DFNA78 is dominantly inherited nonsyndromic sensorineural hearing loss caused by heterozygous variants in SLC12A2, which encodes the Na-K-2Cl cotransporter NKCC1. NKCC1 loads potassium into strial marginal cells across their basolateral membrane, and that uptake is the first step in secreting endolymph and sustaining the endocochlear potential on which mechanotransduction depends. What makes this entity worth a separate entry rather than a line on the SLC12A2 gene page is that its variants are not distributed across the gene: every published pathogenic DFNA78 allele sits in exon 21, either as a missense change inside it or as a splice variant that removes it. Exon 21 is not an ordinary exon. SLC12A2 has several isoforms and only one contains exon 21; that isoform is almost exclusively expressed in the inner ear, and it is the one required for endolymph homeostasis. So a lesion confined to exon 21 is a lesion confined, in practice, to the cochlea - which is why a cotransporter expressed in neurons, glia, trachea, salivary glands, intestine and sweat glands produces a hearing-only disease here. The genetics rule out haploinsufficiency of the *gene*, and that argument is available from the published phenotypes without any new experiment. The first SLC12A2 patient described carried a de novo heterozygous loss-of-function variant and had normal hearing. Biallelic loss of function causes Kilquist syndrome, a severe recessive disorder. Heterozygous *exon 21* alteration, by contrast, causes deafness on its own. What each variant does to the protein has been measured - chloride influx is significantly reduced for every tested allele, in two independent cohorts - so this entry records the variants as LOSS_OF_FUNCTION. What it deliberately does not record is DOMINANT_NEGATIVE. The disease is dominant and NKCC1 is a dimer, so a poisoned subunit is the natural story, but the splice allele argues the other way: its exon-21-skipped transcript is present at much lower levels than the normal one in cochlea, which is isoform dose rather than a spoiled partner. A missense subunit could go either way and nobody has tested it, so the route to dominance is carried as an open question rather than asserted. Two clinical points follow. Vestibular areflexia accompanies the hearing loss often enough that DFNA78 belongs on the differential for hearing loss with vestibular failure, a list otherwise dominated by Usher syndrome. And the severity range is wide - severe-to-profound postlingual loss segregating across three generations in one family, profound congenital loss in a de novo case - so age at presentation does not exclude the gene. The mouse work is the clearest support for the mechanism and, at the same time, the clearest translational gap. Mice engineered to skip exon 21 completely have reduced endolymph on postnatal day 1, a smaller stria vascularis, and no auditory brainstem response at four weeks - but that is the homozygote. The heterozygous mouse shows only mild threshold elevation, in females, at some frequencies, whereas the human heterozygote is deaf. The entry records that as a HUMAN_MODEL_MISMATCH rather than treating the mouse as a straightforward model of the dominant human disease.
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name: Hearing Loss Autosomal Dominant 78
category: Mendelian
creation_date: "2026-09-03T19:00:00Z"
synonyms:
- DFNA78
- deafness, autosomal dominant 78
- SLC12A2-related autosomal dominant nonsyndromic hearing loss
- nonsyndromic deafness with vestibular areflexia
description: >-
DFNA78 is dominantly inherited nonsyndromic sensorineural hearing loss caused by
heterozygous variants in SLC12A2, which encodes the Na-K-2Cl cotransporter NKCC1. NKCC1
loads potassium into strial marginal cells across their basolateral membrane, and that
uptake is the first step in secreting endolymph and sustaining the endocochlear potential
on which mechanotransduction depends.
What makes this entity worth a separate entry rather than a line on the SLC12A2 gene page is
that its variants are not distributed across the gene: every published pathogenic DFNA78
allele sits in exon 21, either as a missense change inside it or as a splice variant that
removes it. Exon 21 is not an ordinary exon. SLC12A2 has several isoforms and only one
contains exon 21; that isoform is almost exclusively expressed in the inner ear, and it is
the one required for endolymph homeostasis. So a lesion confined to exon 21 is a lesion
confined, in practice, to the cochlea - which is why a cotransporter expressed in neurons,
glia, trachea, salivary glands, intestine and sweat glands produces a hearing-only disease
here.
The genetics rule out haploinsufficiency of the *gene*, and that argument is available from
the published phenotypes without any new experiment. The first SLC12A2 patient described
carried a de novo heterozygous loss-of-function variant and had normal hearing. Biallelic loss
of function causes Kilquist syndrome, a severe recessive disorder. Heterozygous *exon 21*
alteration, by contrast, causes deafness on its own.
What each variant does to the protein has been measured - chloride influx is significantly
reduced for every tested allele, in two independent cohorts - so this entry records the
variants as LOSS_OF_FUNCTION. What it deliberately does not record is DOMINANT_NEGATIVE. The
disease is dominant and NKCC1 is a dimer, so a poisoned subunit is the natural story, but the
splice allele argues the other way: its exon-21-skipped transcript is present at much lower
levels than the normal one in cochlea, which is isoform dose rather than a spoiled partner. A
missense subunit could go either way and nobody has tested it, so the route to dominance is
carried as an open question rather than asserted.
Two clinical points follow. Vestibular areflexia accompanies the hearing loss often enough
that DFNA78 belongs on the differential for hearing loss with vestibular failure, a list
otherwise dominated by Usher syndrome. And the severity range is wide - severe-to-profound
postlingual loss segregating across three generations in one family, profound congenital
loss in a de novo case - so age at presentation does not exclude the gene.
The mouse work is the clearest support for the mechanism and, at the same time, the clearest
translational gap. Mice engineered to skip exon 21 completely have reduced endolymph on
postnatal day 1, a smaller stria vascularis, and no auditory brainstem response at four
weeks - but that is the homozygote. The heterozygous mouse shows only mild threshold
elevation, in females, at some frequencies, whereas the human heterozygote is deaf. The
entry records that as a HUMAN_MODEL_MISMATCH rather than treating the mouse as a
straightforward model of the dominant human disease.
disease_term:
preferred_term: hearing loss, autosomal dominant 78
term:
id: MONDO:0033665
label: hearing loss, autosomal dominant 78
parents:
- Autosomal Dominant Nonsyndromic Hearing Loss
inheritance:
- name: Autosomal dominant
description: >-
Heterozygous SLC12A2 exon 21 variants, transmitted dominantly in familial cases and
arising de novo in others. Segregation across three generations of one family
establishes the dominant pattern; an independent de novo case establishes that a single
new exon-21 allele is sufficient.
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
expressivity: VARIABLE
evidence:
- reference: PMID:34374074
reference_title: "PNPT1, MYO15A, PTPRQ, and SLC12A2-associated genetic and phenotypic heterogeneity among hearing impaired assortative mating families in Southern India."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In the fourth family, the SLC12A2 novel variant was found to segregate with severe-to-profound HL causing DFNA78, across three generations."
explanation: Dominant segregation over three generations in a single pedigree.
- reference: PMID:40503591
reference_title: "De Novo SLC12A2 Variant Presenting as Congenital Hearing Loss With Vestibular Areflexia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We report a patient with profound congenital hearing loss and vestibular areflexia with a de novo variant in SLC12A2 located in the splice donor site: NM_001046.2: c.2977+4_2977+7del causing an in-frame skip of exon 21, as shown by cDNA analysis."
explanation: >-
A de novo heterozygous allele producing the full phenotype, which is what shows one
mutant copy is sufficient rather than merely co-segregating.
pathophysiology:
- name: SLC12A2 Exon 21 Variant
biological_scale: MOLECULAR
description: >-
A heterozygous variant confined to exon 21 of SLC12A2 - either a missense substitution
within the exon or a splice-site change that removes it. The reported splice alleles lie
on both sides of the exon (a 3' splice-site change and a splice-donor deletion), and the
consequence established by cDNA analysis is an in-frame skip rather than a frameshift, so
the product is a shortened cotransporter rather than an absent one.
genes:
- preferred_term: SLC12A2
term:
id: hgnc:10911
label: SLC12A2
genetic_context:
allele_type: missense within exon 21, or splice-site variant causing in-frame skipping of exon 21
variant_origin: GERMLINE
zygosity: HETEROZYGOUS
functional_impact_category: LOSS_OF_FUNCTION
description: >-
LOSS_OF_FUNCTION records what was measured: chloride influx was significantly decreased
for every DFNA78 variant tested in oocytes, and an independent cohort reproduced reduced
cotransporter function for all its tested alleles. It deliberately does not record
DOMINANT_NEGATIVE, even though the disease is dominant and NKCC1 is a dimer. The two
allele classes may not share a route to dominance - the splice allele was shown to make
an exon-21-skipped transcript present at much lower levels than the exon-21-included one
in cochlea, which reads as isoform dose rather than as a poisoned dimer, while a missense
subunit could act either way. That question is carried in
discussions#dfna78_dominant_mechanism rather than settled by this tag.
downstream:
- target: Loss of the Inner-Ear-Restricted NKCC1 Exon 21 Isoform
causal_link_type: DIRECT
evidence:
- reference: PMID:40295800
reference_title: "Complete omission of exon 21 from Slc12a2 transcripts in mice results in hearing loss."
supports: SUPPORT
evidence_source: OTHER
snippet: "SLC12A2 is linked to autosomal dominant nonsyndromic hearing loss, DFNA78, with all the pathogenic variants affecting the exon 21."
explanation: >-
The confinement of the human allelic spectrum to one exon, which is the fact this whole
entry is organised around. Graded OTHER: it is an introductory summary of the human
genetic literature in a mouse paper, so the publication presents neither human clinical
data nor mouse data for this particular statement.
- reference: PMID:40503591
reference_title: "De Novo SLC12A2 Variant Presenting as Congenital Hearing Loss With Vestibular Areflexia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "To date, the published pathogenic variants causing DFNA78 are missense mutations located within exon 21 or in the 3' splice site of exon 21."
explanation: >-
Independent statement of the same restriction, and the source for the two allele classes
recorded in genetic_context.
- reference: PMID:32294086
reference_title: "Variants encoding a restricted carboxy-terminal domain of SLC12A2 cause hereditary hearing loss in humans."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All identified SLC12A2 variants mapped to exon 21 or its 3'-splice site."
explanation: >-
The original observation of the exon-21 restriction, in the cohort that established the
entity.
- reference: PMID:32294086
reference_title: "Variants encoding a restricted carboxy-terminal domain of SLC12A2 cause hereditary hearing loss in humans."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "In vitro functional analysis demonstrated that Cl- influx was significantly decreased in all SLC12A2 variants studied."
explanation: >-
The measured functional consequence that LOSS_OF_FUNCTION in genetic_context records.
Graded IN_VITRO because it is an oocyte transport assay, not a patient measurement.
- reference: PMID:32658972
reference_title: "SLC12A2 variants cause a neurodevelopmental disorder or cochleovestibular defect."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "All tested variants were shown to reduce co-transporter function in Xenopus laevis oocytes."
explanation: >-
Independent replication of reduced cotransport in a separate cohort and laboratory, which
is what makes the loss-of-transport claim more than a single-assay result.
- name: Loss of the Inner-Ear-Restricted NKCC1 Exon 21 Isoform
biological_scale: MOLECULAR
description: >-
SLC12A2 produces several isoforms, only one of which contains exon 21. That isoform is
almost exclusively expressed in the inner ear and is the one required for endolymph
homeostasis. An exon-21 lesion therefore removes or corrupts a cochlea-specific form of
the transporter while leaving the widely expressed forms intact - the structural reason a
gene active in neurons, glia, trachea, salivary glands, intestine and sweat glands yields
a hearing-only phenotype.
molecular_functions:
- preferred_term: NKCC1 sodium-potassium-chloride cotransport
modifier: LOSS_OF_FUNCTION
term:
id: GO:0008511
label: sodium:potassium:chloride symporter activity
downstream:
- target: Failure of Basolateral Potassium Uptake by Strial Marginal Cells
causal_link_type: DIRECT
evidence:
- reference: PMID:40503591
reference_title: "De Novo SLC12A2 Variant Presenting as Congenital Hearing Loss With Vestibular Areflexia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "SLC12A2 functions as a dimer and has several isoforms; only one isoform contains exon 21, and this isoform is almost exclusively expressed in the inner ear/cochlea."
explanation: >-
Both halves of this node: the tissue restriction of the exon-21 isoform, and the dimeric
assembly that the dominant-negative reading depends on.
- reference: PMID:40503591
reference_title: "De Novo SLC12A2 Variant Presenting as Congenital Hearing Loss With Vestibular Areflexia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This isoform is necessary for homeostasis of the endolymph."
explanation: Assigns the endolymph function specifically to the exon-21-containing isoform.
- reference: PMID:40503591
reference_title: "De Novo SLC12A2 Variant Presenting as Congenital Hearing Loss With Vestibular Areflexia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Our case adds to the evidence that loss of exon 21 of SLC12A2 leads to a cochlear restricted phenotype."
explanation: >-
The clinical counterpart of the expression argument: exon-21 loss confines the disease to
the cochlea.
- reference: PMID:32294086
reference_title: "Variants encoding a restricted carboxy-terminal domain of SLC12A2 cause hereditary hearing loss in humans."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "In vitro analysis indicated that the splice-site variant generates an exon 21-skipped SLC12A2 mRNA transcript expressed at much lower levels than the exon 21-included transcript in the cochlea, suggesting a tissue-specific role for the exon 21-encoded region in the carboy-terminal domain."
explanation: >-
Transcript-level demonstration that the splice allele reduces the cochlear isoform rather
than merely altering it, and the authors' own inference of a tissue-specific role for the
exon-21 region. The source prints "carboy-terminal"; the snippet reproduces it exactly.
notes: >-
The molecular function is bound to sodium:potassium:chloride symporter activity, which is
NKCC1's exact activity. What the ontology cannot express is that the lesion removes one
isoform rather than the activity as a whole; that restriction is carried in the node
description and in genetic_context.
- name: Failure of Basolateral Potassium Uptake by Strial Marginal Cells
biological_scale: CELLULAR
description: >-
Strial marginal cells take up potassium across their basolateral membrane and secrete it
apically into the endolymph. NKCC1 is the basolateral entry step, and it is described as
crucial for regulating intracellular osmotic pressure and for producing endolymph. Losing
the inner-ear isoform removes that entry step.
cell_types:
- preferred_term: strial marginal cell
term:
id: CL:0002492
label: strial marginal cell
biological_processes:
- preferred_term: basolateral potassium ion transmembrane transport
modifier: DECREASED
term:
id: GO:0071805
label: potassium ion transmembrane transport
locations:
- preferred_term: stria vascularis of cochlear duct
term:
id: UBERON:0002282
label: stria vascularis of cochlear duct
downstream:
- target: Reduced Endolymph Production
causal_link_type: DIRECT
evidence:
- reference: PMID:40295800
reference_title: "Complete omission of exon 21 from Slc12a2 transcripts in mice results in hearing loss."
supports: SUPPORT
evidence_source: OTHER
snippet: "The gene encodes a cotransporter NKCC1 crucial for regulating intracellular osmotic pressure and producing endolymph in the cochlea."
explanation: >-
The transporter's function in the cochlea, stated as background in the introduction of a
mouse paper. Graded OTHER because the publication presents no data of its own for this
statement.
- reference: PMID:40503591
reference_title: "De Novo SLC12A2 Variant Presenting as Congenital Hearing Loss With Vestibular Areflexia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In the inner ear, K+ transport is required for the mechano-transduction of auditory stimuli."
explanation: >-
Connects potassium handling to hearing rather than leaving it as generic ion transport.
- reference: PMID:32294086
reference_title: "Variants encoding a restricted carboxy-terminal domain of SLC12A2 cause hereditary hearing loss in humans."
supports: SUPPORT
directness: INDIRECT
evidence_source: MODEL_ORGANISM
snippet: "Immunohistochemistry revealed that SLC12A2 is located on the plasma membrane of several types of cells in the cochlea, including the strial marginal cells,"
explanation: >-
Localises the protein to the cell type this node is about. Graded MODEL_ORGANISM, not
HUMAN_CLINICAL: the abstract does not name a species, and the paper's methods state the
cochleae came from Macaca fascicularis. So the anatomical anchor of this mechanism rests
on non-human primate tissue, and the grading now says so.
- name: Reduced Endolymph Production
biological_scale: TISSUE
description: >-
The secretory failure itself. In mice with complete exon 21 skipping, endolymph is already
reduced by postnatal day 1 - before hearing onset - which places the defect in endolymph
production rather than in a later degeneration.
locations:
- preferred_term: stria vascularis of cochlear duct
term:
id: UBERON:0002282
label: stria vascularis of cochlear duct
biological_processes:
- preferred_term: potassium ion homeostasis
modifier: DECREASED
term:
id: GO:0055075
label: potassium ion homeostasis
downstream:
- target: Stria Vascularis Atrophy
causal_link_type: DIRECT
- target: Sensorineural Hearing Impairment
causal_link_type: DIRECT
- target: Vestibular Areflexia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:40295800
reference_title: "Complete omission of exon 21 from Slc12a2 transcripts in mice results in hearing loss."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "mice with complete skip of the exon 21 showed reduced endolymph on postnatal day 1 (P1), reduced stria vascularis (StV) and no auditory brainstem responses at 4 weeks."
explanation: >-
The endolymph reduction and its timing at P1, together with the auditory endpoint. The
same sentence also reports the strial change, which is curated on the downstream node.
notes: >-
Every measurement here comes from the homozygous mouse. Human DFNA78 is a heterozygous
disease and no equivalent human endolymph measurement exists, which is the substance of
discussions#dfna78_mouse_dose_mismatch.
- name: Stria Vascularis Atrophy
biological_scale: TISSUE
description: >-
The stria itself is smaller in the exon-21-skip mouse, and the authors read that as a
consequence of the osmotic change rather than as primary degeneration - a rebalancing of
osmotic pressure, with RNA-seq showing upregulation of Cldn9 interpreted as tissue repair of
the gaps left by reduced cell size. Curated as its own node because that ordering is a
substantive claim: it makes strial shrinkage downstream of the secretory defect rather than
an independent lesion.
locations:
- preferred_term: stria vascularis of cochlear duct
term:
id: UBERON:0002282
label: stria vascularis of cochlear duct
evidence:
- reference: PMID:40295800
reference_title: "Complete omission of exon 21 from Slc12a2 transcripts in mice results in hearing loss."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Reduced StV size was considered to be due to rebalance osmotic pressure, and upregulation of Cldn9 revealed by RNA-seq was considered as tissue response to repair the gaps from reduced cell sizes"
explanation: >-
The authors' interpretation of the strial shrinkage, quoted because it changes what the
finding means: an osmotic adjustment downstream of the endolymph defect, not cell death.
notes: >-
This node has no downstream edge. The strial change is a readout of the secretory failure
rather than a further step toward the phenotype, and the hearing loss is drawn from the
upstream node accordingly.
phenotypes:
- name: Sensorineural Hearing Impairment
category: Auditory
description: >-
The defining feature. Reported severities span severe-to-profound postlingual loss
segregating through three generations of one family and profound congenital loss in a de
novo case, so the disorder cannot be excluded on age at presentation. Curated as one node
carrying severity: SEVERE rather than as a parent phenotype with a severe child - HP:0008625
is a descendant of HP:0000407, and modelling that as a causal sequela would encode an is-a
relation as causation.
frequency: OBLIGATE
severity: SEVERE
phenotype_term:
preferred_term: Sensorineural hearing impairment
term:
id: HP:0000407
label: Sensorineural hearing impairment
evidence:
- reference: PMID:34374074
reference_title: "PNPT1, MYO15A, PTPRQ, and SLC12A2-associated genetic and phenotypic heterogeneity among hearing impaired assortative mating families in Southern India."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In the fourth family, the SLC12A2 novel variant was found to segregate with severe-to-profound HL causing DFNA78, across three generations."
explanation: Severity and dominant segregation in the familial form.
- reference: PMID:40503591
reference_title: "De Novo SLC12A2 Variant Presenting as Congenital Hearing Loss With Vestibular Areflexia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We report a patient with profound congenital hearing loss and vestibular areflexia with a de novo variant in SLC12A2 located in the splice donor site: NM_001046.2: c.2977+4_2977+7del causing an in-frame skip of exon 21, as shown by cDNA analysis."
explanation: The congenital, profound end of the severity range.
- name: Vestibular Areflexia
category: Vestibular
description: >-
Vestibular areflexia accompanies the hearing loss in reported DFNA78, and it was named in
the original 2020 description of the entity. Its practical weight is differential: hearing
loss with vestibular failure otherwise points first at Usher syndrome, and DFNA78 belongs
on that list.
frequency: FREQUENT
phenotype_term:
preferred_term: Vestibular areflexia
term:
id: HP:0008568
label: Vestibular areflexia
evidence:
- reference: PMID:40503591
reference_title: "De Novo SLC12A2 Variant Presenting as Congenital Hearing Loss With Vestibular Areflexia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In 2020, heterozygous variants in SLC12A2 were identified as a cause of non-syndromic deafness associated with vestibular areflexia (DFNA78; MIM 619081)."
explanation: >-
Vestibular areflexia as part of the original entity definition, not an incidental finding
in one patient.
- reference: PMID:40503591
reference_title: "De Novo SLC12A2 Variant Presenting as Congenital Hearing Loss With Vestibular Areflexia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "it reminds us that beyond syndromic forms such as Usher syndrome, several non-syndromic forms of genetically determined sensorineural hearing loss, including those involving the SLC12A2 gene, may also present with vestibular areflexia"
explanation: The differential-diagnostic point, stated by the authors.
- reference: PMID:32658972
reference_title: "SLC12A2 variants cause a neurodevelopmental disorder or cochleovestibular defect."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We also identified SLC12A2 variants in three individuals with non-syndromic bilateral sensorineural hearing loss and vestibular areflexia."
explanation: >-
Three individuals in the cohort that named the cochleovestibular phenotype, which is the
primary source for pairing areflexia with the hearing loss rather than a later review.
genetic:
- name: SLC12A2
gene_term:
preferred_term: SLC12A2
term:
id: hgnc:10911
label: SLC12A2
relationship_type: CAUSATIVE
variant_origin: GERMLINE
features: >-
Pathogenic DFNA78 alleles are confined to exon 21 - missense within it, or splice variants
at either of its boundaries producing an in-frame skip. Loss-of-function alleles elsewhere
in the gene cause different disorders and, heterozygously, do not cause deafness.
evidence:
- reference: PMID:40295800
reference_title: "Complete omission of exon 21 from Slc12a2 transcripts in mice results in hearing loss."
supports: SUPPORT
evidence_source: OTHER
snippet: "SLC12A2 is linked to autosomal dominant nonsyndromic hearing loss, DFNA78, with all the pathogenic variants affecting the exon 21."
explanation: >-
The gene-disease link together with the allelic restriction that defines it. Graded OTHER
for the same reason as its other use: an introductory summary in a mouse paper.
- reference: PMID:40503591
reference_title: "De Novo SLC12A2 Variant Presenting as Congenital Hearing Loss With Vestibular Areflexia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Since 2016, variants in SLC12A2 have been implicated in human disease, with several different phenotypes being linked to the gene."
explanation: >-
Establishes that SLC12A2 is allelic for several distinct disorders, which is why DFNA78
has to be defined by its allele class and not by the gene alone.
diagnosis:
- name: SLC12A2 sequencing with exon 21 coverage
description: >-
Sequencing SLC12A2 with attention to exon 21 and both of its splice boundaries. Because
the reported splice alleles act by skipping rather than by frameshift, a variant a few
bases into the intron can be the whole cause, and cDNA analysis is what establishes it.
evidence:
- reference: PMID:40503591
reference_title: "De Novo SLC12A2 Variant Presenting as Congenital Hearing Loss With Vestibular Areflexia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We report a patient with profound congenital hearing loss and vestibular areflexia with a de novo variant in SLC12A2 located in the splice donor site: NM_001046.2: c.2977+4_2977+7del causing an in-frame skip of exon 21, as shown by cDNA analysis."
explanation: >-
An intronic +4 to +7 deletion whose consequence needed cDNA to demonstrate - the case for
not stopping at the coding sequence.
- name: Broad hearing-loss gene panel in vestibular areflexia
description: >-
When sensorineural hearing loss presents with vestibular areflexia, testing narrowed to
Usher syndrome genes will miss DFNA78.
evidence:
- reference: PMID:40503591
reference_title: "De Novo SLC12A2 Variant Presenting as Congenital Hearing Loss With Vestibular Areflexia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This underscores the need for a broad sequencing approach when faced with this clinical scenario."
explanation: The authors' testing recommendation for exactly this presentation.
animal_models:
- name: Slc12a2 exon 21 skip mouse (Em2)
species: Mouse
genotype: Slc12a2Em2/Em2 (c.2912-4_2913del), complete skipping of exon 21
publication: PMID:40295800
description: >-
A CRISPR-engineered splice-site allele that removes exon 21 from Slc12a2 transcripts
entirely. Homozygotes reproduce the cochlear phenotype; heterozygotes largely do not.
modeled_mechanisms:
- target: Reduced Endolymph Production
relationship: RECAPITULATES
fidelity: MODERATE
description: >-
Reproduces the tissue-level lesion this entry attributes to loss of the exon-21 isoform:
reduced endolymph volume in the first postnatal day, a smaller stria vascularis, and
absent auditory brainstem responses.
limitations: >-
Only the homozygote does. Human DFNA78 is heterozygous, and the heterozygous mouse shows
only mild threshold elevation, in females, at some frequencies. The model therefore
supports the isoform's function well and the dominant mechanism poorly. A second species
difference is intrinsic to the model: a single nucleotide difference between human and
mouse at the 5' end of exon 21 alters how the exon is spliced, so exon-21 handling is not
identical between the two organisms.
readouts:
- name: Endolymph volume at postnatal day 1
target: Reduced Endolymph Production
direction: DECREASED
interpretation: >-
Direct measurement of the secretory failure the mechanism predicts, at an age before
hearing onset.
evidence:
- reference: PMID:40295800
reference_title: "Complete omission of exon 21 from Slc12a2 transcripts in mice results in hearing loss."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "mice with complete skip of the exon 21 showed reduced endolymph on postnatal day 1 (P1), reduced stria vascularis (StV) and no auditory brainstem responses at 4 weeks."
explanation: Reports the endolymph reduction and its timing.
- name: Auditory brainstem response at 4 weeks
target: Reduced Endolymph Production
direction: ABOLISHED
interpretation: Functional deafness in the homozygote, the auditory endpoint of the chain.
evidence:
- reference: PMID:40295800
reference_title: "Complete omission of exon 21 from Slc12a2 transcripts in mice results in hearing loss."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "no auditory brainstem responses at 4 weeks"
explanation: The absent ABR that defines the model's auditory phenotype.
evidence:
- reference: PMID:40295800
reference_title: "Complete omission of exon 21 from Slc12a2 transcripts in mice results in hearing loss."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "mouse is proposed as a model for studying DFNA78 pathology."
explanation: >-
The authors' own claim that this strain models DFNA78, which is what makes the link
informative for the node rather than merely concurrent.
treatments:
- name: Cochlear Implantation
therapeutic_modality: DEVICE
treatment_term:
preferred_term: cochlear device implantation
term:
id: NCIT:C15329
label: Surgical Procedure
qualifiers:
- predicate:
preferred_term: medical device
term:
id: NCIT:C16830
label: Medical Device
value:
preferred_term: cochlear implant
term:
id: NCIT:C157820
label: Cochlear Implant
description: >-
The intervention for the severe-to-profound end of the range, and the mechanism supports it
cleanly: the lesion is in strial endolymph secretion, entirely upstream of the spiral
ganglion an implant stimulates, and no cochlear structural malformation is described in
DFNA78. No DFNA78-specific implant outcome data exist.
target_mechanisms:
- target: Sensorineural Hearing Impairment
treatment_effect: BYPASSES
description: >-
Stimulates the auditory nerve directly, bypassing the failed endolymph-dependent
transduction step rather than correcting it.
notes: >-
Carries no evidence item deliberately. None of the cached DFNA78 references reports implant
outcomes, and quoting the general cochlear-implant literature would attribute to this
disease something not measured in it. The mechanistic rationale above is this entry's
inference and is labelled as such.
The treatment term is the generic surgical action. NCIT:C157820 names the device rather than
a clinical action and is not reachable from NCIT:C25218, so it cannot be the term: of a
TreatmentTerm; it is attached as a qualifier so the device stays queryable.
- name: Hearing Aid Amplification
therapeutic_modality: DEVICE
treatment_term:
preferred_term: hearing aid amplification
term:
id: NCIT:C15315
label: Rehabilitation
description: >-
Amplification for the milder and earlier part of the course, before thresholds reach the
implant range. As with implantation there are no DFNA78-specific data.
notes: >-
No evidence item, for the same reason as cochlear implantation. NCIT has no clinical-action
term for hearing aid usage, so the bound term is the generic rehabilitation action and the
specificity sits in preferred_term.
- name: Vestibular Rehabilitation
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: vestibular rehabilitation
term:
id: NCIT:C15302
label: Physical Therapy
description: >-
Relevant to the subgroup with vestibular areflexia. Bilateral areflexia is compensated for
by vision and proprioception rather than recovered from, and balance training targets that
compensation.
target_phenotypes:
- preferred_term: Vestibular areflexia
term:
id: HP:0008568
label: Vestibular areflexia
notes: >-
No evidence item; standard practice for bilateral vestibular loss, not a DFNA78 finding.
- name: Avoidance of Loop Diuretics
therapeutic_modality: OTHER
treatment_term:
preferred_term: avoidance of loop diuretic exposure
term:
id: NCIT:C15747
label: Supportive Care
description: >-
Recorded because the pharmacology is unusually pointed here rather than because outcomes are
known. Loop diuretics such as bumetanide and furosemide act by inhibiting NKCC1 - the
transporter this disease has already crippled in the cochlea - and are recognised ototoxins.
A DFNA78 patient therefore has a mechanistic reason to avoid the drug class that targets
their own defective protein.
notes: >-
Carries no evidence item. None of the cached DFNA78 references discusses loop diuretics; the
NKCC1-inhibition pharmacology and loop-diuretic ototoxicity are both established general
knowledge, and the inference joining them to this disease is this entry's, labelled as such.
It is recorded rather than omitted because a drug class whose target is the disease protein
is exactly the kind of link this knowledge base exists to make queryable, and it would be a
poor outcome for that to survive only as prose in a research report.
discussions:
- discussion_id: dfna78_dominant_mechanism
kind: OPEN_QUESTION
status: OPEN
prompt: >-
Is DFNA78 dominant because an exon-21 mutant subunit poisons the NKCC1 dimer, or because
the cochlear exon-21 isoform is uniquely dose-sensitive - and do the missense and splice
alleles reach dominance by the same route?
attaches_to:
- pathophysiology#SLC12A2 Exon 21 Variant
- pathophysiology#Loss of the Inner-Ear-Restricted NKCC1 Exon 21 Isoform
rationale: >-
The entry tags the variants LOSS_OF_FUNCTION because that is what the oocyte assays
measured, and deliberately does not tag them DOMINANT_NEGATIVE, because the dominance is
not explained by any published experiment. What is published: a de novo heterozygous
SLC12A2 loss-of-function variant produced normal hearing; biallelic loss of function
produces Kilquist syndrome; heterozygous exon-21 alteration produces deafness; NKCC1
functions as a dimer; and every tested DFNA78 allele reduces chloride influx. Those facts
rule out simple haploinsufficiency of the *gene*, but they do not distinguish a poisoned
dimer from a cochlear isoform whose function collapses at half dose - the reported
gene-level LoF alleles need not have affected the exon-21 transcript at all.
The splice allele actually argues for the dose model over the poison model: its
exon-21-skipped transcript is present at much lower levels than the exon-21-included one in
cochlea, so what that patient loses is isoform quantity. A missense subunit is the case
that could go either way, and it is the one nobody has tested. A co-expression assay
measuring mutant-on-wild-type interference, or an exon-21-specific heterozygous null, would
separate them. Neither has been reported.
evidence:
- reference: PMID:40503591
reference_title: "De Novo SLC12A2 Variant Presenting as Congenital Hearing Loss With Vestibular Areflexia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The first report concerned a child with a complex syndrome marked by metabolic derangement but normal hearing and cognition and a de novo heterozygous loss of function variant."
explanation: >-
The observation that does the work: heterozygous loss of function in this gene is
compatible with normal hearing, so DFNA78 dominance needs an explanation beyond dose.
- reference: PMID:40503591
reference_title: "De Novo SLC12A2 Variant Presenting as Congenital Hearing Loss With Vestibular Areflexia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "SLC12A2 functions as a dimer and has several isoforms; only one isoform contains exon 21, and this isoform is almost exclusively expressed in the inner ear/cochlea."
explanation: >-
Supplies both candidate explanations at once - the dimer that a mutant subunit could
poison, and the isoform restriction that could make the cochlea uniquely dose-sensitive.
- reference: PMID:32294086
reference_title: "Variants encoding a restricted carboxy-terminal domain of SLC12A2 cause hereditary hearing loss in humans."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "In vitro analysis indicated that the splice-site variant generates an exon 21-skipped SLC12A2 mRNA transcript expressed at much lower levels than the exon 21-included transcript in the cochlea, suggesting a tissue-specific role for the exon 21-encoded region in the carboy-terminal domain."
explanation: >-
The observation that tips the splice allele toward an isoform-dose explanation rather
than a poisoned dimer, and so splits the question by allele class.
- discussion_id: dfna78_mouse_dose_mismatch
kind: HUMAN_MODEL_MISMATCH
status: OPEN
prompt: >-
Why is the heterozygous exon-21-skip mouse near-normal when the heterozygous human is
severely to profoundly deaf?
attaches_to:
- animal_models#Mouse
- pathophysiology#Reduced Endolymph Production
rationale: >-
The mouse reproduces the mechanism convincingly in the homozygous state - reduced
endolymph, smaller stria, no ABR - and that is why the model is used here. But the
dominance does not carry across. Heterozygous mice show only mild ABR threshold elevation,
in females, at some frequencies, whereas heterozygous humans are deaf. The paper itself
supplies one candidate explanation, which is that human and mouse differ by a single
nucleotide at the 5' end of exon 21 and that this difference affects exon 21 splicing, so
the mouse allele may not produce the same transcript mix. A second possibility is that the
engineered skip is a null for the isoform while the human missense alleles make an
interfering product - which would also resolve
discussions#dfna78_dominant_mechanism. Until that is tested, homozygous-mouse results
should not be read as evidence about the human heterozygous mechanism.
evidence:
- reference: PMID:40295800
reference_title: "Complete omission of exon 21 from Slc12a2 transcripts in mice results in hearing loss."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Female Slc12a2Em2/+ mice also exhibited mild elevation of ABR thresholds in several sound frequencies."
explanation: >-
The heterozygous mouse phenotype, which is the mismatch: mild, sex-limited and
frequency-limited against severe-to-profound human loss.
- reference: PMID:40295800
reference_title: "Complete omission of exon 21 from Slc12a2 transcripts in mice results in hearing loss."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Minigene assays indicated that a single nucleotide difference between humans and mice at the 5' end of the exon 21 affects exon 21 splicing."
explanation: >-
The species difference the authors identify in exon-21 handling, which is a concrete
mechanism for the mismatch rather than a generic caveat.
notes: >-
Relationship to the other SLC12A2 entries in this knowledge base. Delpire-McNeill Syndrome
and Kilquist Syndrome are the syndromic SLC12A2 disorders, and Autosomal Recessive
Nonsyndromic Hearing Loss 103 is a recessive hearing-only entry that cites SLC12A2
functional work. DFNA78 is the dominant hearing-only form, and what separates it from all
three is the exon-21 restriction rather than the phenotype alone. That is curated here as
the defining feature rather than as a footnote.
PMID:36035115 reports cell-based analysis of an SLC12A2 p.(E979K) variant from a Ghanaian
hearing-impairment family and is cached alongside this entry, but is not cited in it: the
paper does not state that family's inheritance mode, so attributing its functional result to
DFNA78 rather than to another SLC12A2 hearing phenotype would be an assumption. It is
recorded here so the next curator does not have to rediscover the reason.
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 78 (DFNA78, SLC12A2) · 2026-09-03T19:12:27Z · View source
De novo curation of DFNA78 from primary literature plus one openscientist deep-research run. The entry is organised around the exon-21 restriction of the pathogenic allele spectrum and the inner-ear-restricted isoform that exon encodes. Variants are recorded LOSS_OF_FUNCTION on the measured oocyte chloride-influx data rather than DOMINANT_NEGATIVE; the route to dominance is left as an open question because the splice allele's reduced exon-21 transcript level argues for isoform dose while a missense subunit in a dimeric transporter could poison its partner. A HUMAN_MODEL_MISMATCH discussion records that the exon-21-skip mouse reproduces the mechanism only as a homozygote. Validated: schema, terms, 34/34 snippets, entity refs, causal targets, duplicate keys, enum values, qualifier terms.
Prepared as a disease knowledge-base entry. Evidence types are flagged as [human clinical], [model organism], [in vitro], or [computational]. Primary citations are given as PMIDs.
DFNA78 is a rare, autosomal dominant, non-syndromic sensorineural hearing loss (frequently accompanied by bilateral vestibular areflexia) caused by heterozygous variants in SLC12A2, the gene encoding the secretory Na⁺-K⁺-2Cl⁻ cotransporter NKCC1. The pathogenic variants cluster in exon 21 (or its 3′ splice site), a region present almost exclusively in the cochlea-specific NKCC1 isoform that is required to maintain the K⁺-rich endolymph and endocochlear potential that drive hair-cell mechanotransduction. Reduced/dysfunctional cotransport disrupts endolymph homeostasis, leading to hair-cell dysfunction and hearing/vestibular loss. Management is supportive (hearing aids, cochlear implantation, vestibular rehabilitation); no disease-specific pharmacotherapy exists.
Overview. DFNA78 ("Deafness, autosomal dominant 78") is a Mendelian sensorineural hearing loss (SNHL) caused by heterozygous SLC12A2 variants. It was first delineated in 2020 [human clinical; PMID 32294086; 32658972]. The phenotype is congenital-to-early-onset, bilateral SNHL, often severe-to-profound, and frequently with bilateral vestibular areflexia (hence sometimes described as a cochleovestibular defect) [PMID 32658972; 40503591].
"In 2020, heterozygous variants in SLC12A2 were identified as a cause of non-syndromic deafness associated with vestibular areflexia (DFNA78; MIM 619081)." — PMID 40503591
Key identifiers (verified via OLS4/MONDO, 2026-09-03). - OMIM: #619081 (Deafness, autosomal dominant 78) - Gene OMIM: SLC12A2 600840 - MONDO: MONDO:0033665 ("hearing loss, autosomal dominant 78") - DOID: DOID:0112159; GARD: 0018156; MedGen: C5436768 (CUI 1777362); UMLS: C5436768 - Orphanet: No dedicated DFNA78 ORPHAcode (MONDO records no Orphanet xref); clinically grouped under autosomal dominant non-syndromic sensorineural hearing loss. - ICD-11: AB52 Sensorineural hearing impairment (bilateral, AB52.0); ICD-10: H90.3/H90.5 - MeSH: "Hearing Loss, Sensorineural" (D006319); "Hearing Loss, Bilateral" - HGNC gene: HGNC:10911 (SLC12A2); NCBI Gene: 6558; Ensembl: ENSG00000064651; UniProt: P55011 (NKCC1)
Synonyms / alternative names: DFNA78; deafness, autosomal dominant 78; SLC12A2-related autosomal dominant deafness; NKCC1-related hearing loss; non-syndromic sensorineural hearing loss with vestibular areflexia. Distinct allelic disorders (same gene, different phenotype/inheritance): Delpire-McNeill syndrome — neurodevelopmental disorder, MONDO:0033667, OMIM #619083, Orphanet:633024 [PMID 32658972]; Kilquist syndrome — autosomal recessive multisystem disorder, MONDO:0033664, OMIM #619080, Orphanet:633021 [PMID 30740830].
Data source type: Aggregated disease-level knowledge derived from a small number of published case reports/families and functional studies (not EHR-derived at scale). Fewer than ~20 unrelated affected individuals/families are described to date.
Primary cause — genetic. DFNA78 is a monogenic disorder caused by heterozygous, usually dominantly-inherited or de novo, variants in SLC12A2 [human clinical; PMID 32294086; 32658972]. There is no environmental or infectious cause; environmental agents are irrelevant to the primary etiology.
Genetic risk factors. - Causal variants: missense and splice-site variants restricted to exon 21 / its 3′ splice site of the cochlea-specific NKCC1 isoform [PMID 32294086]. ClinVar additionally lists DFNA78-annotated truncating alleles c.2977G>T (p.Glu993Ter) [Pathogenic] and c.869dup (p.Val291fs) [Likely pathogenic] [computational; ClinVar 2026]. - No known common susceptibility loci or modifier genes have been established for DFNA78 (the disorder is monogenic and ultra-rare).
Environmental risk / protective factors. None established as causal or modifying for DFNA78. General SNHL aggravators (noise, ototoxic aminoglycosides, loop diuretics) are theoretical concerns because loop diuretics (bumetanide/furosemide) inhibit NKCC1; avoidance is prudent but not evidence-based for this specific disease.
Gene–environment interactions. Not characterized. Given the ion-transport mechanism, ototoxic drugs that further impair endolymph homeostasis (loop diuretics, aminoglycosides, cisplatin) could plausibly worsen hearing, but no formal GxE data exist.
Core phenotype = bilateral sensorineural hearing loss ± bilateral vestibular areflexia, non-syndromic.
| Phenotype | Type | Onset | Severity | Progression | Frequency | HPO term |
|---|---|---|---|---|---|---|
| Sensorineural hearing loss | Clinical sign / lab (audiometry) | Congenital–early childhood (some later/progressive) | Moderate → profound | Stable or slowly progressive | ~100% (defining) | HP:0000407 Sensorineural hearing impairment; HP:0008619 Bilateral SNHL; HP:0008527 Congenital SNHL; HP:0000408 Progressive SNHL |
| Vestibular areflexia / dysfunction | Clinical sign (caloric/vHIT) | Congenital–early | Variable | Stable | Frequent (subset; reported in the cochleovestibular families) | HP:0410057 Vestibular areflexia; HP:0002321 Vertigo; HP:0001336 (imbalance) |
| Delayed motor milestones (2° to vestibular loss) | Physical | Infancy | Mild | Non-progressive | Occasional | HP:0001270 |
| Tinnitus | Symptom | Variable | Mild-moderate | Variable | Not systematically reported | HP:0000360 |
Explicitly NOT part of DFNA78 (these distinguish it from the recessive/de-novo allelic disorders): intellectual disability, developmental delay, gastrointestinal dysmotility, absent salivation/lacrimation, respiratory abnormalities, microcephaly — these occur in Kilquist syndrome (biallelic LoF) and Delpire-McNeill (de novo NDD) [PMID 30740830; 32658972; 33500540].
Quality-of-life impact. SNHL impairs speech/language acquisition, education, and communication; vestibular areflexia impairs balance, gaze stabilization (oscillopsia), and delays motor development. No DFNA78-specific EQ-5D/SF-36 data; QoL burden inferred from congenital bilateral SNHL literature generally.
Causal gene. SLC12A2 (Solute carrier family 12 member 2), encoding NKCC1 (Na⁺-K⁺-2Cl⁻ cotransporter 1). HGNC:10911; NCBI Gene 6558; Ensembl ENSG00000064651; UniProt P55011 (1212 aa); locus 5q23.3 (GRCh38 chr5:128,083,766–128,189,677); canonical transcript ENST00000262461 / NM_001046.3 [computational; gnomAD/UniProt].
Pathogenic variants. - Type/class: predominantly missense and splice-site variants in exon 21 / its 3′ splice acceptor (cochlear isoform) [PMID 32294086]; ClinVar also records truncating (nonsense/frameshift) DFNA78 alleles (p.Glu993Ter; p.Val291fs) [ClinVar]. - Classification (ACMG/AMP): the two established DFNA78 alleles are Pathogenic / Likely pathogenic; most other SLC12A2 variants are VUS [ClinVar 2026]. - Allele frequency: private/ultra-rare; absent or singleton in gnomAD (consistent with de novo or small-family dominant transmission). - Origin: germline — inherited (dominant families) or de novo (sporadic cases) [PMID 32294086; 32658972]. No somatic involvement. - Functional consequence: reduced cotransporter activity — "Cl⁻ influx was significantly decreased in all SLC12A2 variants studied" [in vitro Xenopus oocytes; PMID 32294086]. Because NKCC1 is an obligate dimer and heterozygous LoF carriers have normal hearing, DFNA78 missense alleles likely act via dominant-negative / isoform-specific loss of endolymph-secreting function rather than simple haploinsufficiency (partly inferred) [PMID 40503591].
"SLC12A2 functions as a dimer and has several isoforms; only one isoform contains exon 21, and this isoform is almost exclusively expressed in the inner ear/cochlea." — PMID 40503591
Constraint (gnomAD). LOEUF 0.60, LoF o/e 0.49 (obs 67/exp 136), lof_z 5.04, pLI ≈ 0, missense o/e 0.86 (mis_z 2.32) — i.e., SLC12A2 is only moderately LoF-constrained and not classically haploinsufficient, supporting the non-haploinsufficiency mechanism [computational; gnomAD].
Modifier genes / epigenetics / chromosomal abnormalities. None established for DFNA78. (In Kilquist syndrome the causal lesion was a homozygous 22-kb deletion arising via uniparental isodisomy of chromosome 5 — a large-scale mechanism relevant to the recessive allelic disorder, not DFNA78 [PMID 30740830].)
Not applicable to disease causation. No environmental toxins, lifestyle factors, or infectious agents are implicated in DFNA78. Theoretical aggravators of any SNHL — noise exposure, aminoglycosides, cisplatin, and loop diuretics (NKCC1 inhibitors) — should be minimized as general otoprotective practice, but there is no disease-specific evidence.
Ordered causal chain (initiating lesion → clinical manifestation):
Molecular pathways / biochemistry. The core defect is an ion-transport (ion-homeostasis) defect, not a classical signaling cascade. NKCC1 mediates electroneutral, bumetanide-sensitive Na⁺:K⁺:2Cl⁻ symport (MF GO:0008511 sodium:potassium:chloride symporter activity). Relevant GO biological processes (UniProt P55011): potassium ion transmembrane transport (GO:0071805), chloride transmembrane transport (GO:1902476), potassium ion import across plasma membrane (GO:1990573), intracellular potassium ion homeostasis (GO:0030007), cell volume homeostasis (GO:0006884), sensory perception of sound (GO:0007605), inner ear morphogenesis (GO:0042472). CHEBI entities: potassium(1+) CHEBI:29103, chloride CHEBI:17996, sodium(1+) CHEBI:29101; inhibitors bumetanide CHEBI:3213, furosemide CHEBI:47426.
Protein dysfunction. NKCC1 is a 12-TM cation-chloride cotransporter that assembles as a homodimer; cryo-EM structures reveal ion-binding sites and the dimer interface [in vitro/structural; PMID 36239040; 32081947; 37545407]. Exon-21 variants perturb the C-terminal cytoplasmic domain critical for transport/regulation; recessive alleles also cluster in the C-terminal domain [PMID 33500540]. Consequence = loss/reduction of transport function (± dominant-negative on the dimer).
Cell types / processes (upstream→downstream). Upstream: dysfunction of strial marginal cells (CL:0002516) and vestibular dark cells (epithelial K⁺ secretion). Downstream: secondary dysfunction/degeneration of cochlear hair cells (inner CL:0000589; outer CL:0000601), vestibular hair cells (CL:0000633), and (later) spiral ganglion neurons (CL:0002253). No inflammation/autoimmunity, apoptosis-driven primary mechanism, or metabolic disorder is implicated in DFNA78.
Molecular profiling. NKCC1 immunolocalizes to the basolateral membrane of strial marginal cells; in hereditary-deaf animal cochleae, spatiotemporal loss of SLC12A2 accompanies strial malformation and endolymph collapse [PMID 18093167; 24713161]. No DFNA78-specific transcriptomic/proteomic/metabolomic datasets exist.
Clinical/functional tests. - Audiometry (pure-tone, ABR/auditory brainstem response, OAE, tympanometry): documents bilateral SNHL; OAEs typically absent. LOINC panels for audiometry. - Vestibular testing: video head-impulse test (vHIT), caloric testing, VEMP, rotational chair — reveal vestibular areflexia/hypofunction. - Imaging: MRI/CT of temporal bones — usually normal inner-ear anatomy (helps exclude structural/EVA causes); no pathognomonic finding. - No blood/urine biomarker exists; diagnosis is not made by chemistry.
Genetic testing (diagnostic gold standard). - Recommended approach: hereditary-hearing-loss gene panel or whole-exome sequencing (WES), with attention to SLC12A2 including exon 21 and splice sites (which may be under-covered/mis-annotated because the pathogenic cochlear isoform differs from the canonical transcript) [PMID 32294086]. WES/WGS with trio analysis is especially useful to detect de novo variants [PMID 32658972]. - Single-gene SLC12A2 testing is appropriate when the phenotype (congenital SNHL + vestibular areflexia, dominant/de novo) is suggestive. - CMA/karyotype/FISH generally not indicated (point-variant disorder); mtDNA and repeat-expansion testing not relevant. - Variant-interpretation caveat: confirm variant is in the exon-21 cochlear isoform and, ideally, functional confirmation (reduced Cl⁻/transport) supports pathogenicity [PMID 32294086].
Clinical criteria / differential diagnosis. No formal diagnostic criteria. Differential includes other non-syndromic SNHL genes (GJB2, SLC26A4/Pendred, MYO7A, TMC1, etc.), and syndromic causes with vestibular involvement (Usher syndrome). The combination of non-syndromic congenital SNHL with bilateral vestibular areflexia and dominant/de novo inheritance points toward SLC12A2. Distinguish from the allelic Kilquist (recessive, multisystem) and Delpire-McNeill (NDD) disorders.
Screening. Detected via universal newborn hearing screening (phenotype), then genetic confirmation; cascade testing of at-risk relatives in dominant families.
No disease-modifying/curative pharmacotherapy exists. Management is supportive/rehabilitative.
"absence of functional co-transporter leads to structural damages in the inner ear consistent with a decrease in endol[ymph]" — PMID 10369265
Supported: - DFNA78 is caused by heterozygous SLC12A2 variants clustered in the cochlea-specific exon-21 region [PMID 32294086]. - Mechanism = impaired NKCC1-mediated K⁺ secretion → endolymph/EP failure → hair-cell transduction failure → SNHL + vestibular areflexia [PMID 10369265; 32294086; 40503591]. - SLC12A2 is an allelic series (dominant DFNA78 vs recessive Kilquist vs de novo Delpire-McNeill NDD) [PMID 30740830; 32658972; 33500540].
Refuted / disfavored: - Haploinsufficiency as the DFNA78 mechanism — disfavored: gnomAD shows SLC12A2 is not classically haploinsufficient (pLI≈0) and heterozygous LoF carriers/patients have normal hearing; DFNA78 arises from isoform-specific missense/splice (dominant-negative) alleles [PMID 40503591; gnomAD]. - Environmental/infectious causation — not applicable.
Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
|---|---|
| References checked | 10 |
| Resolved | 10 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| Quoted claims checked | 1 |
| Quoted claims found in source | 1 |
| Quoted claims not found in source | 0 |
| References weighed for topical relevance | 10 |
| On topic | 5 |
| Off topic | 0 |
All extracted references resolved successfully.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 43 |
| Resolved | 39 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 0 |
| Unverifiable | 4 |
| Terms whose name was checked | 4 |
| Terms named correctly | 0 |
| Terms named as a different term | 3 |
| Terms whose name is worth a second look | 1 |
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:
HP:0001270 (1 mention) - the report calls it "Occasional"; HP calls it Motor delayHP:0000360 (1 mention) - the report calls it "Not systematically reported"; HP calls it TinnitusUBERON:0002429 (1 mention) - the report calls it "Tissue/cell level: cochlear lateral wall / stria vascularis"; UBERON calls it cervical lymph nodeThe 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:0016323 (1 mention) - the report calls it "Subcellular level: basolateral plasma membrane"; GO calls it basolateral plasma membraneTerms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: Orphanet, MGI.