DFNA72 is autosomal dominant nonsyndromic sensorineural hearing loss attributed to a heterozygous SLC44A4 variant. It is one of the thinnest gene-disease relationships in the DFNA series and this entry is written around that fact rather than around a mechanism. The whole clinical literature is one Chinese kindred reported in 2017, in which whole-exome sequencing found SLC44A4 c.466A>G (p.Met156Val) segregating with postlingual, non-syndromic, mid-frequency sensorineural hearing loss. The ClinGen Hearing Loss Gene Curation Expert Panel evaluated the pair in 2018, re-evaluated it in 2022, and both times classified it Limited - one proband, one publication, a segregation LOD of 2.1 - while noting that nothing has emerged to contradict it. No second family has been published in the nine years since. A reader should treat everything below as one family's disease until that changes. The audiometric configuration is the one clinically distinctive feature. Autosomal dominant nonsyndromic hearing loss is characteristically high-frequency and sloping; this family's loss is mid-frequency, which is uncommon enough in the DFNA series that it carried the original report's title. The proposed mechanism is cholinergic and efferent rather than about the hair bundle. The reporting authors framed SLC44A4 as a choline transport protein, showed that cells expressing the mutant took up less choline and released less acetylcholine than cells expressing wild type, and reasoned from there to the olivocochlear efferent bundle, whose cholinergic synapses onto outer hair cells are known - from mouse work on the alpha9 nicotinic receptor - to protect the organ of Corti from acoustic injury. That chain is a hypothesis assembled across three systems, and the authors wrote it with "may cause". It is curated here as EMERGING, and every causal edge along it is hedged accordingly. There is a specific reason not to state the choline step as settled. The only direct molecular characterisation of human SLC44A4 identifies it as the colonic thiamine pyrophosphate transporter, with uptake that is high-affinity and specific for thiamine pyrophosphate and explicitly *not* affected by choline. Two literatures therefore assign the same protein two different substrates, and no inner-ear transport assay has been published for either. The alternative is recorded as its own hypothesis instead of being left out.
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name: Hearing Loss Autosomal Dominant 72
category: Mendelian
creation_date: "2026-09-04T00:00:00Z"
synonyms:
- DFNA72
- deafness, autosomal dominant 72
- autosomal dominant nonsyndromic deafness 72
- SLC44A4-related autosomal dominant nonsyndromic hearing loss
description: >-
DFNA72 is autosomal dominant nonsyndromic sensorineural hearing loss attributed to a
heterozygous SLC44A4 variant. It is one of the thinnest gene-disease relationships in the
DFNA series and this entry is written around that fact rather than around a mechanism.
The whole clinical literature is one Chinese kindred reported in 2017, in which
whole-exome sequencing found SLC44A4 c.466A>G (p.Met156Val) segregating with postlingual,
non-syndromic, mid-frequency sensorineural hearing loss. The ClinGen Hearing Loss Gene
Curation Expert Panel evaluated the pair in 2018, re-evaluated it in 2022, and both times
classified it Limited - one proband, one publication, a segregation LOD of 2.1 - while
noting that nothing has emerged to contradict it. No second family has been published in
the nine years since. A reader should treat everything below as one family's disease until
that changes.
The audiometric configuration is the one clinically distinctive feature. Autosomal dominant
nonsyndromic hearing loss is characteristically high-frequency and sloping; this family's
loss is mid-frequency, which is uncommon enough in the DFNA series that it carried the
original report's title.
The proposed mechanism is cholinergic and efferent rather than about the hair bundle. The
reporting authors framed SLC44A4 as a choline transport protein, showed that cells
expressing the mutant took up less choline and released less acetylcholine than cells
expressing wild type, and reasoned from there to the olivocochlear efferent bundle, whose
cholinergic synapses onto outer hair cells are known - from mouse work on the alpha9
nicotinic receptor - to protect the organ of Corti from acoustic injury. That chain is a
hypothesis assembled across three systems, and the authors wrote it with "may cause". It
is curated here as EMERGING, and every causal edge along it is hedged accordingly.
There is a specific reason not to state the choline step as settled. The only direct
molecular characterisation of human SLC44A4 identifies it as the colonic thiamine
pyrophosphate transporter, with uptake that is high-affinity and specific for thiamine
pyrophosphate and explicitly *not* affected by choline. Two literatures therefore assign
the same protein two different substrates, and no inner-ear transport assay has been
published for either. The alternative is recorded as its own hypothesis instead of being
left out.
disease_term:
preferred_term: hearing loss, autosomal dominant 72
term:
id: MONDO:0033259
label: hearing loss, autosomal dominant 72
parents:
- Autosomal Dominant Nonsyndromic Hearing Loss
mappings:
mondo_mappings:
- term:
id: MONDO:0033259
label: hearing loss, autosomal dominant 72
mapping_predicate: skos:exactMatch
mapping_source: MONDO
references:
- reference: PMID:28013291
title: "SLC44A4 mutation causes autosomal dominant hereditary postlingual non-syndromic mid-frequency hearing loss."
- reference: CGGV:assertion_3ddbe083-55c3-483b-8c32-fc9bdbef10c6-2022-11-22T170000.000Z
title: "SLC44A4 / nonsyndromic genetic hearing loss (Limited)"
- reference: PMID:24379411
title: "Molecular identification and functional characterization of the human colonic thiamine pyrophosphate transporter."
- reference: PMID:12486177
title: "Efferent protection from acoustic injury is mediated via alpha9 nicotinic acetylcholine receptors on outer hair cells."
- reference: PMID:37371710
title: "Autosomal Dominant Non-Syndromic Hearing Loss (DFNA): A Comprehensive Narrative Review."
inheritance:
- name: Autosomal dominant
description: >-
A heterozygous SLC44A4 variant segregating with hearing loss across the generations of a
single Chinese kindred. The segregation is the strongest piece of human genetic evidence
the disease has, and its LOD score of 2.1 falls short of the conventional threshold for
linkage in a single family. No second pedigree has been reported, so penetrance,
de novo rate and variable expressivity are all unknown.
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
evidence:
- reference: CGGV:assertion_3ddbe083-55c3-483b-8c32-fc9bdbef10c6-2022-11-22T170000.000Z
reference_title: "SLC44A4 / nonsyndromic genetic hearing loss (Limited)"
supports: SUPPORT
evidence_source: OTHER
snippet: "The variant was shown to segregate in the presented kindred with a LOD score of 2.1."
explanation: >-
The expert panel's own statement of the segregation evidence, including the number
that makes it suggestive rather than conclusive.
- reference: CGGV:assertion_3ddbe083-55c3-483b-8c32-fc9bdbef10c6-2022-11-22T170000.000Z
reference_title: "SLC44A4 / nonsyndromic genetic hearing loss (Limited)"
supports: SUPPORT
evidence_source: OTHER
snippet: "SLC44A4 | HGNC:13941 | nonsyndromic genetic hearing loss | MONDO:0019497 | AD | Limited | SOP9 | Hearing Loss Gene Curation Expert Panel | 2022-11-22T17:00:00.000Z"
explanation: >-
The classification row, which records the mode of inheritance the panel curated
against (AD) alongside the strength of the relationship (Limited).
mechanistic_hypotheses:
- hypothesis_group_id: cholinergic_efferent_model
hypothesis_label: Reduced cholinergic supply to the olivocochlear efferent synapse on outer hair cells
status: EMERGING
description: >-
The mechanism proposed by the reporting authors, and the only one anyone has proposed.
Its three links were each measured in a different system and never in the same one.
The first link is cellular and is the strongest: SH-SY5Y neuroblastoma cells transfected
with wild-type SLC44A4 took up more choline and released more acetylcholine than cells
transfected with the mutant construct, so the variant reduces the output of the
choline-acetylcholine pathway in a cell that can be made to run it.
The second link is anatomical and is imported: the medial olivocochlear bundle synapses
cholinergically onto outer hair cells, and in mice that synapse is protective -
overexpressing the alpha9 nicotinic receptor subunit in outer hair cells reduces acoustic
injury. That establishes the pathway matters for cochlear survival; it says nothing about
SLC44A4.
The third link is the one with no data at all. Nobody has shown that SLC44A4 is expressed
in olivocochlear efferent neurons, or that acetylcholine release at that particular
synapse depends on it, or that a heterozygous p.Met156Val allele changes anything in a
cochlea. The zebrafish experiment that is sometimes read as filling this gap is a
morpholino knockdown showing gross inner-ear and neuromast malformation, which is a
developmental phenotype in a fish that has no cochlea and no mid-frequency place code.
EMERGING is therefore the honest status, and the authors' own verb - "may cause" - is
the reason.
evidence:
- reference: PMID:28013291
reference_title: "SLC44A4 mutation causes autosomal dominant hereditary postlingual non-syndromic mid-frequency hearing loss."
supports: SUPPORT
evidence_source: OTHER
snippet: "We concluded that mutation of SLC44A4 may cause defects in the Choline- acetylcholine system, which is crucial to the efferent innervation of hair cells in the olivocochlear bundle for the maintenance of physiological function of outer hair cells and the protection of hair cells from acoustic injury, leading to hearing loss."
explanation: >-
The hypothesis in the authors' own words, hedged in the authors' own words. Graded
OTHER because the sentence is the paper's synthesis across its human, cell and fish
arms rather than the report of any one of them.
- reference: PMID:28013291
reference_title: "SLC44A4 mutation causes autosomal dominant hereditary postlingual non-syndromic mid-frequency hearing loss."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "SH-SY5Y cells transfected with SLC44A4 showed higher choline uptake and acetylcholine release than that of cells transfected with mutant SLC44A4."
explanation: >-
The measured functional difference between wild-type and mutant protein, and the only
quantitative support the hypothesis has.
- hypothesis_group_id: thiamine_pyrophosphate_transport_model
hypothesis_label: SLC44A4 is a thiamine pyrophosphate transporter and the choline step is misassigned
status: ALTERNATIVE
description: >-
SLC44A4 sits in the SLC44 "choline transporter-like" family, and the family name is where
the choline attribution comes from. The one study that characterised the human protein
directly reaches a different answer: expressed in ARPE19 cells it drives high-affinity,
saturable uptake of thiamine pyrophosphate with an apparent Km of 0.17 micromolar, and
that uptake is unaffected by free thiamine, thiamine monophosphate, or choline. Its
tissue distribution is colonic, at the apical membrane of polarised epithelium.
If that is the protein's actual transport activity, the DFNA72 mechanism as published
loses its first step, and the disease would need a different account - perhaps a
thiamine-pyrophosphate-dependent one, since thiamine pyrophosphate is the cofactor of
pyruvate dehydrogenase and transketolase and the cochlea is metabolically demanding, but
nothing at all has been published along those lines.
Recorded as ALTERNATIVE rather than as a refutation because the two are not strictly
exclusive. A transporter can have more than one substrate, the assays were done in
different cell backgrounds, and neither was done in inner-ear tissue. What would settle
it is a choline and thiamine pyrophosphate uptake comparison in the same system, with
and without the p.Met156Val allele. It has not been done.
evidence:
- reference: PMID:24379411
reference_title: "Molecular identification and functional characterization of the human colonic thiamine pyrophosphate transporter."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Here we report on the molecular identification of the colonic TPP uptake system as the product of the SLC44A4 gene."
explanation: >-
The competing substrate assignment, from the study that cloned and expressed the human
protein.
- reference: PMID:24379411
reference_title: "Molecular identification and functional characterization of the human colonic thiamine pyrophosphate transporter."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "highly specific for TPP and not affected by free thiamine, thiamine monophosphate, or choline"
explanation: >-
The direct observation that makes this an alternative and not merely an additional
activity: choline did not compete with the transport this assay measured.
- reference: PMID:28013291
reference_title: "SLC44A4 mutation causes autosomal dominant hereditary postlingual non-syndromic mid-frequency hearing loss."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: "Whole-exome sequencing revealed SLC44A4, which encodes the choline transport protein, as the pathogenic gene in this family."
explanation: >-
Cuts against this hypothesis: the sentence asserts the competing choline assignment.
It is weak as a refutation - the DFNA72 report states the choline function as a
premise rather than measuring it, which is the point the ALTERNATIVE turns on - but
the direction is against, not for. The same sentence is quoted with SUPPORT in the
substrate-identity discussion, where the claim being supported is that the two
literatures disagree rather than that either is right.
pathophysiology:
- name: SLC44A4 p.Met156Val Heterozygous Variant
description: >-
A single missense allele, c.466A>G (p.Met156Val), in a family of Chinese ancestry. It is
the only SLC44A4 variant ever curated in relation to hearing loss. ClinVar records it
against the DFNA72 concept without a classification from unflagged submissions, and no
other SLC44A4 variant carries a pathogenic or likely pathogenic classification for this
disease, so the allelic spectrum of DFNA72 is a single change in a single kindred.
The reporting authors did not assay the mutant protein's stability, localisation or
oligomerisation, so how a heterozygous missense change produces a dominant phenotype is
unaddressed. The expert panel records the reported mechanism as loss of function, which
for a dominant disease implies haploinsufficiency, but no truncating allele, deletion or
dosage evidence exists to support that reading.
biological_scale: MOLECULAR
genes:
- preferred_term: SLC44A4
term:
id: hgnc:13941
label: SLC44A4
downstream:
- target: Reduced Choline Uptake
causal_link_type: DIRECT
hypothesis_groups:
- cholinergic_efferent_model
evidence:
- reference: CGGV:assertion_3ddbe083-55c3-483b-8c32-fc9bdbef10c6-2022-11-22T170000.000Z
reference_title: "SLC44A4 / nonsyndromic genetic hearing loss (Limited)"
supports: SUPPORT
evidence_source: OTHER
snippet: "One variant (c.466A>G p.M156V) has been reported in one proband in one publication (PMID: 28013291) and is included in this curation."
explanation: >-
The allele and the size of the evidence base behind it, from the expert panel that
counted both.
- reference: CGGV:assertion_3ddbe083-55c3-483b-8c32-fc9bdbef10c6-2022-11-22T170000.000Z
reference_title: "SLC44A4 / nonsyndromic genetic hearing loss (Limited)"
supports: SUPPORT
evidence_source: OTHER
snippet: "The mechanism of pathogenicity is reported to be LOF."
explanation: >-
The reported mechanism, recorded as reported. The panel attributes it rather than
endorsing it, and no dosage or truncating evidence exists.
- name: Reduced Choline Uptake
description: >-
In SH-SY5Y neuroblastoma cells, transfection with wild-type SLC44A4 produced higher
choline uptake than transfection with the mutant construct. This is a comparison between
two transfected constructs in a cell line, not a measure of what a heterozygous carrier's
cells do.
Whether this node exists at all depends on which hypothesis is right: on the
thiamine-pyrophosphate reading of SLC44A4 the protein does not carry choline, and the
difference measured here would need another explanation. That is why the refuting item
below sits on this node and not on the one after it.
biological_scale: MOLECULAR
molecular_functions:
- preferred_term: choline transmembrane transporter activity
term:
id: GO:0015220
label: choline transmembrane transporter activity
modifier: DECREASED
downstream:
- target: Reduced Acetylcholine Release
causal_link_type: DIRECT
hypothesis_groups:
- cholinergic_efferent_model
evidence:
- reference: PMID:28013291
reference_title: "SLC44A4 mutation causes autosomal dominant hereditary postlingual non-syndromic mid-frequency hearing loss."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "SH-SY5Y cells transfected with SLC44A4 showed higher choline uptake and acetylcholine release than that of cells transfected with mutant SLC44A4."
explanation: >-
The measurement this node is, stated in the direction the paper reports it: wild type
higher, mutant lower.
- reference: PMID:24379411
reference_title: "Molecular identification and functional characterization of the human colonic thiamine pyrophosphate transporter."
supports: REFUTE
evidence_source: IN_VITRO
snippet: "highly specific for TPP and not affected by free thiamine, thiamine monophosphate, or choline"
explanation: >-
Cuts against the node as stated. In the assay that characterised human SLC44A4
directly, choline did not compete with the transport the protein performs, which is
hard to reconcile with a choline uptake step.
- name: Reduced Acetylcholine Release
description: >-
The same cells released less acetylcholine when transfected with the mutant construct
than with wild type. Curated separately from the uptake step because the two are
different measurements with different exposure to the substrate question: less choline
entering a cell is a claim about what SLC44A4 transports, whereas less acetylcholine
leaving it is a claim about the downstream consequence and would survive - needing a
different upstream explanation - even if the choline assignment turned out to be wrong.
Both were measured in one experiment, in one cell line, on transfected constructs rather
than on patient cells.
biological_scale: MOLECULAR
biological_processes:
- preferred_term: acetylcholine secretion, neurotransmission
term:
id: GO:0014055
label: acetylcholine secretion, neurotransmission
modifier: DECREASED
downstream:
- target: Impaired Cholinergic Olivocochlear Efferent Signalling
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
hypothesis_groups:
- cholinergic_efferent_model
evidence:
- reference: PMID:28013291
reference_title: "SLC44A4 mutation causes autosomal dominant hereditary postlingual non-syndromic mid-frequency hearing loss."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "SH-SY5Y cells transfected with SLC44A4 showed higher choline uptake and acetylcholine release than that of cells transfected with mutant SLC44A4."
explanation: >-
The release half of the same measurement, in the direction the paper reports it: wild
type higher, mutant lower.
- name: Impaired Cholinergic Olivocochlear Efferent Signalling
description: >-
The hypothesised organ-level consequence: less acetylcholine available at the medial
olivocochlear synapse onto outer hair cells. Nothing has been measured here in DFNA72.
No SLC44A4 expression has been reported in olivocochlear neurons, no efferent function
test - contralateral suppression of otoacoustic emissions, for example - has been
published in a carrier, and no animal carries the human allele.
The node is kept in the graph rather than dropped because it is the step the published
mechanism turns on, and leaving it out would make the chain look shorter and better
supported than it is.
biological_scale: TISSUE
cell_types:
- preferred_term: efferent neuron
term:
id: CL:0000527
label: efferent neuron
locations:
- preferred_term: olivocochlear bundle
term:
id: UBERON:0002775
label: olivocochlear bundle
biological_processes:
- preferred_term: acetylcholine secretion, neurotransmission
term:
id: GO:0014055
label: acetylcholine secretion, neurotransmission
modifier: DECREASED
downstream:
- target: Loss of Efferent Protection of Outer Hair Cells
causal_link_type: DIRECT
hypothesis_groups:
- cholinergic_efferent_model
evidence:
- reference: PMID:28013291
reference_title: "SLC44A4 mutation causes autosomal dominant hereditary postlingual non-syndromic mid-frequency hearing loss."
supports: SUPPORT
evidence_source: OTHER
snippet: "We concluded that mutation of SLC44A4 may cause defects in the Choline- acetylcholine system, which is crucial to the efferent innervation of hair cells in the olivocochlear bundle for the maintenance of physiological function of outer hair cells and the protection of hair cells from acoustic injury, leading to hearing loss."
explanation: >-
The only published statement placing the lesion at the olivocochlear efferent synapse.
It is a conclusion drawn across systems and hedged with "may", which is why every
edge on this chain is enrolled in the cholinergic_efferent_model hypothesis group
rather than asserted as established.
- name: Loss of Efferent Protection of Outer Hair Cells
description: >-
Outer hair cells that receive weakened cholinergic efferent input. What is established -
in mice, not in this disease - is that the alpha9 nicotinic receptor at that synapse is
protective: overexpressing it in outer hair cells reduces acoustic injury from exposures
that otherwise cause temporary or permanent damage, without changing baseline
sensitivity. The inference DFNA72 needs is the mirror image, that weakening the same
input leaves outer hair cells vulnerable over years of ordinary sound exposure.
That inference is consistent with a postlingual, later-onset loss rather than a
congenital one, and it is the only part of the model with a natural explanation for the
onset. It has not been tested in a carrier.
biological_scale: CELLULAR
cell_types:
- preferred_term: cochlear outer hair cell
term:
id: CL:0000601
label: cochlear outer hair cell
downstream:
- target: Mid-Frequency Sensorineural Hearing Loss
causal_link_type: DIRECT
hypothesis_groups:
- cholinergic_efferent_model
- target: Sensorineural Hearing Impairment
causal_link_type: DIRECT
hypothesis_groups:
- cholinergic_efferent_model
evidence:
- reference: PMID:12486177
reference_title: "Efferent protection from acoustic injury is mediated via alpha9 nicotinic acetylcholine receptors on outer hair cells."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
snippet: "These data demonstrate that efferent protection is mediated via the alpha9 nAChR in the outer hair cells and provide direct evidence for a protective role, in vivo, of a member of the nAChR family."
explanation: >-
Establishes that the cholinergic efferent synapse onto outer hair cells is protective.
Indirect with respect to DFNA72: the experiment is a mouse transgenic overexpressing a
receptor subunit, and involves neither SLC44A4 nor a human allele.
- reference: PMID:12486177
reference_title: "Efferent protection from acoustic injury is mediated via alpha9 nicotinic acetylcholine receptors on outer hair cells."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
snippet: "Here, we show that overexpression of alpha9 nAChR in the outer hair cells of bacterial artificial chromosome transgenic mice significantly reduces acoustic injury from exposures causing either temporary or permanent damage, without changing pre-exposure cochlear sensitivity to low- or moderate-level sound."
explanation: >-
The measurement behind the protection claim, and the detail that matters for onset:
the effect is on injury from exposure, not on baseline thresholds.
phenotypes:
- name: Mid-Frequency Sensorineural Hearing Loss
category: Auditory
description: >-
Sensorineural hearing loss with a mid-frequency configuration in the single reported
kindred. This is what makes DFNA72 clinically recognisable: dominant nonsyndromic
hearing loss is usually high-frequency and sloping, and a mid-frequency ("U-shaped" or
"cookie-bite") audiogram is the exception in the DFNA series. Thresholds, laterality and
progression *are* described in the 2017 report - the falcon research artifact committed
with this entry, which had retrieval access to the full text, gives 40-50 dB HL centred
on 1-2 kHz, bilateral involvement, and progression to all frequencies while the
mid-frequency shape persists. None of that is curated here because the paper's full text
is paywalled and cannot be cached, and a dismech snippet must be an exact substring of a
cached source. A curator with journal access should split this record accordingly. No
frequency band is recorded because the denominator is one pedigree.
phenotype_term:
preferred_term: Mid-frequency hearing loss
term:
id: HP:0012781
label: Mid-frequency hearing loss
evidence:
- reference: PMID:28013291
reference_title: "SLC44A4 mutation causes autosomal dominant hereditary postlingual non-syndromic mid-frequency hearing loss."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Clinical, genetic, and functional investigations were performed to identify the causative mutation in a distinctive Chinese family with postlingual non-syndromic mid-frequency sensorineural hearing loss."
explanation: >-
The clinical description of the family, and the source of both the configuration and
the word "distinctive" that the authors applied to it.
- reference: PMID:37371710
reference_title: "Autosomal Dominant Non-Syndromic Hearing Loss (DFNA): A Comprehensive Narrative Review."
supports: SUPPORT
evidence_source: OTHER
directness: INDIRECT
snippet: "in most cases, HL tends to be bilateral, post-lingual in onset (childhood to early adulthood), high-frequency (sloping audiometric configuration), progressive, and variable in severity (mild to profound degree)"
explanation: >-
The class background against which the mid-frequency configuration is unusual. Indirect
because the review describes autosomal dominant nonsyndromic hearing loss as a group
and does not discuss DFNA72.
- name: Sensorineural Hearing Impairment
category: Auditory
description: >-
The loss is sensorineural rather than conductive or mixed. Curated as its own record
because HP:0012781 encodes the audiometric configuration and says nothing about the type
of loss, and the type is what places the lesion in the cochlea or the auditory nerve
rather than the middle ear - which is the whole premise of the outer-hair-cell mechanism
this entry curates.
Nothing published distinguishes a cochlear from a retrocochlear lesion in these patients.
No otoacoustic emission, auditory brainstem response or imaging result is quotable from
the cached source.
phenotype_term:
preferred_term: Sensorineural hearing impairment
term:
id: HP:0000407
label: Sensorineural hearing impairment
evidence:
- reference: PMID:28013291
reference_title: "SLC44A4 mutation causes autosomal dominant hereditary postlingual non-syndromic mid-frequency hearing loss."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Clinical, genetic, and functional investigations were performed to identify the causative mutation in a distinctive Chinese family with postlingual non-syndromic mid-frequency sensorineural hearing loss."
explanation: >-
The same clinical sentence that gives the configuration also gives the type, which is
why one quote grounds both records.
- name: Postlingual Onset
category: Auditory
description: >-
The loss in the reported family was postlingual - it appeared after speech had been
acquired rather than being present at birth. An age of onset *is* reported: the falcon
research artifact committed with this entry, reading the paper's full text, gives roughly
26-30 years, with tinnitus as the presenting symptom. It is not curated here because that
text is paywalled and unquotable, not because it does not exist - and with one pedigree
it would in any case be a single family's onset rather than a range for the disease.
phenotype_term:
preferred_term: Postlingual sensorineural hearing impairment
term:
id: HP:0008596
label: Postlingual sensorineural hearing impairment
notes: >-
Deliberately unwired: this record has no incoming causal edge. Onset timing is a
property of when the hearing loss record appears, not a separate consequence of the
pathophysiology, and drawing an edge into it from the outer hair cell node would assert
that the efferent model explains the timing. The model is compatible with a late onset -
a cumulative-exposure mechanism should spare a newborn - but nothing has tested that,
and an edge would state it.
evidence:
- reference: PMID:28013291
reference_title: "SLC44A4 mutation causes autosomal dominant hereditary postlingual non-syndromic mid-frequency hearing loss."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Clinical, genetic, and functional investigations were performed to identify the causative mutation in a distinctive Chinese family with postlingual non-syndromic mid-frequency sensorineural hearing loss."
explanation: The onset descriptor for the family, from the paper's clinical summary.
genetic:
- name: SLC44A4
notes: >-
SLC44A4 is one of five human SLC44 family members, named "choline transporter-like"
proteins by homology rather than by assay. Which substrate the protein actually carries
is unresolved and is curated as two competing hypotheses in this entry: the hearing-loss
literature treats it as a choline transporter, while the study that cloned and expressed
the human protein identifies it as the colonic apical thiamine pyrophosphate transporter,
with uptake unaffected by choline.
Its documented expression is colonic and high, negligible in small intestine. No
inner-ear expression study specific to SLC44A4 has been published; the ClinGen curation
counts "expression level data" among the supporting evidence, all of it from the single
2017 report.
The gene is also known as a tumour-associated antigen and as the Colon Cancer
Antigen-associated protein in other literatures, which is not curated here.
relationship_type: CAUSATIVE
gene_term:
preferred_term: SLC44A4
term:
id: hgnc:13941
label: SLC44A4
variants:
- name: c.466A>G (p.Met156Val)
description: >-
The only SLC44A4 variant reported in a person with hearing loss, heterozygous in every
affected member of the single Chinese kindred and the sole allele in the ClinGen
curation. No clinical_significance is recorded here: ClinVar carries the variant
against the DFNA72 concept but returns no classification from unflagged submissions,
and asserting one would go beyond both ClinVar and the ClinGen Limited classification
of the gene-disease pair itself.
gene:
preferred_term: SLC44A4
term:
id: hgnc:13941
label: SLC44A4
type: missense_variant
evidence:
- reference: CGGV:assertion_3ddbe083-55c3-483b-8c32-fc9bdbef10c6-2022-11-22T170000.000Z
reference_title: "SLC44A4 / nonsyndromic genetic hearing loss (Limited)"
supports: SUPPORT
evidence_source: OTHER
snippet: "One variant (c.466A>G p.M156V) has been reported in one proband in one publication (PMID: 28013291) and is included in this curation."
explanation: The allele in the form the expert panel records it, with its evidence base.
evidence:
- reference: CGGV:assertion_3ddbe083-55c3-483b-8c32-fc9bdbef10c6-2022-11-22T170000.000Z
reference_title: "SLC44A4 / nonsyndromic genetic hearing loss (Limited)"
supports: SUPPORT
evidence_source: OTHER
snippet: "In summary, there is limited evidence to support this gene-disease relationship."
explanation: >-
The expert panel's bottom line, and the reason this record is CAUSATIVE with a caveat
rather than a settled gene-disease assertion.
- reference: CGGV:assertion_3ddbe083-55c3-483b-8c32-fc9bdbef10c6-2022-11-22T170000.000Z
reference_title: "SLC44A4 / nonsyndromic genetic hearing loss (Limited)"
supports: SUPPORT
evidence_source: OTHER
snippet: "This gene-disease relationship is also supported by an animal model and rescue of the phenotype as well as expression level data (PMID: 28013291)."
explanation: >-
What else the panel counted beyond the pedigree - all of it from the same single
publication, which is why the total remains Limited.
- reference: PMID:24379411
reference_title: "Molecular identification and functional characterization of the human colonic thiamine pyrophosphate transporter."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Expression of the human TPP transporter was found to be high in the colon and negligible in the small intestine."
explanation: >-
The documented tissue distribution of the protein, which is gastrointestinal and says
nothing about the inner ear either way.
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
One family, reported once, in 2017. No prevalence or incidence estimate has been
published and no second kindred has appeared, so ULTRA_RARE is a qualitative band and no
rate_per_100000 is recorded. The count that matters clinically is the one the expert
panel gives: a single proband in a single publication.
evidence:
- reference: CGGV:assertion_3ddbe083-55c3-483b-8c32-fc9bdbef10c6-2022-11-22T170000.000Z
reference_title: "SLC44A4 / nonsyndromic genetic hearing loss (Limited)"
supports: SUPPORT
evidence_source: OTHER
snippet: "One variant (c.466A>G p.M156V) has been reported in one proband in one publication (PMID: 28013291) and is included in this curation."
explanation: >-
The published case count as of the 2022 re-evaluation, which is also the count today.
diagnosis:
- name: SLC44A4 on hearing loss gene panels, read against a Limited gene-disease classification
description: >-
DFNA72 is reached, if at all, by a comprehensive hearing loss panel or exome sequencing
that includes SLC44A4, with segregation testing across the pedigree. The specific caution
is what to do with a hit: because ClinGen classifies the gene-disease relationship as
Limited, an SLC44A4 variant in a hearing-impaired person is not on its own a diagnosis,
and ACMG/AMP variant interpretation for genes at Limited validity should not be treated
as it would be for a Definitive gene. A mid-frequency audiogram in a dominant pedigree is
the phenotype that makes the finding worth pursuing rather than filing as incidental.
evidence:
- reference: CGGV:assertion_3ddbe083-55c3-483b-8c32-fc9bdbef10c6-2022-11-22T170000.000Z
reference_title: "SLC44A4 / nonsyndromic genetic hearing loss (Limited)"
supports: SUPPORT
evidence_source: OTHER
snippet: "Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship."
explanation: >-
The panel's position in full: not enough evidence to rely on, and no reason to discard
it either. That is exactly the interpretive situation a laboratory faces with an
SLC44A4 hit.
treatments:
- name: Hearing Amplification
description: >-
Hearing aids, the first-line intervention for postlingual sensorineural loss of this
degree. No management detail of any kind is reported for the DFNA72 family - not aided
thresholds, not device use, not speech scores - so this record is the standard of care
for the class rather than an observation about this disease. A mid-frequency
configuration is worth naming to a fitter, since amplification prescriptions built around
the usual sloping high-frequency loss are not the right target here.
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
target_mechanisms:
- target: Mid-Frequency Sensorineural Hearing Loss
description: >-
Raises the sound pressure reaching the cochlea to compensate for the threshold loss. It
does nothing to the cholinergic efferent mechanism proposed upstream, so no
treatment_effect value is recorded - every value in that enum asserts a change to the
mechanism, and amplification makes no such claim.
evidence:
- reference: PMID:37371710
reference_title: "Autosomal Dominant Non-Syndromic Hearing Loss (DFNA): A Comprehensive Narrative Review."
supports: SUPPORT
evidence_source: OTHER
directness: INDIRECT
snippet: "A long audiological follow-up is of paramount importance to identify hearing threshold deteriorations early and ensure prompt treatment with hearing aids or cochlear implants."
explanation: >-
Class-level support: a narrative review of autosomal dominant nonsyndromic hearing loss
as a group, not of DFNA72. Graded INDIRECT for that reason and OTHER because it is a
review. No DFNA72-specific management report exists.
- name: Cochlear Implantation
description: >-
Implantation when thresholds deteriorate past what amplification can address. Curated
separately from amplification because the two make different claims about the mechanism:
an implant stimulates the spiral ganglion electrically and does not depend on outer hair
cells surviving, so it operates downstream of the node this disease's proposed mechanism
damages. No DFNA72-specific implantation outcome exists, and the published audiometric
picture is a mid-frequency loss rather than a profound one, so this record notes the
intervention as part of the class management pathway without claiming it has been used
in this genotype.
therapeutic_modality: DEVICE
treatment_term:
preferred_term: cochlear 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
target_mechanisms:
- target: Loss of Efferent Protection of Outer Hair Cells
treatment_effect: BYPASSES
description: >-
The proposed lesion is in the cholinergic efferent support of outer hair cells. An
implant does not need outer hair cells at all, so it operates downstream of the node
that fails rather than acting on it.
evidence:
- reference: PMID:37371710
reference_title: "Autosomal Dominant Non-Syndromic Hearing Loss (DFNA): A Comprehensive Narrative Review."
supports: SUPPORT
evidence_source: OTHER
directness: INDIRECT
snippet: "A long audiological follow-up is of paramount importance to identify hearing threshold deteriorations early and ensure prompt treatment with hearing aids or cochlear implants."
explanation: >-
Class-level support for implantation as part of the management pathway for dominant
nonsyndromic hearing loss. Graded INDIRECT because the review is about the group, not
this disease; no SLC44A4 implantation outcome is reported anywhere.
- name: Genetic Counselling
description: >-
Counselling for a dominant condition carries a 50 percent transmission risk, but the
disease-specific content here is about certainty rather than risk. The gene-disease
relationship is classified Limited on one family, so an SLC44A4 result should be
presented as a possible rather than an established explanation, and predictive testing of
an unaffected relative cannot be interpreted. Penetrance has never been estimated.
therapeutic_modality: OTHER
treatment_term:
preferred_term: genetic counseling
term:
id: NCIT:C15240
label: Genetic Counseling
notes: >-
No target_mechanisms link is recorded. Counselling does not act on a pathograph node,
and every TreatmentEffectEnum value asserts a change to a mechanism. No SLC44A4-directed
therapy, and no DFNA72-specific clinical trial, has been reported.
evidence:
- reference: CGGV:assertion_3ddbe083-55c3-483b-8c32-fc9bdbef10c6-2022-11-22T170000.000Z
reference_title: "SLC44A4 / nonsyndromic genetic hearing loss (Limited)"
supports: SUPPORT
evidence_source: OTHER
snippet: "In summary, there is limited evidence to support this gene-disease relationship."
explanation: >-
The fact that has to be conveyed in the counselling room, and the reason a positive
SLC44A4 result is not a closed diagnostic question.
animal_models:
- name: slc44a4 morpholino knockdown zebrafish
species: Zebrafish
genotype: slc44a4 morpholino knockdown (transient antisense knockdown; no stable line)
publication: PMID:28013291
description: >-
The only in vivo work on this gene in relation to hearing. Morpholino knockdown of
zebrafish slc44a4 produced abnormalities of the inner ear and of the lateral line
neuromasts, with hearing and balance deficits described by the authors as present "to
some extent". The ClinGen curation counts this model, and a rescue of the phenotype,
among the evidence supporting the gene-disease relationship - and still classifies the
total as Limited.
genes:
- preferred_term: SLC44A4
term:
id: hgnc:13941
label: SLC44A4
modeled_mechanisms:
- target: Mid-Frequency Sensorineural Hearing Loss
relationship: PARTIALLY_RECAPITULATES
fidelity: LOW
description: >-
A hearing and balance deficit does appear when the fish orthologue is knocked down,
which is the reason to think the gene matters for the ear at all. What it cannot model
is the disease: fish have no cochlea and no mid-frequency place code, so the one
clinically distinctive feature of DFNA72 has no counterpart in this system.
limitations: >-
Three separate gaps. First, direction and dose: this is a knockdown approximating
complete loss of function, while patients are heterozygous for a missense allele whose
effect on the protein was never assayed. Second, transience and specificity: morpholino
knockdown is a developmental, non-genetic manipulation, and morphant inner-ear
phenotypes are a known source of off-target artefact - no stable mutant line has been
made. Third, the phenotype is gross malformation of the ear and neuromasts, which is
developmental, whereas the human disease is postlingual and appears in an ear that
formed normally. Fidelity is LOW because the model and the disease differ in mechanism
class, not only in degree.
readouts:
- name: Inner ear and lateral line neuromast morphology
target: Mid-Frequency Sensorineural Hearing Loss
direction: ALTERED
interpretation: >-
Structural abnormality of the fish auditory and mechanosensory organs following
knockdown, the primary observation of the model.
evidence:
- reference: PMID:28013291
reference_title: "SLC44A4 mutation causes autosomal dominant hereditary postlingual non-syndromic mid-frequency hearing loss."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In the zebrafish model, downregulation of slc44a4 using morpholinos led to significant abnormalities in the zebrafish inner ear and lateral line neuromasts and contributed, to some extent, to disabilities in hearing and balance."
explanation: >-
The structural and behavioural result together, in the authors' own hedged
phrasing.
evidence:
- reference: CGGV:assertion_3ddbe083-55c3-483b-8c32-fc9bdbef10c6-2022-11-22T170000.000Z
reference_title: "SLC44A4 / nonsyndromic genetic hearing loss (Limited)"
supports: SUPPORT
evidence_source: OTHER
snippet: "This gene-disease relationship is also supported by an animal model and rescue of the phenotype as well as expression level data (PMID: 28013291)."
explanation: >-
Independent confirmation that the model, including its rescue arm, was weighed by the
expert panel and treated as informative for the gene-disease relationship.
discussions:
- discussion_id: dfna72_gene_disease_validity_is_limited
kind: KNOWLEDGE_GAP
prompt: >-
Is SLC44A4 a hearing loss gene? Nine years after the founding report there is still one
proband, one publication and one variant, and ClinGen has twice classified the
relationship Limited. What would a second family change, and what should a laboratory do
with an SLC44A4 hit in the meantime?
attaches_to:
- genetic#SLC44A4
- pathophysiology#SLC44A4 p.Met156Val Heterozygous Variant
- diagnosis#SLC44A4 on hearing loss gene panels, read against a Limited gene-disease classification
rationale: >-
This is the gap that governs how everything else in the entry should be read. The Hearing
Loss Gene Curation Expert Panel first assessed SLC44A4 in April 2018, re-assessed it in
November 2022, and the classification did not move: Limited, on one variant in one
proband with a segregation LOD of 2.1, plus a morpholino model and expression data from
the same paper. Nothing in the published record has been added since.
The asymmetry worth stating is that Limited is not Disputed and not Refuted. The panel
notes explicitly that no convincing contradictory evidence has emerged. So the honest
position is neither that DFNA72 is established nor that it has been retired - it is that
a single kindred has never been replicated, and that the sequencing volume of the last
decade means the absence of a second family is beginning to be informative in itself.
What would resolve it is ordinary: a second unrelated pedigree with a segregating
SLC44A4 variant and a mid-frequency audiogram. Failing that, a mechanistic result that
connects the gene to cochlear physiology - inner-ear expression, an efferent function
measurement in a carrier, or a knock-in animal carrying p.Met156Val - would move it more
than another association would.
evidence:
- reference: CGGV:assertion_3ddbe083-55c3-483b-8c32-fc9bdbef10c6-2022-11-22T170000.000Z
reference_title: "SLC44A4 / nonsyndromic genetic hearing loss (Limited)"
supports: SUPPORT
evidence_source: OTHER
snippet: "This gene-disease pair was originally evaluated by the Hearing Loss GCEP on 04/24/2018. It was reevaluated on 11/16/2022. As a result of this reevaluation, the classification did not change from limited (SOP Version 9)."
explanation: >-
Two independent assessments four years apart reaching the same conclusion, which is
what makes this a stable gap rather than a curation that is merely out of date.
- reference: CGGV:assertion_3ddbe083-55c3-483b-8c32-fc9bdbef10c6-2022-11-22T170000.000Z
reference_title: "SLC44A4 / nonsyndromic genetic hearing loss (Limited)"
supports: SUPPORT
evidence_source: OTHER
snippet: "Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship."
explanation: >-
The reason this is a knowledge gap and not a refutation, in the panel's own framing.
- discussion_id: dfna72_morphant_versus_human_heterozygous_missense
kind: HUMAN_MODEL_MISMATCH
prompt: >-
The only in vivo evidence for DFNA72 is a transient morpholino knockdown in a fish
without a cochlea, standing in for a heterozygous human missense allele causing
postlingual mid-frequency loss. How much of that model transfers?
attaches_to:
- animal_models#slc44a4 morpholino knockdown zebrafish
- pathophysiology#Loss of Efferent Protection of Outer Hair Cells
- mechanistic_hypotheses#cholinergic_efferent_model
rationale: >-
The model and the disease differ on every axis that usually matters. Dose: the morphant
approximates loss of the gene product, the patients carry one missense allele alongside a
normal one. Timing: morpholino knockdown acts through early development and produces
gross malformation of the ear and neuromasts, while the human loss is postlingual in an
ear that formed normally. Anatomy: the distinguishing clinical feature of DFNA72 is a
mid-frequency audiogram, and a fish has neither a cochlea nor a tonotopic place code in
which "mid-frequency" means anything.
There is also a methodological point that is specific rather than generic. Morpholino
phenotypes in the zebrafish inner ear are a well-known site of off-target effect, and the
usual remedy is a stable mutant line; none exists for slc44a4. The knockdown was rescued,
which the expert panel counted, and rescue does control for some off-target effects - but
it controls for the knockdown's specificity, not for the relevance of a null phenotype to
a heterozygous missense disease.
The consequence for this entry is concrete. The fish supports "this gene is needed for a
normal ear" and does not support any step of the cholinergic efferent chain, which is why
the model's modeled_mechanisms link points at the phenotype rather than at an internal
node, and why the efferent nodes carry no model evidence at all.
evidence:
- reference: PMID:28013291
reference_title: "SLC44A4 mutation causes autosomal dominant hereditary postlingual non-syndromic mid-frequency hearing loss."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In the zebrafish model, downregulation of slc44a4 using morpholinos led to significant abnormalities in the zebrafish inner ear and lateral line neuromasts and contributed, to some extent, to disabilities in hearing and balance."
explanation: >-
The model result, including the authors' own qualifier "to some extent" on the
functional arm.
- reference: PMID:28013291
reference_title: "SLC44A4 mutation causes autosomal dominant hereditary postlingual non-syndromic mid-frequency hearing loss."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Clinical, genetic, and functional investigations were performed to identify the causative mutation in a distinctive Chinese family with postlingual non-syndromic mid-frequency sensorineural hearing loss."
explanation: >-
The human side of the mismatch: postlingual onset and a mid-frequency configuration,
neither of which the fish model can represent.
- discussion_id: dfna72_substrate_identity_of_slc44a4
kind: KNOWLEDGE_GAP
prompt: >-
Does SLC44A4 transport choline or thiamine pyrophosphate, and does the DFNA72 mechanism
survive if the answer is thiamine pyrophosphate?
attaches_to:
- pathophysiology#Reduced Choline Uptake
- pathophysiology#Reduced Acetylcholine Release
- mechanistic_hypotheses#thiamine_pyrophosphate_transport_model
- mechanistic_hypotheses#cholinergic_efferent_model
rationale: >-
The first step of the published DFNA72 mechanism is choline uptake, and the only direct
characterisation of human SLC44A4 says the protein carries thiamine pyrophosphate with
high affinity and is not affected by choline at all. The two results come from different
cell backgrounds - SH-SY5Y neuroblastoma against ARPE19 - and neither from inner-ear
tissue, so they are not a clean contradiction, but they cannot both be the whole story.
The family name is part of how this happened. SLC44A4 belongs to the "choline
transporter-like" family, which is a homology label, and the hearing-loss report states
the choline function as an established premise rather than measuring it. The uptake
difference that report measured is real; what it measured uptake *of* rests on that
premise.
The stakes are not merely nomenclatural. On the thiamine pyrophosphate reading the
acetylcholine-release result needs another explanation, the olivocochlear efferent
framing loses its rationale, and a cochlear mechanism would have to be built around a
cofactor for pyruvate dehydrogenase and transketolase instead. No one has attempted that,
and this entry does not, because nothing has been published to build it from.
The resolving experiment is a side-by-side choline and thiamine pyrophosphate uptake
comparison in one system, with and without the p.Met156Val allele.
evidence:
- reference: PMID:24379411
reference_title: "Molecular identification and functional characterization of the human colonic thiamine pyrophosphate transporter."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "highly specific for TPP and not affected by free thiamine, thiamine monophosphate, or choline"
explanation: >-
The observation that opens the gap - choline does not compete with this transport.
- reference: PMID:28013291
reference_title: "SLC44A4 mutation causes autosomal dominant hereditary postlingual non-syndromic mid-frequency hearing loss."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Whole-exome sequencing revealed SLC44A4, which encodes the choline transport protein, as the pathogenic gene in this family."
explanation: >-
The other side of the gap, and the point at which the choline attribution enters the
hearing-loss literature as an assumption.
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.
Create: Hearing Loss Autosomal Dominant 72 (DFNA72, SLC44A4) · 2026-09-04T22:08:26Z · View source
Identity resolved from the stub's MONDO xref chain rather than from MONDO itself, which records no causal gene for MONDO:0033259: OLS gave OMIM:617606, NCBI mim2gene_medgen mapped that MIM to GeneID 80736, and NCBI Gene resolved it to SLC44A4 (6p21.33). Coverage recheck by gene against origin/main found no existing kb/ entry for SLC44A4, so DFNA72 is curated as a new Disease rather than folded into an existing gene-named entry. Evidence base is deliberately small because the literature is. The whole clinical record is one four-generation Chinese kindred (PMID:28013291), and the ClinGen Hearing Loss GCEP classifies the SLC44A4 / nonsyndromic genetic hearing loss relationship as Limited on two separate evaluations (2018, 2022). That ClinGen assertion is cited as a structured CGGV: reference and is what the entry's diagnosis, genetic and prevalence records are built around. Two mechanistic hypotheses are recorded rather than one. The published cholinergic olivocochlear model is EMERGING: its three links were measured in three different systems (transfected SH-SY5Y cells, mouse alpha9 nAChR transgenics for efferent protection, and nothing at all for the SLC44A4-in-efferent-neuron step), and the authors themselves wrote 'may cause'. The ALTERNATIVE thiamine_pyrophosphate_transport_model records that the only direct characterisation of human SLC44A4 (PMID:24379411) identifies it as the colonic thiamine pyrophosphate transporter with uptake explicitly unaffected by choline - a competing substrate assignment that the hearing-loss literature imports as a premise. That paper is also cited as a REFUTE item on the choline-uptake node. Deep research: falcon, on-topic (SLC44A4 55 mentions in the report, no substituted disease; preflight-dr SKIPs because MONDO records no canonical gene, so substitution was checked by manual gene grep). The report's own term validation flagged one invented CURIE (HP:0004076); nothing from the report was bound. The report's additional clinical detail (onset 26-30 years, 1-2 kHz 40-50 dB HL U-shaped audiogram, screening of 1000 controls and 500 sporadic cases) comes from the paper's full text, which is paywalled and not cacheable, so it was NOT curated as evidence. Validation: just validate (schema + terms + references) passed; 32/32 snippets verified, no prefix skips; check-entity-refs, check-duplicate-keys, check-causal-targets, check-enum-values, check-qualifier-terms all clean. One phenotype (Postlingual Onset) is deliberately unwired with a notes: explanation.
Hearing loss, autosomal dominant 72 (DFNA72) is an exceptionally rare, postlingual, progressive, nonsyndromic sensorineural hearing-loss phenotype attributed to heterozygous SLC44A4 dysfunction. The published human evidence derives from a single four-generation Chinese pedigree: SLC44A4 c.466A>G (p.Met156Val) was found in all eight tested affected relatives and none of 13 tested unaffected relatives. Functional studies showed impaired choline uptake and acetylcholine synthesis in transfected cells, while zebrafish slc44a4 knockdown produced auditory-system abnormalities that were rescued with human SLC44A4 RNA. Nevertheless, independent human replication, variant-specific animal modeling, population epidemiology, and disease-specific treatment studies were not identified through 2024. The gene–disease association should therefore be treated more cautiously than a repeatedly replicated deafness-gene relationship. (ma2017slc44a4mutationcauses pages 2-3, ma2017slc44a4mutationcauses pages 1-2, ma2017slc44a4mutationcauses pages 6-7)
| Domain | Established finding | Evidence type | Confidence or limitation |
|---|---|---|---|
| Human genetic evidence | One four-generation Chinese pedigree with 37 members linked DFNA72 to heterozygous SLC44A4 c.466A>G (p.Met156Val). The variant occurred in all 8 tested affected relatives and none of 13 tested unaffected relatives; it was also absent from 1,000 ethnically matched controls and 500 sporadic hearing-loss cases. (ma2017slc44a4mutationcauses pages 2-3, ma2017slc44a4mutationcauses pages 3-4, ma2017slc44a4mutationcauses pages 9-9) | Human pedigree; whole-exome sequencing; Sanger segregation; case-control screening | Strong within-family segregation and rarity evidence, but only one pedigree and one candidate variant have been reported; independent human replication was not identified through 2024. |
| Clinical phenotype | Postlingual tinnitus and sensorineural hearing loss began at approximately 26–30 years. Early loss primarily involved 0.5–4 kHz, especially 1–2 kHz, with approximately 40–50 dB HL thresholds and a U-shaped or bowl-shaped audiogram; it progressed to involve all frequencies while generally retaining the mid-frequency configuration. (ma2017slc44a4mutationcauses pages 2-3, ma2017slc44a4mutationcauses pages 3-4) | Human clinical and audiometric observations | Findings were consistent among reported affected relatives, but phenotype frequencies and severity estimates cannot be generalized beyond the single family. |
| Nonsyndromic classification | Tympanometry and temporal-bone imaging were normal. No retrocochlear disorder, vertigo, ototoxic-drug or sustained-noise exposure, or cardiovascular, diabetic, visual, neurologic, or other syndromic manifestations were reported. (ma2017slc44a4mutationcauses pages 2-3, ma2017slc44a4mutationcauses pages 1-2) | Human clinical examination; auditory brainstem response; CT and MRI; exposure history | Supports nonsyndromic sensorineural hearing loss in the original pedigree, although long-term surveillance data are limited. |
| Cellular function | In SH-SY5Y cells, mutant SLC44A4 produced lower radiolabeled choline uptake and reduced acetylcholine synthesis relative to wild-type SLC44A4. (ma2017slc44a4mutationcauses pages 8-9, ma2017slc44a4mutationcauses pages 5-6) | In-vitro transfection and biochemical assays | Supports impaired transporter activity, but SH-SY5Y cells are not native human olivocochlear neurons or cochlear cells; the precise dominant mechanism remains unresolved. |
| Proposed pathophysiology | Reduced choline transport is proposed to limit acetylcholine production and release by medial olivocochlear neurons, weakening efferent regulation and protection of outer hair cells and thereby causing progressive hearing loss. (ma2017slc44a4mutationcauses pages 8-9, ma2017slc44a4mutationcauses pages 6-7) | Mechanistic inference integrating cellular assays and auditory physiology | Biologically plausible but not demonstrated directly in affected human cochleae; haploinsufficiency, dominant-negative activity, and gain of function have not been distinguished. |
| Zebrafish model | Morpholino-mediated slc44a4 knockdown caused abnormal otoliths, fewer or malformed inner-ear and lateral-line hair cells and neuromasts, abnormal stereocilia, and balance or startle deficits. Human SLC44A4 RNA rescued otolith, hair-cell, stereocilia, and hearing phenotypes. (ma2017slc44a4mutationcauses pages 1-2, ma2017slc44a4mutationcauses pages 6-7) | Zebrafish loss-of-function and rescue experiments | Supports conserved auditory function and gene-level causality, but morpholino knockdown is not a p.Met156Val knock-in and may model loss of function rather than the human dominant allele. |
| Epidemiology and replication | No disease-specific prevalence, incidence, carrier-frequency, founder-effect, sex-ratio, or geographic estimates were identified. No additional independently replicated DFNA72 family was found through 2024. | Evidence-gap assessment | DFNA72 appears exceptionally rare, but its population frequency and gene-disease validity cannot be quantified confidently from available evidence. |
| Treatment and trials | No SLC44A4-targeted drug, gene therapy, RNA therapy, or DFNA72-specific clinical trial was identified. Current care is supportive: serial audiometry, hearing aids when beneficial, communication rehabilitation, and cochlear-implant evaluation for severe or profound functional loss. | Standard hearing-loss management extrapolated to DFNA72; clinical-trial evidence gap | No DFNA72-specific response rates or comparative outcomes are available; supportive interventions do not correct the molecular defect. |
Table: Compact evidence map summarizing the human genetic, clinical, cellular, zebrafish, epidemiologic, and treatment evidence for SLC44A4-associated DFNA72. It emphasizes that the association rests on one pedigree despite supportive functional experiments.
Definition. DFNA72 is a Mendelian form of autosomal-dominant, postlingual, nonsyndromic sensorineural hearing loss characterized in the original family by a U-shaped or “bowl-shaped” audiogram, predominant mid-frequency impairment, tinnitus at onset, and subsequent progression across the frequency range. “DFNA” denotes autosomal-dominant nonsyndromic deafness; “72” is the assigned locus/disease number. (ma2017slc44a4mutationcauses pages 2-3, ma2017slc44a4mutationcauses pages 3-4)
Names and synonyms:
Identifiers. The disease is represented principally by its DFNA72/OMIM nomenclature. An exact MONDO identifier and a disease-specific Orphanet identifier could not be verified from the retrieved evidence. ICD-10 and ICD-11 do not provide a DFNA72-specific code; practical coding uses the appropriate general sensorineural-hearing-loss category, such as ICD-10-CM H90.3 when bilateral. Relevant MeSH concepts include Hearing Loss, Sensorineural and Hearing Loss, Hereditary. These broad codes must not be interpreted as unique DFNA72 identifiers.
Data provenance. Disease-specific clinical information is not an aggregate EHR-derived phenotype. It comes primarily from one research pedigree, HN-01, containing 37 members across four generations, supplemented by in-vitro and zebrafish experiments. (ma2017slc44a4mutationcauses pages 2-3, ma2017slc44a4mutationcauses pages 9-9)
The reported initiating lesion is a germline heterozygous missense substitution in SLC44A4, encoding solute carrier family 44 member 4/choline transporter-like protein 4: c.466A>G (p.Met156Val) in exon 6. It segregated with hearing loss in the informative relatives and was absent from 1,000 ethnically matched controls and 500 individuals with sporadic hearing loss. (ma2017slc44a4mutationcauses pages 2-3, ma2017slc44a4mutationcauses pages 3-4)
The evidence supports impaired transporter function, but the precise dominant molecular mechanism—haploinsufficiency, dominant-negative interference, altered trafficking, or another gain-of-abnormal-function effect—has not been resolved.
No protective allele, modifier gene, dietary intervention, or pharmacologic prophylaxis has been demonstrated. The proposed loss of medial olivocochlear protection suggests that noise might aggravate cochlear injury, but this is a mechanistic inference rather than a demonstrated human gene–environment interaction. Avoiding excessive noise and unnecessary ototoxic drugs is prudent general hearing conservation, not proven DFNA72-specific prevention. (ma2017slc44a4mutationcauses pages 8-9, ma2017slc44a4mutationcauses pages 6-7)
| Phenotype | Characteristics in the reported family | Suggested HPO term |
|---|---|---|
| Sensorineural hearing impairment | Postlingual; initially approximately 40–50 dB HL in the described early phenotype; progressive | Sensorineural hearing impairment, HP:0000407 |
| Mid-frequency hearing loss | Approximately 0.5–4 kHz, most prominent at 1–2 kHz; U-shaped/bowl-shaped audiogram | Mid-frequency hearing loss, HP:0008315 |
| Progressive hearing impairment | Gradually extends to all frequencies; some advanced measurements showed absent responses | Progressive hearing impairment, HP:0001730 |
| Bilateral hearing impairment | Family phenotype was consistent with bilateral nonsyndromic loss | Bilateral sensorineural hearing impairment, HP:0008619 |
| Adult/young-adult onset | Approximately 26–30 years, after speech acquisition | Adult onset, HP:0003581; Postlingual sensorineural hearing impairment, HP:0004076 |
| Tinnitus | Reported near the beginning of the clinical course | Tinnitus, HP:0000360 |
The frequency of each feature cannot be converted into robust population percentages because only one family was described. Hearing loss was reported by nine of 37 pedigree members; eight affected relatives underwent segregation testing. The published clinical evaluations found normal tympanograms and no retrocochlear abnormality on auditory brainstem response. CT/MRI showed normal cochleae, mastoids, ossicles, internal auditory meatuses, and membranous labyrinth. Vertigo and cardiovascular, diabetic, visual, neurologic, or other syndromic manifestations were not reported. (ma2017slc44a4mutationcauses pages 2-3, ma2017slc44a4mutationcauses pages 3-4, ma2017slc44a4mutationcauses pages 1-2)
Quality of life. No DFNA72-specific EQ-5D, SF-36, PROMIS, speech-recognition, employment, educational, or psychosocial data exist. Progressive mid-frequency loss would be expected to impair speech audibility and communication, but quantitative impact should not be assigned from this pedigree alone.
There is no evidence that toxins, radiation, air pollution, smoking, alcohol, diet, exercise, or an infectious agent causes DFNA72. The original family’s history did not identify chronic noise or ototoxic-drug exposure. Noise vulnerability is biologically plausible because medial olivocochlear signaling protects outer hair cells, but this has not been quantified in SLC44A4-variant carriers. DFNA72 is not infectious and has no zoonotic or person-to-person transmission. (ma2017slc44a4mutationcauses pages 1-2, ma2017slc44a4mutationcauses pages 6-7)
Branch from gene dysfunction: experimental reduction of zebrafish slc44a4 leads to abnormal otoliths, reduced/malformed hair cells and neuromasts, abnormal stereocilia, and balance/startle deficits; rescue by human SLC44A4 RNA supports a conserved auditory role, although it does not reproduce the heterozygous human missense genotype. (ma2017slc44a4mutationcauses pages 1-2, ma2017slc44a4mutationcauses pages 6-7)
No disease-specific immune, inflammatory, apoptotic, autophagic, endocrine, metabolomic, lipidomic, epigenomic, single-cell, spatial-transcriptomic, proteomic, or CRISPR-screen signature has been reported. The available biochemical phenotype is reduced choline uptake and acetylcholine production. No affected-human cochlear tissue has been profiled.
The primary organ is the inner ear, particularly the cochlear auditory apparatus. The proposed cellular targets are the medial olivocochlear efferent pathway and cochlear outer hair cells; zebrafish experiments additionally implicate sensory hair cells, stereocilia, otolith organs, and lateral-line neuromasts. Human temporal-bone imaging was structurally normal, indicating functional/microscopic rather than gross malformative disease. (ma2017slc44a4mutationcauses pages 3-4, ma2017slc44a4mutationcauses pages 6-7)
Suggested ontology annotations include:
The loss appears bilateral. No secondary-organ disease has been established.
Onset was insidious and postlingual, consistently around 26–30 years in the reported family. Early disease involved tinnitus and mild-to-moderate mid-frequency threshold elevation, especially at 1–2 kHz. It then progressed chronically to involve the full tested frequency range while retaining a bowl-shaped configuration. Advanced disease could include absent responses at selected frequencies. There is no evidence of episodic fluctuation, spontaneous remission, relapse, or recovery of unaided thresholds. (ma2017slc44a4mutationcauses pages 2-3, ma2017slc44a4mutationcauses pages 3-4)
No validated stage system or annual dB progression rate exists. The likely intervention window is early after measurable threshold decline, when amplification and communication support can be introduced, but this has not been tested specifically in DFNA72.
Inheritance in HN-01 was autosomal dominant across four generations. The segregation pattern was fully concordant among tested relatives, but formal age-adjusted penetrance cannot be inferred because young noncarriers/carriers, ascertainment, and longitudinal follow-up were not fully characterized. Expressivity included progression and variable severity by age. Anticipation, germline mosaicism, consanguinity effects, parent-of-origin effects, and modifier loci have not been reported. (ma2017slc44a4mutationcauses pages 2-3, ma2017slc44a4mutationcauses pages 9-9)
No prevalence, incidence, carrier frequency, sex ratio, founder frequency, or population-attributable fraction is available. The only reported family was Chinese; absence of p.Met156Val in 1,000 ethnically matched controls supports rarity but does not establish a geographically restricted founder effect. (ma2017slc44a4mutationcauses pages 3-4)
Diagnosis begins with history, three-generation pedigree, otoscopy, pure-tone audiometry, speech audiometry, tympanometry, and serial comparison of thresholds. The characteristic clue is bilateral postlingual progressive mid-frequency SNHL with a U-shaped audiogram. Auditory brainstem response or otoacoustic-emission testing may help localize dysfunction; CT/MRI is reserved for atypical, asymmetric, conductive, vestibular, or retrocochlear presentations rather than confirming DFNA72. The original study tested 250–8,000 Hz and used tympanometry, ABR, otoacoustic emissions, CT, and MRI. (ma2017slc44a4mutationcauses pages 9-9)
Single-gene SLC44A4 testing is most defensible when the familial variant is already known. CMA, karyotyping, FISH, mitochondrial sequencing, and repeat-expansion testing are not first-line tests for this phenotype unless other clinical findings indicate them. RNA-seq, proteomics, metabolomics, methylation testing, and liquid biopsy have no established diagnostic role.
Differential diagnosis: other causes of U-shaped/mid-frequency dominant hearing loss, including TECTA, COL11A2, EYA4, and POU4F3, as well as broader dominant deafness genes; acquired noise/ototoxic injury; autoimmune inner-ear disease; otosclerosis; and retrocochlear pathology. Normal tympanometry and imaging support a sensorineural rather than conductive or structural cause.
Screening: cascade genetic testing and baseline audiometry are appropriate for relatives after identification of a familial variant. Newborn physiologic screening may be normal because DFNA72 is postlingual.
No mortality attributable to DFNA72 has been reported, and there is no evidence of reduced life expectancy. Prognosis concerns chronic auditory morbidity rather than survival. The natural history in the single pedigree indicates progressive threshold deterioration without spontaneous remission. Severity at older ages and baseline progression are plausible prognostic factors, but no validated biomarker or prediction model exists. (ma2017slc44a4mutationcauses pages 2-3, ma2017slc44a4mutationcauses pages 3-4)
Potential long-term consequences include communication disability, reduced speech understanding—especially in noise—tinnitus burden, social isolation, and occupational impairment. DFNA72-specific disability-adjusted life years, quality-of-life scores, cochlear-implant outcomes, and treatment-response statistics are unavailable.
There is no approved SLC44A4-targeted pharmacotherapy, choline-based treatment, RNA therapy, gene therapy, or genome-editing intervention. Reduced cellular choline uptake does not establish that oral choline will restore cochlear neurotransmission, and supplementation should not be presented as disease-modifying treatment.
Current management is extrapolated from standard sensorineural-hearing-loss care:
Suggested NCIt intervention concepts include Hearing Aid, Cochlear Implantation, Audiologic Rehabilitation, Genetic Counseling, and Supportive Care; release-specific NCIt codes should be validated before database loading.
No DFNA72/SLC44A4-specific interventional trial or NCT identifier was found. Thus, there are no disease-specific response rates, comparative-effectiveness data, pharmacogenomic recommendations, or adverse-event estimates.
Primary prevention: a germline pathogenic allele cannot be prevented by lifestyle modification. Reproductive options after counseling may include prenatal diagnosis or preimplantation genetic testing for a confirmed familial variant, subject to local law, ethics, and patient preferences.
Secondary prevention: cascade testing, baseline audiometry in at-risk relatives, and periodic surveillance can detect presymptomatic or early loss. Because onset is usually postlingual, a normal newborn screen does not exclude later DFNA72.
Tertiary prevention: timely amplification, hearing rehabilitation, communication support, and hearing conservation may reduce disability and avoidable superimposed cochlear injury. No vaccine, prophylactic drug, dietary regimen, or preventive procedure is disease specific.
No naturally occurring SLC44A4-associated veterinary disease, breed predisposition, or zoonotic phenomenon was identified. Zebrafish (Danio rerio; NCBI Taxonomy 7955) possess a conserved slc44a4 ortholog; reported human–zebrafish protein similarity was approximately 75.7%. Knockdown affected otic and lateral-line sensory structures, supporting evolutionary conservation of auditory function. (ma2017slc44a4mutationcauses pages 6-7)
This is an experimental induced phenotype, not evidence of naturally occurring DFNA72 in fish. Cross-species transmission is not applicable.
Morpholino-mediated slc44a4 knockdown produced smaller or abnormal inner-ear structures/otoliths, fewer neuromasts and sensory hair cells, malformed stereocilia, and abnormal balance or sound-startle behavior. Co-injection/restoration with human SLC44A4 RNA rescued otolith, hair-cell, stereocilia, and hearing phenotypes, supporting gene-level functional conservation. (ma2017slc44a4mutationcauses pages 3-4, ma2017slc44a4mutationcauses pages 1-2, ma2017slc44a4mutationcauses pages 6-7)
Applications: auditory-development studies, hair-cell biology, choline-transport investigation, and preliminary functional assessment of SLC44A4.
Limitations: the model used transient knockdown rather than a stable heterozygous p.Met156Val knock-in. It therefore resembles reduced gene function and cannot establish the exact dominant mechanism, adult-onset progression, human cochlear frequency pattern, or allele-specific therapeutic response.
Transfected SH-SY5Y neuroblastoma cells demonstrated lower choline uptake and acetylcholine synthesis with mutant than wild-type SLC44A4. This is useful for transporter-function assays but does not reproduce mature human cochlear hair cells or olivocochlear circuitry. (ma2017slc44a4mutationcauses pages 8-9, ma2017slc44a4mutationcauses pages 5-6)
No mouse knock-in, conditional mammalian model, patient-derived iPSC hair-cell model, cochlear organoid, or CRISPR-engineered p.Met156Val model was identified.
No disease-specific 2023–2024 primary study or independent family was identified. Consequently, the 2017 pedigree remains the central evidence. The most important research priorities are: independent case ascertainment; contemporary ClinGen/ClinVar reassessment; accurate population-frequency analysis; stable p.Met156Val knock-in models; direct study of olivocochlear neurons and outer hair cells; longitudinal audiometric modeling; and allele-specific rescue studies.
The original publication’s metadata are inconsistent in the retrieved records: the article text identifies Human Molecular Genetics volume 26, pages 383–394, advance publication 23 December 2016, and DOI 10.1093/hmg/ddw394, whereas the search record labels July 2017 and DOI 10.1093/hmg/ddx232. Database ingestion should verify the publisher/PubMed record before assigning DOI or PMID. (ma2017slc44a4mutationcauses pages 1-2)
An exact abstract quotation could not be supplied reliably because the retrieved full-text evidence did not expose a stable verbatim abstract. The article title itself—“SLC44A4 mutation causes autosomal dominant hereditary postlingual non-syndromic mid-frequency hearing loss”—accurately states the authors’ principal conclusion, but should not be represented as an abstract quote. Overall, DFNA72 is a biologically plausible and clinically coherent candidate Mendelian disorder with strong segregation in one pedigree, but limited replication and insufficient evidence for disease-specific epidemiology, prognosis statistics, or precision treatment.
References
(ma2017slc44a4mutationcauses pages 2-3): Zhaoxin Ma, Wenjun Xia, Fei Liu, Jing Ma, Shaoyang Sun, Jin Zhang, Nan Jiang, Xu Wang, Jiongjiong Hu, and Duan Ma. Slc44a4 mutation causes autosomal dominant hereditary postlingual non-syndromic mid-frequency hearing loss. Jul 2017. URL: https://doi.org/10.1093/hmg/ddx232, doi:10.1093/hmg/ddx232. This article has 21 citations and is from a domain leading peer-reviewed journal.
(ma2017slc44a4mutationcauses pages 1-2): Zhaoxin Ma, Wenjun Xia, Fei Liu, Jing Ma, Shaoyang Sun, Jin Zhang, Nan Jiang, Xu Wang, Jiongjiong Hu, and Duan Ma. Slc44a4 mutation causes autosomal dominant hereditary postlingual non-syndromic mid-frequency hearing loss. Jul 2017. URL: https://doi.org/10.1093/hmg/ddx232, doi:10.1093/hmg/ddx232. This article has 21 citations and is from a domain leading peer-reviewed journal.
(ma2017slc44a4mutationcauses pages 6-7): Zhaoxin Ma, Wenjun Xia, Fei Liu, Jing Ma, Shaoyang Sun, Jin Zhang, Nan Jiang, Xu Wang, Jiongjiong Hu, and Duan Ma. Slc44a4 mutation causes autosomal dominant hereditary postlingual non-syndromic mid-frequency hearing loss. Jul 2017. URL: https://doi.org/10.1093/hmg/ddx232, doi:10.1093/hmg/ddx232. This article has 21 citations and is from a domain leading peer-reviewed journal.
(ma2017slc44a4mutationcauses pages 3-4): Zhaoxin Ma, Wenjun Xia, Fei Liu, Jing Ma, Shaoyang Sun, Jin Zhang, Nan Jiang, Xu Wang, Jiongjiong Hu, and Duan Ma. Slc44a4 mutation causes autosomal dominant hereditary postlingual non-syndromic mid-frequency hearing loss. Jul 2017. URL: https://doi.org/10.1093/hmg/ddx232, doi:10.1093/hmg/ddx232. This article has 21 citations and is from a domain leading peer-reviewed journal.
(ma2017slc44a4mutationcauses pages 9-9): Zhaoxin Ma, Wenjun Xia, Fei Liu, Jing Ma, Shaoyang Sun, Jin Zhang, Nan Jiang, Xu Wang, Jiongjiong Hu, and Duan Ma. Slc44a4 mutation causes autosomal dominant hereditary postlingual non-syndromic mid-frequency hearing loss. Jul 2017. URL: https://doi.org/10.1093/hmg/ddx232, doi:10.1093/hmg/ddx232. This article has 21 citations and is from a domain leading peer-reviewed journal.
(ma2017slc44a4mutationcauses pages 8-9): Zhaoxin Ma, Wenjun Xia, Fei Liu, Jing Ma, Shaoyang Sun, Jin Zhang, Nan Jiang, Xu Wang, Jiongjiong Hu, and Duan Ma. Slc44a4 mutation causes autosomal dominant hereditary postlingual non-syndromic mid-frequency hearing loss. Jul 2017. URL: https://doi.org/10.1093/hmg/ddx232, doi:10.1093/hmg/ddx232. This article has 21 citations and is from a domain leading peer-reviewed journal.
(ma2017slc44a4mutationcauses pages 5-6): Zhaoxin Ma, Wenjun Xia, Fei Liu, Jing Ma, Shaoyang Sun, Jin Zhang, Nan Jiang, Xu Wang, Jiongjiong Hu, and Duan Ma. Slc44a4 mutation causes autosomal dominant hereditary postlingual non-syndromic mid-frequency hearing loss. Jul 2017. URL: https://doi.org/10.1093/hmg/ddx232, doi:10.1093/hmg/ddx232. This article has 21 citations and is from a domain leading peer-reviewed journal.
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These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:
HP:0004076 (1 mention) - HP does not contain this termThe 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:0055085 (1 mention) - the report calls it "Suggested GO biological processes: transmembrane transport"; GO calls it transmembrane transport**GO:0005886 (2 mentions) - the report calls it "Suggested GO cellular components: plasma membrane"; GO calls it plasma membrane**, and lists "integral component of plasma membrane" among its other names