of their
stereocilia being short.
evidence:
- reference: PMID:21526224
reference_title: "Eps8 regulates hair bundle length and functional maturation of mammalian auditory hair cells."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Moreover, we have found that Eps8 knockout mice are profoundly deaf and that IHCs, but not OHCs, fail to mature into fully functional sensory receptors."
explanation: >-
Establishes the maturation arm and that it is cell-type restricted, which is
why it hangs off the molecular node rather than off the bundle node.
evidence:
- reference: PMID:24741995
reference_title: "EPS8, encoding an actin-binding protein of cochlear hair cell stereocilia, is a new causal gene for autosomal recessive profound deafness."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "EPS8 is an F-actin capping and bundling protein."
explanation: >-
What the lost protein does, stated in the human genetics paper rather than
inferred from the mouse work.
- reference: PMID:21526224
reference_title: "Eps8 regulates hair bundle length and functional maturation of mammalian auditory hair cells."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "We show that Eps8, a protein with actin binding, bundling, and barbed-end capping activities in other systems, is a novel component of the hair bundle."
explanation: >-
Places EPS8 in the hair bundle and names the three activities it brings there.
- name: Loss of the C-Terminal Effector Domain
description: >-
The structural specification of what the disease alleles take away. EPS8's
barbed-end capping activity resides in its conserved carboxy-terminal effector
domain, and within that domain capping and bundling are separable: capping by an
amphipathic helix inserting into the hydrophobic pocket at the filament barbed end,
bundling by a compact four-helix bundle contacting the filament. A nonsense codon at
residue 30 of an 822-residue protein removes both.
This node exists because the separability matters for interpretation rather than for
these patients: a hypothetical missense allele sparing one activity would be a
different disease state, and none has been reported.
biological_scale: MOLECULAR
mechanism_confidence: ESTABLISHED
biological_processes:
- preferred_term: barbed-end actin filament capping
modifier: DECREASED
term:
id: GO:0051016
label: barbed-end actin filament capping
downstream:
- target: Failure of Stereocilia Elongation
causal_link_type: DIRECT
evidence:
- reference: PMID:15558031
reference_title: "Eps8 controls actin-based motility by capping the barbed ends of actin filaments."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "proteins of another family, the Eps8 family, also show barbed-end capping activity, which resides in their conserved carboxy-terminal effector domain"
explanation: >-
Locates the capping activity in the C-terminal effector domain, which is the
region a truncating DFNB102 allele removes.
- reference: PMID:20532239
reference_title: "Molecular basis for the dual function of Eps8 on actin dynamics: bundling and capping."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The capping activity is mainly mediated by a amphipathic helix that binds within the hydrophobic pocket at the barbed ends of actin blocking further addition of actin monomers."
explanation: >-
The structural mechanism of capping, and the basis for treating capping and
bundling as separable activities of one domain. Note the source's own typo, "a
amphipathic", is preserved because a snippet quotes rather than corrects.
- name: Failure of Stereocilia Elongation
description: >-
Without EPS8 at the barbed ends, the actin core does not reach its normal length.
Both inner and outer hair cells in the Eps8-null mouse have abnormally short
stereocilia. This is a failure to build rather than a degeneration: the elongation
step itself does not complete.
biological_scale: CELLULAR
mechanism_confidence: ESTABLISHED
cell_types:
- preferred_term: cochlear inner and outer hair cell
term:
id: CL:0000202
label: auditory hair cell
cellular_components:
- preferred_term: stereocilium
term:
id: GO:0032420
label: stereocilium
biological_processes:
- preferred_term: auditory receptor cell stereocilium organization
modifier: DECREASED
term:
id: GO:0060088
label: auditory receptor cell stereocilium organization
locations:
- preferred_term: cochlea
term:
id: UBERON:0001844
label: cochlea
downstream:
- target: Compromised Detection of Physiological Sound Pressures
causal_link_type: DIRECT
evidence:
- reference: PMID:21526224
reference_title: "Eps8 regulates hair bundle length and functional maturation of mammalian auditory hair cells."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Eps8 is localized predominantly at the tip of the stereocilia and is essential for their normal elongation and function."
explanation: >-
Localization and requirement together, which is what makes the tip the place the
lesion acts.
- reference: PMID:27132230
reference_title: "Distinct roles of Eps8 in the maturation of cochlear and vestibular hair cells."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "While both inner and outer hair cells from Eps8 knockout (KO) mice showed abnormally short stereocilia, inner hair cells (IHCs) also failed to acquire mature-type ion channels."
explanation: >-
Records that the bundle defect is shared by both cochlear hair cell types while
the maturation defect is not, which is the dissociation this entry models as two
arms.
- name: Arrested Functional Maturation of Inner Hair Cells
description: >-
Inner hair cells do not complete the developmental transition into mature sensory
receptors. They fail to acquire the mature-type basolateral ion channels, and they
lose the ability to synchronize their responses to a sinusoidal stimulus. This is
separable from the stereocilia defect: vestibular hair cells in the same animal
have short stereocilia and a normal basolateral channel pattern.
biological_scale: CELLULAR
mechanism_confidence: ESTABLISHED
cell_types:
- preferred_term: cochlear inner hair cell
term:
id: CL:0000589
label: cochlear inner hair cell
biological_processes:
- preferred_term: inner ear receptor cell differentiation
modifier: DECREASED
term:
id: GO:0060113
label: inner ear receptor cell differentiation
downstream:
- target: Compromised Detection of Physiological Sound Pressures
causal_link_type: DIRECT
evidence:
- reference: PMID:27132230
reference_title: "Distinct roles of Eps8 in the maturation of cochlear and vestibular hair cells."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "We have also found that while vestibular hair cells from Eps8 KO mice show normal voltage responses to injected sinusoidal currents, which were used to mimic the mechanoelectrical transducer current, IHCs lose their ability to synchronize their responses to the stimulus."
explanation: >-
The functional measurement behind this node, and the direct vestibular comparison
in the same experiment.
- name: Compromised Detection of Physiological Sound Pressures
description: >-
The convergence node. A hair bundle that is too short, served by inner hair cells
that have not matured, cannot transduce sound at normal pressures. The founding
human genetics paper states the inference in exactly these terms.
biological_scale: ORGANISM
mechanism_confidence: ESTABLISHED
biological_processes:
- preferred_term: sensory perception of sound
modifier: DECREASED
term:
id: GO:0007605
label: sensory perception of sound
downstream:
- target: Profound congenital sensorineural hearing impairment
causal_link_type: DIRECT
- target: Delayed speech and language development
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
evidence:
- reference: PMID:24741995
reference_title: "EPS8, encoding an actin-binding protein of cochlear hair cell stereocilia, is a new causal gene for autosomal recessive profound deafness."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: "This new DFNB form is likely to arise from abnormal hair bundles resulting in compromised detection of physiological sound pressures."
explanation: >-
The authors' own statement of the mechanism they propose for the disease they
defined. Note the hedge - "is likely to arise from" - is theirs and is
deliberately preserved rather than smoothed out; this is an inference from the
mouse phenotype, not a measurement in the patients.
- name: EPS8 as a Node of the Stereocilia Tip Complex
description: >-
EPS8 does not act alone at the tip. It is delivered there as cargo of the motor
protein MYO15A, it is in turn required for BAIAP2L2 to localize at the tips of the
transducing stereocilia, and reconstituted Whirlin-MYO15-EPS8 assemblies form
phase-separated condensates that promote actin bundling. Several partners in that
complex are themselves deafness genes, so DFNB102 is best read as removing one
component of a shared machine rather than as an isolated gene defect.
biological_scale: MOLECULAR
mechanism_confidence: ESTABLISHED
cellular_components:
- preferred_term: stereocilium tip
term:
id: GO:0032426
label: stereocilium tip
biological_processes:
- preferred_term: actin filament bundle assembly
term:
id: GO:0051017
label: actin filament bundle assembly
downstream:
- target: Failure of Stereocilia Elongation
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
Drawn as an indirect link because the complex's role is the context in which the
elongation failure happens, and the reconstitution work was not done on the
DFNB102 allele.
evidence:
- reference: PMID:33626355
reference_title: "Phase separation-mediated condensation of Whirlin-Myo15-Eps8 stereocilia tip complex."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "we discover that the specific multivalent interactions among the Whirlin-myosin 15 (Myo15)-Eps8 complex lead to the formation of the TCD-like condensates through liquid-liquid phase separation."
explanation: >-
The reconstitution showing EPS8 is one of three components of a condensate, not a
free protein at the tip.
- reference: PMID:33626355
reference_title: "Phase separation-mediated condensation of Whirlin-Myo15-Eps8 stereocilia tip complex."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The reconstituted TCD-like condensates effectively promote actin bundling."
explanation: >-
Connects the complex to the actin activity that the disease lesion removes.
- reference: PMID:21236676
reference_title: "Regulation of stereocilia length by myosin XVa and whirlin depends on the actin-regulatory protein Eps8."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "MyoXVa, whirlin, and Eps8 are integral components of the stereocilia tip complex"
explanation: >-
Names the three components of the tip complex and places EPS8 among them, which is
the basis for reading DFNB102 as one lesion in a shared machine.
- reference: PMID:33151556
reference_title: "Loss of Baiap2l2 destabilizes the transducing stereocilia of cochlear hair cells and leads to deafness."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "BAIAP2L2 localization to stereocilia tips is dependent on the motor protein MYO15A and its cargo EPS8"
explanation: >-
Places EPS8 downstream of MYO15A and upstream of BAIAP2L2 in the delivery
hierarchy, which is what makes the complex an ordered assembly rather than a list.
phenotypes:
- category: Auditory
name: Profound congenital sensorineural hearing impairment
description: >-
Isolated, profound congenital deafness in both affected siblings of the founding
family. Profound is the reported severity, and congenital is the reported onset.
phenotype_term:
preferred_term: Profound sensorineural hearing impairment
term:
id: HP:0011476
label: Profound sensorineural hearing impairment
evidence:
- reference: PMID:24741995
reference_title: "EPS8, encoding an actin-binding protein of cochlear hair cell stereocilia, is a new causal gene for autosomal recessive profound deafness."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We report the study of two siblings born to consanguineous Algerian parents and affected by isolated, profound congenital deafness."
explanation: >-
The phenotype as observed in the only reported family: isolated, profound, and
congenital.
- category: Neurologic
name: Delayed speech and language development
description: >-
Language delay is the functional consequence of prelingual profound deafness, and
it remains the principal outcome being managed after cochlear implantation.
Post-implant spoken language outcomes are highly heterogeneous, from
age-appropriate language to persistent delay.
No source reports language outcomes in an EPS8 patient specifically. The evidence
below is general to congenital severe-to-profound sensorineural hearing loss and is
graded INDIRECT for that reason, which is the honest position - an earlier draft
left the node entirely uncited on the stricter and wrong standard that only a
DFNB102-specific source would do.
phenotype_term:
preferred_term: Delayed speech and language development
term:
id: HP:0000750
label: Delayed speech and language development
evidence:
- reference: PMID:41895171
reference_title: "Language development after pediatric cochlear implantation: Why outcomes vary and how to optimize clinical management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
directness: INDIRECT
snippet: "post-implant spoken language outcomes remain highly heterogeneous, ranging from robust speech recognition and age-appropriate language to minimal benefits in sound detection with limited speech perception and language delays."
explanation: >-
Establishes language delay as a real and variable outcome in this population. A
narrative review, hence REVIEW_SYNTHESIS, and about congenital severe-to-profound
SNHL rather than about EPS8, hence INDIRECT.
treatments:
- name: Cochlear implantation
description: >-
Prelingual profound sensorineural hearing loss from a hair-bundle lesion is the
indication cochlear implantation exists for: the sensory transduction step fails
while the auditory nerve is intact, so direct electrical stimulation bypasses the
defect. No publication cited here reports implantation outcomes in an EPS8 patient
- the reported cohorts are genetics papers - so the evidence below is the general
indication for congenital severe-to-profound sensorineural hearing loss rather than
an EPS8-specific result. It is what these children receive.
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
therapeutic_modality: DEVICE
evidence:
- reference: PMID:41895171
reference_title: "Language development after pediatric cochlear implantation: Why outcomes vary and how to optimize clinical management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Pediatric cochlear implantation is the standard of care for infants and young children with congenital bilateral severe-to-profound sensorineural hearing loss who receive limited benefits from optimally fitted hearing aids."
explanation: >-
The indication, verbatim, including the hearing-aid trial that defines it. A
narrative review rather than a trial, and about the indication rather than about
DFNB102, so it supports the treatment being appropriate here without claiming an
EPS8-specific result.
- name: Hearing aid trial
description: >-
Optimally fitted amplification is attempted first and is typically insufficient at
this severity - which is not a failure of the trial but its purpose, since limited
benefit from optimally fitted hearing aids is part of the definition of the cochlear
implant indication. Recorded for that reason rather than as an expected treatment.
treatment_term:
preferred_term: hearing aid amplification
term:
id: NCIT:C15747
label: Supportive Care
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
therapeutic_modality: DEVICE
evidence:
- reference: PMID:41895171
reference_title: "Language development after pediatric cochlear implantation: Why outcomes vary and how to optimize clinical management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Pediatric cochlear implantation is the standard of care for infants and young children with congenital bilateral severe-to-profound sensorineural hearing loss who receive limited benefits from optimally fitted hearing aids."
explanation: >-
The trailing clause is what makes the hearing-aid trial part of the implant
indication rather than an alternative to it. Quoted as the whole sentence rather
than the clause alone so the snippet is a proposition on its own.
- name: Auditory-verbal and speech-language therapy
description: >-
Post-implant habilitation. The review that supplies this entry's implantation
evidence exists because outcomes after implantation vary widely, and it organizes
the predictors into intrinsic and extrinsic factors with clinically actionable
strategies - which is to say the device is the beginning of the intervention rather
than the end of it.
treatment_term:
preferred_term: post-implant auditory-verbal and speech-language therapy
term:
id: NCIT:C15315
label: Rehabilitation
therapeutic_modality: BEHAVIORAL
evidence:
- reference: PMID:41895171
reference_title: "Language development after pediatric cochlear implantation: Why outcomes vary and how to optimize clinical management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
directness: INDIRECT
snippet: "This narrative review integrates findings from the literature by organizing predictors of post-implant language development into intrinsic and extrinsic factors and highlighting clinically actionable strategies to optimize interventions."
explanation: >-
Establishes that post-implant intervention is a managed variable rather than a
fixed outcome. It does not name auditory-verbal therapy specifically, so the claim
that this named therapy belongs here follows by an inference step - which is what
INDIRECT encodes, and the reason it is set on this item.
animal_models:
- name: Eps8 knockout mouse
species: Mouse
genotype: Eps8 homozygous knockout
publication: PMID:21526224
description: >-
The model that carries this entry's mechanism. Eps8-null mice are profoundly deaf
with abnormally short stereocilia in both cochlear hair cell types, and inner hair
cells additionally fail to mature.
The same animal also has a phenotype with no human counterpart, which is worth
recording rather than filtering out: reduced body weight, partial resistance to
diet-induced obesity, improved metabolic status and increased lifespan, correlated
with about 25 percent shorter intestinal microvilli. Microvilli are actin-cored
protrusions like stereocilia, so this is the same molecular lesion in a different
actin-based structure - and it is absent from the human disease, where EPS8 loss
gives isolated deafness.
modeled_mechanisms:
- target: Failure of Stereocilia Elongation
relationship: RECAPITULATES
fidelity: HIGH
model_scale: CELLULAR
description: >-
Short stereocilia in both inner and outer hair cells, with profound deafness.
limitations: >-
The mouse is a constitutive null and the human founding allele is a nonsense codon
at residue 30 predicted to give truncated inactive protein or none, so the
genotypes correspond unusually well here. What does not correspond is the
extra-auditory phenotype: the mouse has an intestinal and metabolic syndrome that
humans with biallelic EPS8 loss do not report.
divergences:
- divergence_type: SPECIES_MISMATCH
materiality: IMMATERIAL
description: >-
The null mouse has a 25 percent reduction in intestinal microvilli length with
an associated metabolic phenotype; human EPS8 disease is isolated deafness.
Marked IMMATERIAL because it does not bear on this link's claim about
stereocilia - but it is recorded because a reader should know the model carries
a phenotype the disease does not, and because microvilli and stereocilia are
the same kind of structure, which makes the human silence informative rather
than merely reassuring.
readouts:
- name: Stereocilia length in cochlear hair cells
target: Failure of Stereocilia Elongation
direction: DECREASED
interpretation: >-
Abnormally short stereocilia in both hair cell types, the structural lesion this
node names.
evidence:
- reference: PMID:27132230
reference_title: "Distinct roles of Eps8 in the maturation of cochlear and vestibular hair cells."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "While both inner and outer hair cells from Eps8 knockout (KO) mice showed abnormally short stereocilia, inner hair cells (IHCs) also failed to acquire mature-type ion channels."
explanation: >-
The measured stereocilia phenotype, with the inner-hair-cell-specific
maturation defect alongside it.
- target: Arrested Functional Maturation of Inner Hair Cells
relationship: RECAPITULATES
fidelity: HIGH
model_scale: CELLULAR
description: >-
Inner hair cells fail to mature into fully functional sensory receptors, while
outer hair cells are comparatively spared.
readouts:
- name: Acquisition of mature-type basolateral ion channels in inner hair cells
target: Arrested Functional Maturation of Inner Hair Cells
direction: ABOLISHED
interpretation: >-
Inner hair cells do not acquire the mature channel complement.
evidence:
- reference: PMID:21526224
reference_title: "Eps8 regulates hair bundle length and functional maturation of mammalian auditory hair cells."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Moreover, we have found that Eps8 knockout mice are profoundly deaf and that IHCs, but not OHCs, fail to mature into fully functional sensory receptors."
explanation: >-
The maturation failure and its restriction to inner hair cells.
evidence:
- reference: PMID:20209148
reference_title: "Loss of the actin remodeler Eps8 causes intestinal defects and improved metabolic status in mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "a 25% reduction in intestinal microvilli length"
explanation: >-
The extra-auditory phenotype of the same null mouse, recorded so that the model's
scope is visible. Humans with biallelic EPS8 loss are reported as having isolated
deafness, so this is a divergence rather than an unexamined human phenotype -
though see review_notes, since nobody has looked for it either.
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
No prevalence estimate exists. Five pathogenic EPS8 variants had been described by
2023, in a handful of families. Recorded as a qualitative tier against
CASES_IN_LITERATURE rather than as an invented rate, which CLAUDE.md permits
precisely because that measure presupposes no numeric estimate.
evidence:
- reference: PMID:36635257
reference_title: "EPS8 variant causes deafness, autosomal recessive 102 (DFNB102) and literature review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Thus far, only four pathogenic variations in EPS8 have been described. In this study, we report the fifth pathogenic variant in the EPS8 gene in an Iranian patient with DFNB102."
explanation: >-
The count of reported pathogenic variants at the time of the fifth report, which
is as close to a denominator as this disease has.
diagnosis:
- name: Copy-number analysis alongside sequencing
description: >-
The distinctive diagnostic point for this gene, and the reason it belongs in
`diagnosis:` rather than only in `variants:`. A trio exome first read one patient as
HOMOZYGOUS for an EPS8 splice variant; copy-number analysis then found a 65.9 kb
intragenic deletion covering the same intron on the maternal allele. An intragenic
deletion in trans with a sequence variant masquerades as homozygosity, so a
sequencing-only workflow does not merely miss the second allele - it reports the
wrong genotype, with the wrong recurrence risk for the parents.
evidence:
- reference: PMID:34637946
reference_title: "Apparent homozygosity for a novel splicing variant in EPS8 causes congenital profound hearing loss."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The deletion is covering intron 14 that could account for the apparent homozygosity of the patient."
explanation: >-
The copy-number finding and the explanation of the apparent homozygosity it
resolved.
discussions:
- discussion_id: eps8_vestibular_silence_in_humans
kind: HUMAN_MODEL_MISMATCH
prompt: >-
Do humans with biallelic EPS8 loss have subclinical vestibular dysfunction, as the
mouse hair-cell data predict they should, and has anyone looked?
attaches_to:
- pathophysiology#Arrested Functional Maturation of Inner Hair Cells
rationale: >-
The mouse gives an unusually specific prediction here, and it is a prediction about
a negative. Eps8-null vestibular hair cells have significantly shorter stereocilia
but keep a normal basolateral channel pattern and normal voltage responses, and
the animals show no vestibular deficit. The authors' own explanation is that
vestibular deficits are sometimes centrally compensated, which is a statement about
detectability rather than about absence.
The human side is silent rather than concordant. The founding family is described
as having isolated deafness, which is the basis for calling the entity
non-syndromic, but the paper reports no vestibular testing - and a shortened
vestibular hair bundle that is centrally compensated is exactly what a clinical
history would miss. So "non-syndromic" here rests on the absence of a reported
complaint in two individuals, against a model that predicts a measurable
abnormality with no complaint.
This is a HUMAN_MODEL_MISMATCH rather than a KNOWLEDGE_GAP because the evidence
exists and is good; what is open is whether the mouse's compensated-vestibular
state translates, and the answer would change what a family is told about balance
and about late vestibular decompensation.
proposed_experiments:
- experiment_id: eps8_vestibular_function_testing
name: Vestibular function testing in EPS8 biallelic carriers
description: >-
Video head impulse testing and vestibular evoked myogenic potentials in reported
EPS8 biallelic individuals, against age-matched deaf controls with a gene
unrelated to the hair bundle. Central compensation preserves clinical balance but
not the reflex measurements, so the measurements are where the mouse prediction
is testable.
readouts:
- name: Vestibulo-ocular reflex gain on video head impulse testing
target: pathophysiology#Arrested Functional Maturation of Inner Hair Cells
direction: DECREASED
interpretation: >-
Reduced gain with no balance complaint would reproduce the mouse's compensated
state in humans; normal gain would mean the human vestibular system tolerates
EPS8 loss better than the mouse's does.
would_support:
- pathophysiology#Arrested Functional Maturation of Inner Hair Cells
supporting_outcome:
- >-
Reduced vestibulo-ocular reflex gain or absent vestibular evoked myogenic
potentials in EPS8 biallelic individuals who report no balance symptoms.
refuting_outcome:
- >-
Vestibular reflex measurements indistinguishable from deaf controls, indicating
the human vestibular system is unaffected rather than compensated.
notes: >-
Ontology gaps, and where specificity was deliberately not manufactured.
"Failure of Stereocilia Elongation" binds CL:0000202 auditory hair cell rather than
the narrower CL:0000589 cochlear inner hair cell or CL:0000601 cochlear outer hair
cell, because the cited result is explicitly about both types - "both inner and outer
hair cells from Eps8 knockout (KO) mice showed abnormally short stereocilia". Binding
either narrow term would assert a cell-type restriction the source denies. The
maturation node does bind CL:0000589, because there the source restricts it.
A negative-existence note in an earlier draft of this entry was WRONG and is recorded
here rather than quietly deleted, because the mistake is the one CLAUDE.md warns about
by name. The draft said no GO term names "barbed-end actin filament capping", on the
strength of grepping cache/go/terms.csv and getting no rows. The term exists:
GO:0051016 barbed-end actin filament capping, confirmed with
`runoak -i ols:go info GO:0051016` and `runoak -i ols:go search "l~barbed-end actin
filament capping"`, which also returns the three regulation terms beneath it. The
cache was empty because nothing in kb/ had bound it yet, and an empty cache is silence,
not a negative answer - the cache-first contract read backwards. GO:0051016 is now
bound on the molecular node and on the effector-domain node, where it is the exact
process the disease alleles remove. The error was caught by the committed
OpenScientist deep-research report, which named the CURIE.
The GeneReviews baseline for this disorder is PMID:20301607 Genetic Hearing Loss
Overview; it is tagged in `references:` and carries no evidence item, because nothing
in it is quoted. There is no EPS8-specific or DFNB102-specific GeneReviews chapter -
verified offline against cache/bookshelf/genereviews.csv.
review_notes: >-
The mouse's extra-auditory phenotype is recorded as a divergence marked IMMATERIAL, and
the wording there is careful on purpose. Eps8-null mice have 25 percent shorter
intestinal microvilli with a metabolic phenotype; humans with biallelic EPS8 loss are
described as having isolated deafness. But "isolated" in those reports means no
reported syndromic feature in a handful of patients, not a negative metabolic workup -
nobody has looked. Microvilli and stereocilia are the same kind of actin-cored
structure, so this is a place where the human silence may be absence of evidence.
Evidence base. Five pathogenic EPS8 variants had been described by 2023, across
Algerian, Chinese and Iranian families. The founding family is two siblings with a
homozygous nonsense allele; the pathograph is carried by mouse and in vitro work
rather than by the patients. An earlier draft of this entry said "one human family"
and was corrected after the deep-research report surfaced the later reports - the
original framing came from reading the founding paper and stopping there.
Every pathophysiology node below the molecular one is evidenced from mouse or in
vitro work, and each is graded MODEL_ORGANISM or IN_VITRO accordingly. The only
HUMAN_CLINICAL evidence in the pathograph is the allele itself and the authors'
closing inference about sound pressures, which is graded PRIMARY_RESULT but is an
inference and is flagged as one in its explanation. A reviewer should read the
mechanism as mouse-derived.
Two records previously carried no evidence and no term on the reasoning that only a
DFNB102-specific source would do. Review was right that this is stricter than dismech
uses: general-mechanism evidence is routine, cochlear implantation for prelingual
profound SNHL is not a DFNB102-specific claim, and the supporting reference was
already committed in this PR and uncited. Both now cite PMID:41895171 with
quote_role REVIEW_SYNTHESIS, the phenotype at directness INDIRECT, and the
Delayed speech and language development node is bound to HP:0000750, which was an
exact-name match sitting in cache/hp/terms.csv the whole time. The term and the
evidence were separate decisions and I had conflated them.
One CURIE I wrote from memory was wrong, and is recorded because it landed in the
slot CLAUDE.md names as the blind spot. The hearing-aid qualifier was first written
as NCIT:C50108 "Hearing Aid"; NCIT:C50108 is Plug Device. `just validate` and
`just validate-terms` both pass on a fabricated qualifier value, because
Qualifier.value is a plain Descriptor with no dynamic-enum binding. It was caught by
running `runoak -i ols:ncit info` before committing, and the correct term is
NCIT:C183182 Hearing Aid, which is already in cache/ncit/terms.csv.
Two further defects came out of the push that answered round 1, and both were in
prose rather than in data. The Cochlear implantation description still said the
record carried no evidence block after an evidence block had been added directly
beneath it, which review caught. And a line of the language-delay description ended
in "post-" inside a folded scalar, which turned CI red: `check-folded-hyphens` takes
no file argument, so the per-file loop I had been running could not see it. Both are
fixed here. The shape they share is that neither is reachable from the file being
edited alone.
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.
Record review notes
The mouse's extra-auditory phenotype is recorded as a divergence marked IMMATERIAL, and the wording there is careful on purpose. Eps8-null mice have 25 percent shorter intestinal microvilli with a metabolic phenotype; humans with biallelic EPS8 loss are described as having isolated deafness. But "isolated" in those reports means no reported syndromic feature in a handful of patients, not a negative metabolic workup - nobody has looked. Microvilli and stereocilia are the same kind of actin-cored structure, so this is a place where the human silence may be absence of evidence. Evidence base. Five pathogenic EPS8 variants had been described by 2023, across Algerian, Chinese and Iranian families. The founding family is two siblings with a homozygous nonsense allele; the pathograph is carried by mouse and in vitro work rather than by the patients. An earlier draft of this entry said "one human family" and was corrected after the deep-research report surfaced the later reports - the original framing came from reading the founding paper and stopping there. Every pathophysiology node below the molecular one is evidenced from mouse or in vitro work, and each is graded MODEL_ORGANISM or IN_VITRO accordingly. The only HUMAN_CLINICAL evidence in the pathograph is the allele itself and the authors' closing inference about sound pressures, which is graded PRIMARY_RESULT but is an inference and is flagged as one in its explanation. A reviewer should read the mechanism as mouse-derived. Two records previously carried no evidence and no term on the reasoning that only a DFNB102-specific source would do. Review was right that this is stricter than dismech uses: general-mechanism evidence is routine, cochlear implantation for prelingual profound SNHL is not a DFNB102-specific claim, and the supporting reference was already committed in this PR and uncited. Both now cite PMID:41895171 with quote_role REVIEW_SYNTHESIS, the phenotype at directness INDIRECT, and the Delayed speech and language development node is bound to HP:0000750, which was an exact-name match sitting in cache/hp/terms.csv the whole time. The term and the evidence were separate decisions and I had conflated them. One CURIE I wrote from memory was wrong, and is recorded because it landed in the slot CLAUDE.md names as the blind spot. The hearing-aid qualifier was first written as NCIT:C50108 "Hearing Aid"; NCIT:C50108 is Plug Device. `just validate` and `just validate-terms` both pass on a fabricated qualifier value, because Qualifier.value is a plain Descriptor with no dynamic-enum binding. It was caught by running `runoak -i ols:ncit info` before committing, and the correct term is NCIT:C183182 Hearing Aid, which is already in cache/ncit/terms.csv. Two further defects came out of the push that answered round 1, and both were in prose rather than in data. The Cochlear implantation description still said the record carried no evidence block after an evidence block had been added directly beneath it, which review caught. And a line of the language-delay description ended in "post-" inside a folded scalar, which turned CI red: `check-folded-hyphens` takes no file argument, so the per-file loop I had been running could not see it. Both are fixed here. The shape they share is that neither is reachable from the file being edited alone.
Record notes
Ontology gaps, and where specificity was deliberately not manufactured. "Failure of Stereocilia Elongation" binds CL:0000202 auditory hair cell rather than the narrower CL:0000589 cochlear inner hair cell or CL:0000601 cochlear outer hair cell, because the cited result is explicitly about both types - "both inner and outer hair cells from Eps8 knockout (KO) mice showed abnormally short stereocilia". Binding either narrow term would assert a cell-type restriction the source denies. The maturation node does bind CL:0000589, because there the source restricts it. A negative-existence note in an earlier draft of this entry was WRONG and is recorded here rather than quietly deleted, because the mistake is the one CLAUDE.md warns about by name. The draft said no GO term names "barbed-end actin filament capping", on the strength of grepping cache/go/terms.csv and getting no rows. The term exists: GO:0051016 barbed-end actin filament capping, confirmed with `runoak -i ols:go info GO:0051016` and `runoak -i ols:go search "l~barbed-end actin filament capping"`, which also returns the three regulation terms beneath it. The cache was empty because nothing in kb/ had bound it yet, and an empty cache is silence, not a negative answer - the cache-first contract read backwards. GO:0051016 is now bound on the molecular node and on the effector-domain node, where it is the exact process the disease alleles remove. The error was caught by the committed OpenScientist deep-research report, which named the CURIE. The GeneReviews baseline for this disorder is PMID:20301607 Genetic Hearing Loss Overview; it is tagged in `references:` and carries no evidence item, because nothing in it is quoted. There is no EPS8-specific or DFNB102-specific GeneReviews chapter - verified offline against cache/bookshelf/genereviews.csv.
Create: Autosomal Recessive Nonsyndromic Hearing Loss 102 (MONDO:0014428) · 2026-09-22T13:32:21Z · View source
De novo curation of DFNB102 / EPS8-related nonsyndromic hearing loss (MONDO:0014428), claimed in #12502. entry_type decision: DISEASE. A single-gene, single-MONDO-term leaf under hearing loss, autosomal recessive. Pathograph: five nodes. One molecular lesion (EPS8 loss of function) with two separable downstream arms - failure of stereocilia elongation, shared by inner and outer hair cells, and arrested functional maturation confined to inner hair cells - converging on compromised detection of physiological sound pressures. A fifth node records EPS8 as one component of the MYO15A/whirlin/GPSM2 stereocilia tip complex rather than as a solo actor. Cell-type binding note: the elongation node binds CL:0000202 auditory hair cell rather than the narrower inner or outer hair cell terms, because the cited result is explicitly about both. The maturation node binds CL:0000589 cochlear inner hair cell, because there the source restricts it. Recorded human-model mismatch: Eps8-null mice have shortened vestibular stereocilia with no vestibular deficit, which the authors attribute to central compensation. The founding human family is described as having isolated deafness, but no vestibular testing is reported - so 'non-syndromic' rests on the absence of a complaint in two individuals against a model that predicts a measurable abnormality with no complaint. Proposed experiment records the reflex measurements that would distinguish the readings. Evidence base is deliberately stated as thin: one human family, two siblings, one homozygous nonsense allele, with the mechanism carried by mouse and in vitro work. Every pathograph node below the molecular one is graded MODEL_ORGANISM or IN_VITRO. One phenotype (Delayed speech and language development) carries no evidence block, deliberately, because no cited source reports speech outcomes in an EPS8 patient. This is stated in the node description and in review_notes. Validation: just validate, just validate-terms, just count-verified-snippets (15/15). Deep research reconciliation. The committed OpenScientist report materially changed this entry and caught one error of mine. Corrected: an earlier draft's notes said no GO term names "barbed-end actin filament capping", on the strength of an empty cache/go/terms.csv grep. The term exists (GO:0051016), confirmed with runoak against ols:go. An empty cache is silence, not a negative answer. The false note is replaced by a note recording the mistake, and GO:0051016 is now bound where it belongs. Corrected: the draft said the entry rests on "one human family". Five pathogenic EPS8 variants had been described by 2023, across Algerian, Chinese and Iranian families. The original framing came from reading the founding paper and stopping. Added from the report, each verified against a freshly fetched cache: a C-terminal-effector-domain pathophysiology node with the structural separation of capping from bundling (PMID:15558031, PMID:20532239); the MYO15A/whirlin/EPS8 tip complex statement (PMID:21236676); the compound splice-plus-65.9 kb-deletion genotype that sequencing alone read as homozygous (PMID:34637946); an Eps8 knockout mouse model with the extra-auditory intestinal and metabolic phenotype recorded as a typed divergence (PMID:20209148); and cochlear implantation. Reference titles were twice written from descriptive text rather than copied from the cache frontmatter, and twice caught by the title check. They are now set programmatically from the references_cache title field. Review round 1 (PR #12512). Both IMPORTANT items and all four suggestions taken. HP:0000750 bound to the Delayed speech and language development phenotype. The node name was verbatim the HPO label and the term was already in cache/hp/terms.csv. My description explained why the node had no evidence and said nothing about why it had no term; those were separate decisions and I had conflated them. PMID:41895171 cited on both the cochlear implantation treatment and the language phenotype. It was committed in this PR and uncited - the shape of a decision made and reversed. The bar I had set, that only a DFNB102-specific source would do, is stricter than dismech uses: general-mechanism evidence is routine, and cochlear implantation for prelingual profound SNHL is not a gene-specific claim. Graded REVIEW_SYNTHESIS, and INDIRECT on the phenotype. Added: prevalence as CASES_IN_LITERATURE with an ULTRA_RARE tier; a diagnosis block covering the copy-number point, which for this gene is not a completeness note but a correctness one - sequencing alone reported the wrong genotype in a real patient; a hearing-aid trial row, recorded because limited benefit from optimally fitted amplification is part of the implant indication rather than an alternative to it; and post-implant auditory-verbal and speech-language therapy. Duplicate PMID:36635257 references entry removed. One CURIE I wrote from memory was wrong. The hearing-aid qualifier was first written as NCIT:C50108 "Hearing Aid"; that code is Plug Device. Both just validate and just validate-terms pass on it, because Qualifier.value is a plain Descriptor with no dynamic-enum binding - the blind spot CLAUDE.md documents. Caught by running runoak before committing. Corrected to NCIT:C183182, verified in cache/ncit/terms.csv, and recorded in the entry notes. HP:0008619 for bilaterality not added. The reviewer marked it optional and noted that carrying laterality as a qualifier is equally defensible; the existing HP:0011476 node's evidence quotes a two-sibling family and no cached source states a bilaterality frequency, so a second phenotype would add a claim without a source.
Disease: Autosomal Recessive Nonsyndromic Hearing Loss 102 (DFNB102) MONDO ID: MONDO:0014428 · OMIM: 615974 · Causal gene: EPS8 (12p12.3) Report type: Aggregated disease-level synthesis of primary literature and ontology resources
Autosomal Recessive Nonsyndromic Hearing Loss 102 (DFNB102) is an ultrarare Mendelian sensorineural deafness caused by biallelic loss-of-function variants in EPS8, the gene encoding Epidermal Growth Factor Receptor Pathway Substrate 8, an 822-amino-acid F-actin capping and bundling protein. The disease was first defined in 2014, when whole-exome sequencing of a consanguineous Algerian family identified a homozygous nonsense variant, c.88C>T (p.Gln30), segregating with isolated profound congenital deafness (PMID: 24741995). DFNB102 is genetically and clinically homogeneous within its small case series: affected individuals present with prelingual/congenital, bilateral, symmetric, severe-to-profound, nonsyndromic sensorineural hearing loss with no consistent vestibular, syndromic, or extra-auditory features. As of 2023, only about five pathogenic EPS8* variants/families had been reported worldwide (Algerian, Chinese, Iranian), underscoring its rarity.
The mechanism is well delineated at the molecular and cellular level thanks to concordant human genetics and mouse models. EPS8 localizes to the tips of cochlear hair-cell stereocilia, where its C-terminal effector domain caps actin filament barbed ends and bundles the actin core. This activity is required for stereocilia to elongate to their correct staircase heights and for inner hair cells (IHCs) to mature into functional mechanoelectrical transducers. When EPS8 is truncated or deleted, this domain is lost; stereocilia remain abnormally short, IHCs fail to mature, mechano-electrical transduction is abolished, and profound deafness results. The Eps8-knockout mouse faithfully recapitulates the human phenotype — it is profoundly deaf with short stereocilia — and the paralog Eps8L2 divides labor with EPS8, handling stereocilia maintenance while EPS8 handles initial elongation.
Because EPS8 is broadly expressed and multifunctional (EGFR signaling, Rac regulation via the EPS8–ABI1–SOS1 complex, intestinal microvillus formation), one might expect a syndromic phenotype; however, human EPS8-null individuals present with isolated deafness only, indicating functional redundancy of EPS8 outside the cochlea (the paralogs EPS8L1/L2/L3 compensate) but a non-redundant role at stereocilia tips. Notably, the Eps8-knockout mouse displays intestinal microvillus shortening and a favorable calorie-restriction-like metabolic phenotype that is absent from human patients, an instructive species divergence. There is no disease-specific pharmacologic or gene therapy; diagnosis relies on exome/genome sequencing with copy-number analysis, and management is cochlear implantation, the standard of care for congenital severe-to-profound sensorineural hearing loss.
Overview. DFNB102 is a form of autosomal recessive nonsyndromic sensorineural hearing loss (SNHL). "Nonsyndromic" means hearing loss occurs in isolation, without associated malformations or dysfunction of other organ systems. "DFNB" designates a recessive (B) locus for deafness (DFN); "102" is its sequential locus number.
Key identifiers.
| Resource | Identifier |
|---|---|
| MONDO | MONDO:0014428 |
| OMIM (phenotype) | 615974 (DEAFNESS, AUTOSOMAL RECESSIVE 102; DFNB102) |
| Gene | EPS8, OMIM 600206, HGNC:3555, NCBI Gene 2059, Ensembl ENSG00000151491, UniProt Q12929 |
| Cytoband | 12p12.3 |
| ICD-10 | H90.3 (sensorineural hearing loss, bilateral) — non-specific |
| ICD-11 | AB52.0 / bilateral sensorineural hearing impairment stem — non-specific |
| MeSH | Closest: "Hearing Loss, Sensorineural" (D006319); no DFNB102-specific MeSH term |
Synonyms / alternative names. DFNB102; Deafness, autosomal recessive 102; EPS8-related nonsyndromic hearing loss; autosomal recessive nonsyndromic sensorineural deafness type DFNB102.
Information source. This entry is derived from aggregated disease-level resources (OMIM, ontology databases) and individual published case reports/families (Algerian, Chinese, Iranian), not from a large EHR cohort. The literature base is small (a handful of families).
Primary cause — genetic. DFNB102 is a monogenic disorder caused by biallelic (homozygous or compound heterozygous) loss-of-function variants in EPS8. It is not caused by environmental, infectious, or acquired factors. The founding evidence: Behlouli et al. 2014 identified a homozygous nonsense variant c.88C>T (p.Gln30*) in two siblings from a consanguineous Algerian family with isolated profound congenital deafness; the variant segregated recessively (heterozygous in unaffected parents and one sib, absent from two unaffected sibs) and was absent from 120 Algerian controls and the Exome Variant Server (PMID: 24741995).
"A biallelic nonsense mutation, c.88C > T (p.Gln30), was identified in EPS8 that encodes epidermal growth factor receptor pathway substrate 8, a 822 amino-acid protein involved in actin dynamics."* — PMID: 24741995
Genetic risk factors. The causal factor is possession of two loss-of-function EPS8 alleles. Consanguinity is a major risk-elevating context (the index family was consanguineous, and homozygous LoF alleles are far more likely in consanguineous unions). Carriers (heterozygotes) are unaffected.
Environmental / lifestyle risk factors. None established for the primary (genetic) disease. General SNHL aggravators (noise, ototoxic drugs, aging) are not documented as modifiers of DFNB102 specifically.
Protective factors. No genetic or environmental protective factors are described. In principle, the paralogs EPS8L1/EPS8L2/EPS8L3 provide functional redundancy in non-cochlear tissues, explaining why the phenotype is confined to hearing (see §4, §6).
Gene–environment interactions. None documented. DFNB102 is a fully penetrant monogenic condition; environmental modulation has not been reported.
The DFNB102 phenotype is dominated by a single, highly consistent manifestation.
| Phenotype | Type | Onset | Severity | Progression | Frequency | Suggested HPO |
|---|---|---|---|---|---|---|
| Sensorineural hearing loss | Clinical sign / audiometric | Congenital / prelingual | Severe-to-profound | Non-progressive (congenitally profound) | ~100% of affected | HP:0000407 (SNHL); HP:0008527 (Congenital SNHL); HP:0000365 (Hearing impairment) |
| Bilateral involvement | Clinical sign | Congenital | — | Stable | ~100% | HP:0008619 (Bilateral SNHL) |
| Profound degree | Audiometric | Congenital | Profound (>90 dB HL) | Stable | Majority | HP:0011476 (Bilateral profound SNHL); HP:0000364 |
| Absence of syndromic features | — | — | — | — | — | (Nonsyndromic) |
Characteristics. Onset is congenital/prelingual (present at or before language acquisition). Severity is severe-to-profound; the Chinese case was congenital profound, the Algerian siblings profound. The loss is bilateral and symmetric. Because it is congenitally profound, it is best described as stable/non-progressive in patients (contrast with EPS8L2 disease, which is late-onset progressive — see §4/§15). No consistent vestibular dysfunction or balance phenotype has been reported, and no extra-auditory (syndromic) features are documented.
"an 11-month-old male infant presented with congenital profound non-syndromic hearing loss" — PMID: 34637946
Quality-of-life impact. Congenital profound hearing loss, if unaddressed in the critical period, severely impairs spoken-language acquisition, literacy, educational attainment, and social participation. Early cochlear implantation substantially mitigates these outcomes (see §11–12). Formal EQ-5D/SF-36 data specific to DFNB102 are not available given the tiny cohort.
Causal gene. EPS8 (Epidermal Growth Factor Receptor Pathway Substrate 8), 12p12.3; HGNC:3555; OMIM 600206; UniProt Q12929; protein length 822 aa. EPS8 is an F-actin capping and bundling protein.
"EPS8 is an F-actin capping and bundling protein." — PMID: 24741995
Reported pathogenic variants. As of 2023, only ~5 pathogenic EPS8 variants had been described (PMID: 36635257).
| Variant (cDNA / protein) | Type | Zygosity / family | Population | Reference |
|---|---|---|---|---|
| c.88C>T (p.Gln30*) | Nonsense (LoF) | Homozygous, consanguineous | Algerian | PMID: 24741995 |
| c.1435-2A>T (p.His479Cysfs*14) | Splice-site (LoF) | Compound het with CNV | Chinese | PMID: 34637946 |
| ~65.9 kb intragenic deletion | Structural / CNV (LoF) | Compound het (maternal) | Chinese | PMID: 34637946 |
| Fifth reported pathogenic variant | (per report) | — | Iranian | PMID: 36635257 |
"Thus far, only four pathogenic variations in EPS8 have been described. In this study, we report the fifth pathogenic variant in the EPS8 gene in an Iranian patient with DFNB102." — PMID: 36635257
Variant classification & type. All reported disease alleles are pathogenic loss-of-function: nonsense, splice-site/frameshift, and a large intragenic deletion. No pathogenic missense variant establishing DFNB102 has been reported; the mechanism requires biallelic loss.
Allele frequency. Reported variants are absent or ultrarare in population databases (c.88C>T absent from 120 Algerian controls and the Exome Variant Server; PMID: 24741995). No common susceptibility allele exists.
Somatic vs germline. All variants are germline.
Functional consequence. Loss of function. Truncating and deletion alleles remove the C-terminal effector domain that carries capping/bundling activity (see §6). In the Chinese case, in vitro splicing and allele-specific expression assays confirmed near-total loss of functional transcript (0-fold WT; 0.25–0.27-fold mutant; P<0.05) (PMID: 34637946).
"further CNVs analysis identified a novel 65.9 kb intragenic deletion and was inherited from his mother" — PMID: 34637946
Modifier genes. The paralog EPS8L2 is functionally relevant: it complements EPS8 at stereocilia tips and its own loss causes progressive hearing loss (PMID: 23918390). EPS8L1/L2/L3 collectively provide redundancy outside the cochlea. No formal disease-severity modifier has been mapped for DFNB102.
Epigenetic / chromosomal. No epigenetic mechanism is implicated. The only "structural" lesion is the intragenic EPS8 deletion; no aneuploidy or translocation is associated.
Environmental factors: None causal or contributory — DFNB102 is monogenic. Lifestyle factors: None established. Infectious agents: None — DFNB102 is not an infectious or acquired deafness (contrast with congenital CMV, rubella, ototoxic exposure). Not applicable.
Branch (developmental vs maintenance): EPS8 drives initial elongation (step 3); its paralog EPS8L2 independently drives maintenance of stereocilia in adult cells. Loss of EPS8 → short bundles from the outset (DFNB102, congenital). Loss of EPS8L2 → normal build-up then decay → late-onset progressive loss (PMID: 23918390).
Actin capping vs bundling — separable activities. Disanza et al. 2004 showed EPS8 caps actin barbed ends with nanomolar affinity through its conserved C-terminal effector domain, with full-length EPS8 auto-inhibited in vitro and de-repressed by Abi1 (PMID: 15558031).
"proteins of another family, the Eps8 family, also show barbed-end capping activity, which resides in their conserved carboxy-terminal effector domain" — PMID: 15558031
Hertzog et al. 2010 resolved the structural basis: bundling is mediated by a compact four-helix bundle contacting three actin subunits along the filament, whereas capping is mediated by an amphipathic helix inserting into the hydrophobic pocket at the barbed end, blocking monomer addition; point mutations can dissociate the two activities (PMID: 20532239).
"The capping activity is mainly mediated by a amphipathic helix that binds within the hydrophobic pocket at the barbed ends of actin blocking further addition of actin monomers." — PMID: 20532239
Because DFNB102 truncating/deletion alleles remove this C-terminal effector domain, both capping and bundling are lost — the mechanistic crux linking genotype to stereocilia failure.
Tip complex context. EPS8 is a central actin-regulatory element within the stereocilia tip complex together with MyosinXVa (MYO15A) and whirlin (WHRN); Eps8-null bundles are shorter than MyoXVa- or whirlin-deficient bundles, placing EPS8 at the heart of elongation control (PMID: 21236676).
"MyoXVa, whirlin, and Eps8 are integral components of the stereocilia tip complex, where Eps8 is a central actin-regulatory element for elongation of the stereocilia actin core." — PMID: 21236676
Krey et al. 2023 showed EPS8 protein accumulation at row-1 tips peaks at the end of developmental stage III, coinciding with row-1 lengthening, and that mechanotransduction normally restricts EPS8 to the tallest row (PMID: 37011103).
Broader signaling role (redundant in cochlea). Outside hair cells, EPS8 regulates Rac-dependent actin remodeling and cell motility via the trimeric EPS8–ABI1–SOS1 complex, participates in EGFR signaling, and can undergo chaperone-mediated autophagy in cancer cells (PMID: 15558031, PMID: 20184880, PMID: 41974702). These functions are not manifest as disease in humans because paralogs compensate — hence isolated deafness.
Molecular pathways / GO terms. GO:0030041 (actin filament polymerization), GO:0051016 (barbed-end actin filament capping), GO:0051017 (actin filament bundle assembly), GO:0060088 (auditory receptor cell stereocilium organization), GO:0032420 (stereocilium), GO:0007605 (sensory perception of sound). Cell types (CL): CL:0000589 (cochlear inner hair cell), CL:0000601 (cochlear outer hair cell).
EPS8 biallelic LoF (nonsense/splice/deletion)
│ removes C-terminal effector domain
▼
Loss of barbed-end CAPPING + actin BUNDLING at stereocilia tips
│
▼
Failed stereocilia ELONGATION → short bundles, decayed staircase
│ ┌───────────────────────────┐
▼ │ Paralog division of labor: │
IHCs fail functional MATURATION │ EPS8 = elongation (DFNB102│
(OHCs comparatively spared) │ EPS8L2= maintenance → │
│ │ progressive HL) │
▼ └───────────────────────────┘
Loss of mechano-electrical transduction (inferred in human)
▼
PROFOUND CONGENITAL BILATERAL SENSORINEURAL HEARING LOSS
Epidemiology. DFNB102 is ultrarare: only ~5 pathogenic variants/families reported worldwide as of 2023 (PMID: 36635257, PMID: 34637946). For context, nonsyndromic hearing loss overall affects ~1 in 1000 newborns and is hereditary in 60–70% of cases, with GJB2 the most common cause (PMID: 19939467; PMID: 10376574); EPS8/DFNB102 accounts for a vanishingly small fraction.
"Nonsyndromic hearing loss is one of the most abundant human sensory disorders, and can be found in 1 out of 1000 newborns. In 60-70% of the cases this disorder is hereditary." — PMID: 19939467
Recommended approach. Diagnosis is molecular, integrated with audiometric confirmation.
Clinical criteria / differential diagnosis. DFNB102 is diagnosed by the combination of nonsyndromic congenital profound SNHL and biallelic EPS8 LoF. Differentials include the far more common GJB2/GJB6 deafness (PMID: 10376574), SLC26A4 (Pendred/EVA), MYO15A, TMC1, OTOF (auditory neuropathy), and syndromic causes (Usher, Pendred, Waardenburg) — distinguished by absence of syndromic features and gene-specific findings. EPS8L2 should be considered in progressive postlingual loss.
Screening. Newborn hearing screening detects the phenotype; cascade/carrier testing of relatives is appropriate once the familial variants are known. There is no population carrier-screening program specific to EPS8.
There is no disease-specific pharmacologic or gene therapy for DFNB102. Management is habilitative.
| Modality | Detail | NCIT suggestion |
|---|---|---|
| Cochlear implantation (standard of care) | For congenital bilateral severe-to-profound SNHL with limited hearing-aid benefit; effective; best outcomes with early implantation (PMID: 41895171) | NCIT:C15694 (Cochlear Implant) |
| Hearing aids | Trialed first; typically insufficient for profound loss | NCIT:C99936 (Hearing Aid) |
| Auditory-verbal / speech-language therapy | Rehabilitation to develop spoken language post-implant | NCIT:C15195 (Rehabilitation Therapy) |
| Educational/communication support | Sign language, assistive listening, early intervention services | — |
"Pediatric cochlear implantation is the standard of care for infants and young children with congenital bilateral severe-to-profound sensorineural hearing loss who receive limited benefits from optimally fitted hearing aids." — PMID: 41895171
Pharmacotherapy / pharmacogenomics: None specific. Gene therapy / RNA therapy / cell therapy: None approved or in DFNB102-specific trials; inner-ear gene therapy is an active field for other deafness genes (e.g., OTOF) but not yet for EPS8. Surgical: Cochlear implant surgery as above. Experimental: No DFNB102-specific NCT-registered trials identified.
The mouse is the definitive model and faithfully recapitulates the human cochlear phenotype, while also revealing species-specific pleiotropy.
| Model | Type | Key phenotype | Human relevance | Reference |
|---|---|---|---|---|
| Eps8-knockout mouse | Constitutive KO (mammalian) | Profoundly deaf; abnormally short stereocilia; IHCs (not OHCs) fail to mature | Faithful DFNB102 model | PMID: 21526224, PMID: 24741995 |
| Eps8L2-knockout mouse | Constitutive KO | Late-onset progressive hearing loss; gradual hair-bundle deterioration | Models maintenance role / progressive HL branch | PMID: 23918390 |
| Eps8/Eps8L2 double-null | Combined KO | Decay of ordered staircase hair-bundle structure | Demonstrates complementary roles | PMID: 23918390 |
| Eps8-KO (systemic phenotypes) | Constitutive KO | ~25% shorter intestinal microvilli; reduced fat absorption; resistance to diet-induced obesity; improved metabolism; increased lifespan | Not seen in human patients — species divergence | PMID: 20209148 |
"whereas Eps8 is essential for the initial elongation of stereocilia, Eps8L2 is required for their maintenance in adult hair cells. In the absence of both proteins, the ordered staircase structure of the hair bundle in the cochlea decays." — PMID: 23918390
"Eps8 knockout mice are profoundly deaf and that IHCs, but not OHCs, fail to mature into fully functional sensory receptors" — PMID: 21526224
Phenotype recapitulation. Excellent for the auditory phenotype — the Eps8-KO mouse independently established EPS8 as an essential stereocilia elongation factor before the human gene was implicated, providing strong cross-species validation.
Model limitations. The mouse KO exhibits extra-cochlear phenotypes (intestinal microvillus shortening, favorable metabolic status, longevity) absent from human isolated deafness — likely reflecting differences in paralog compensation between species. This makes the mouse imperfect for modeling the isolated human presentation but valuable for dissecting EPS8's broader actin biology.
"knockout mice for Eps8, a regulator of actin dynamics, display reduced body weight, partial resistance to age- or diet-induced obesity, and overall improved metabolic status" — PMID: 20209148
Resources: MGI (mouse Eps8), IMPC; in vitro biochemistry and structural biology of EPS8 capping/bundling (PMID: 15558031, PMID: 20532239).
F1 — DFNB102 is caused by biallelic loss-of-function EPS8 variants (12p12.3). WES of a consanguineous Algerian family found homozygous c.88C>T (p.Gln30*) segregating recessively, absent from 120 controls and the Exome Variant Server (PMID: 24741995); only ~5 pathogenic variants known by 2023 (PMID: 36635257).
F2 — EPS8 controls stereocilia elongation and IHC maturation. Eps8-KO mice are profoundly deaf with short stereocilia; IHCs (not OHCs) fail to mature (PMID: 21526224); EPS8 sits in the MYO15A–whirlin tip complex as the central elongation regulator (PMID: 21236676).
F3 — Consistent clinical phenotype: prelingual, bilateral, symmetric, severe-to-profound nonsyndromic SNHL across Algerian, Chinese (compound splice + 65.9 kb deletion; transcript loss P<0.05), and Iranian cases (PMID: 34637946, PMID: 36635257).
F4 — Faithful mouse models; EPS8 vs EPS8L2 divide developmental vs maintenance roles (PMID: 23918390, PMID: 37011103).
F5 — EPS8 is a multifunctional EGFR-pathway actin regulator with a non-redundant cochlear role — broad expression yet isolated deafness implies paralog redundancy elsewhere (PMID: 24741995, PMID: 41974702).
F6 — Ultrarare; diagnosed by WES/WGS + CNV analysis; managed by cochlear implantation (PMID: 19939467, PMID: 41895171).
F7 — Mouse-specific intestinal/metabolic phenotype absent in humans (~25% shorter microvilli, improved metabolism; PMID: 20209148).
F8 — Separable capping and bundling encoded by the C-terminal effector domain, both required and both lost by truncating alleles (PMID: 15558031, PMID: 20532239).
| PMID | How it supports the findings |
|---|---|
| 24741995 | Founding paper: EPS8 = DFNB102 gene; c.88C>T; defines EPS8 as F-actin capping/bundling protein |
| 34637946 | Compound splice variant + 65.9 kb intragenic deletion; congenital profound nonsyndromic HL; CNV diagnostics |
| 36635257 | Fifth pathogenic variant (Iranian); confirms rarity |
| 21526224 | Eps8-KO mouse: profound deafness, short stereocilia, IHC maturation failure |
| 21236676 | EPS8 central in MYO15A–whirlin tip complex for actin-core elongation |
| 23918390 | EPS8L2 maintenance role; double-null staircase decay; progressive HL branch |
| 37011103 | EPS8 timing at stereocilia tips; transduction restricts EPS8 to tallest row |
| 15558031 | Barbed-end capping resides in C-terminal effector domain; Abi1 de-repression; Rac via EPS8–Abi1–Sos1 |
| 20532239 | Structural basis: helix-bundle bundling vs amphipathic-helix capping; separable activities |
| 20209148 | Mouse intestinal/metabolic phenotype (species divergence) |
| 41974702 | EPS8–ABI1 complexes in non-cochlear actin remodeling |
| 41895171 | Cochlear implantation as standard of care |
| 19939467, 10376574 | Epidemiologic context for nonsyndromic HL and GJB2 differential |
Evidence-type mix: Human clinical genetics (24741995, 34637946, 36635257); model organism (21526224, 21236676, 23918390, 37011103, 20209148); in vitro/structural biochemistry (15558031, 20532239); clinical management (41895171).
Report compiled from 8 confirmed findings and 27 reviewed papers across a 5-iteration autonomous investigation. Evidence sources are labeled by type (human clinical, model organism, in vitro/structural, clinical management). Ontology suggestions: MONDO:0014428; HGNC:3555 (EPS8); UBERON:0001844 (cochlea), UBERON:0002227 (organ of Corti); CL:0000589 (cochlear inner hair cell), CL:0000601 (cochlear outer hair cell); GO:0051016 (barbed-end actin filament capping), GO:0051017 (actin filament bundle assembly), GO:0060088 (auditory receptor cell stereocilium organization), GO:0032420 (stereocilium); NCIT:C15694 (Cochlear Implant).
Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
|---|---|
| References checked | 16 |
| Resolved | 16 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 16 |
| On topic | 8 |
| Off topic | 0 |
All extracted references resolved successfully.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 24 |
| Resolved | 23 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 0 |
| Unverifiable | 1 |
| Terms whose name was checked | 16 |
| Terms named correctly | 9 |
| Terms named as a different term | 4 |
| Terms whose name is worth a second look | 3 |
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:0014428 (3 mentions) - the report calls it "MONDO"; MONDO calls it autosomal recessive nonsyndromic hearing loss 102HP:0008619 (2 mentions) - the report calls it "Bilateral SNHL", "Localization / lateralization: Bilateral, symmetric cochlear involvement"; HP calls it Bilateral sensorineural hearing impairment**NCIT:C15694 (2 mentions) - the report calls it "Cochlear Implant"; NCIT calls it Phase II/III TrialNCIT:C99936 (1 mention) - the report calls it "Hearing Aid"; NCIT calls it Catecholaminergic Polymorphic Ventricular Tachycardia by ECG FindingThe report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:
GO:0032420 (3 mentions) - the report calls it "stereocilium", "Subcellular level: The stereocilium"; GO calls it stereociliumUBERON:0002227 (2 mentions) - the report calls it "organ of Corti / spiral organ", "organ of Corti"; UBERON calls it spiral organ of cochlea, and lists "spiral organ of Corti" among its other namesNCIT:C15195 (1 mention) - the report calls it "Rehabilitation Therapy"; NCIT calls it Brachytherapy, and lists "Radiation Brachytherapy" among its other namesThe report gives these identifiers more than one name of its own:
HP:0008619 - called "Bilateral SNHL", "Localization / lateralization: Bilateral**, symmetric cochlear involvement"GO:0032420 - called "stereocilium", "Subcellular level: The stereocilium"CL:0000589 - called "cochlear inner hair cell", "cochlear inner hair cells"UBERON:0002227 - called "organ of Corti / spiral organ", "organ of Corti"