DFNB115 is bilateral, nonsyndromic sensorineural hearing loss of childhood onset caused by biallelic variants in SPNS2, which encodes the plasma-membrane exporter of sphingosine-1-phosphate (S1P). What makes this entry worth having is where the lesion sits. Most curated cochlear entities fail inside the hair cell - in the stereocilia bundle, in transduction, or at the ribbon synapse. SPNS2 does not. The mouse work that identified the gene shows the earliest measurable defect is a fall in the endocochlear potential, and locates the primary lesion in the cochlear lateral wall rather than in the organ of Corti. Hair cell degeneration follows, and the authors read it as secondary. So the pathograph runs from a lipid transport failure, through the battery that drives mechanotransduction, to the sensory cells - and the hair cell loss is a consequence rather than the start. The provenance of that mechanism should be stated plainly, because almost all of it is mouse. The human side of DFNB115 is two published probands: a child from a United States clinic who is compound heterozygous for a frameshift and an in-frame single-codon deletion in SPNS2, and an eight-year-old Iranian girl compound heterozygous for a nonsense and a missense allele. Nobody has measured an endocochlear potential in a person with DFNB115, and no human cochlear tissue has been examined. The entry therefore grades the strial and endocochlear-potential nodes as MODEL_ORGANISM evidence and says so at each node. One mouse result has no human counterpart and is the reason this entity is interesting therapeutically rather than only descriptively. Reactivating Spns2 transcription in mice that had already lost hearing brought auditory brainstem response thresholds back to close to normal at low and mid frequencies, and protected hair cells from the secondary degeneration - but only if done early enough. That is a demonstration that this class of hearing loss is reversible in principle, and a critical-window claim that nothing in the human literature can yet confirm or refute. It is curated as an animal-model rescue and as an open discussion, not as a treatment. OMIM flags the SPNS2 gene-phenotype relationship as provisional, which is recorded here rather than smoothed over: NCBI mim2gene_medgen carries the `question` comment on OMIM:618457, the marker for an OMIM gene-map phenotype entered with a leading question mark. Two unrelated probands with biallelic damaging alleles, a concordant mouse mutant, and a structural study showing that pathogenic substitutions abolish transport is a reasonable body of evidence, but it is not the multi-family segregation a definitive call would need.
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name: Autosomal Recessive Nonsyndromic Hearing Loss 115
category: Mendelian
creation_date: "2026-09-17T00:00:00Z"
synonyms:
- DFNB115
- deafness, autosomal recessive 115
- hearing loss, autosomal recessive 115
- SPNS2-related hearing loss
description: >-
DFNB115 is bilateral, nonsyndromic sensorineural hearing loss of childhood onset caused by
biallelic variants in SPNS2, which encodes the plasma-membrane exporter of
sphingosine-1-phosphate (S1P).
What makes this entry worth having is where the lesion sits. Most curated cochlear
entities fail inside the hair cell - in the stereocilia bundle, in transduction, or at the
ribbon synapse. SPNS2 does not. The mouse work that identified the gene shows the earliest
measurable defect is a fall in the endocochlear potential, and locates the primary lesion
in the cochlear lateral wall rather than in the organ of Corti. Hair cell degeneration
follows, and the authors read it as secondary. So the pathograph runs from a lipid
transport failure, through the battery that drives mechanotransduction, to the sensory
cells - and the hair cell loss is a consequence rather than the start.
The provenance of that mechanism should be stated plainly, because almost all of it is
mouse. The human side of DFNB115 is two published probands: a child from a United States
clinic who is compound heterozygous for a frameshift and an in-frame single-codon deletion
in SPNS2, and an eight-year-old Iranian girl compound heterozygous for a nonsense and a
missense allele. Nobody has measured an endocochlear potential in a person with DFNB115,
and no human cochlear tissue has been examined. The entry therefore grades the strial and
endocochlear-potential nodes as MODEL_ORGANISM evidence and says so at each node.
One mouse result has no human counterpart and is the reason this entity is interesting
therapeutically rather than only descriptively. Reactivating Spns2 transcription in mice
that had already lost hearing brought auditory brainstem response thresholds back to close
to normal at low and mid frequencies, and protected hair cells from the secondary
degeneration - but only if done early enough. That is a demonstration that this class of
hearing loss is reversible in principle, and a critical-window claim that nothing in the
human literature can yet confirm or refute. It is curated as an animal-model rescue and as
an open discussion, not as a treatment.
OMIM flags the SPNS2 gene-phenotype relationship as provisional, which is recorded here
rather than smoothed over: NCBI mim2gene_medgen carries the `question` comment on
OMIM:618457, the marker for an OMIM gene-map phenotype entered with a leading question
mark. Two unrelated probands with biallelic damaging alleles, a concordant mouse mutant,
and a structural study showing that pathogenic substitutions abolish transport is a
reasonable body of evidence, but it is not the multi-family segregation a definitive call
would need.
disease_term:
preferred_term: autosomal recessive nonsyndromic hearing loss 115
term:
id: MONDO:0032762
label: hearing loss, autosomal recessive 115
parents:
- Autosomal Recessive Nonsyndromic Hearing Loss
references:
- reference: PMID:30973865
title: "Mouse screen reveals multiple new genes underlying mouse and human hearing loss."
- reference: PMID:36494063
title: "Compound heterozygous variants in SPNS2 cause sensorineural hearing loss."
- reference: PMID:25356849
title: "Spinster homolog 2 (spns2) deficiency causes early onset progressive hearing loss."
- reference: PMID:37552762
title: "Reversal of an existing hearing loss by gene activation in Spns2 mutant mice."
- reference: PMID:39820269
title: "Transport and inhibition of the sphingosine-1-phosphate exporter SPNS2."
- reference: PMID:32996353
title: "Whole exome sequencing identifies rare coding variants in novel human-mouse ortholog genes in African individuals diagnosed with non-syndromic hearing impairment."
inheritance:
- name: Autosomal recessive
description: >-
Both published probands carry two damaged SPNS2 alleles in trans. In the United States
family the frameshift allele came from the father and the in-frame codon deletion from
the mother, so phase is established by parental transmission rather than inferred. In
the Iranian family compound heterozygosity was confirmed by Sanger sequencing. Neither
report describes an affected heterozygous parent.
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
evidence:
- reference: PMID:36494063
reference_title: "Compound heterozygous variants in SPNS2 cause sensorineural hearing loss."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Sanger sequencing confirmed that the variants are compound heterozygote."
explanation: >-
The configuration of the two alleles in the second reported proband, established by
sequencing rather than by assumption.
- reference: PMID:30973865
reference_title: "Mouse screen reveals multiple new genes underlying mouse and human hearing loss."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: "and an in-frame deletion of a serine codon in SPNS2 from her mother (c.955_957delTCC: p.Ser319del; CADD phred score 20.9)"
explanation: >-
The maternally transmitted allele in the first proband, named with its parent of origin.
Together with the paternal frameshift quoted under diagnosis, this is what establishes
phase by transmission rather than by inference.
pathophysiology:
- name: SPNS2 Biallelic Loss of Function
biological_scale: MOLECULAR
description: >-
Two damaged copies of SPNS2, which encodes a major facilitator superfamily transporter
that exports sphingosine-1-phosphate across the plasma membrane. The four reported human
alleles span two mutation classes: truncating changes that should abolish the protein
(a frameshift, p.Pro356Cysfs, and a nonsense allele, p.Trp302Ter) and in-frame changes
that leave a full-length protein (a single-codon deletion, p.Ser319del, and a missense
substitution, p.Asp163Asn). No patient allele has been assayed for transport activity;
what exists is a structural study of the transporter showing how pathogenic
substitutions abolish export, which is an argument about the mechanism class rather than
about these four alleles.
genes:
- preferred_term: SPNS2
term:
id: hgnc:26992
label: SPNS2
genetic_context:
genes:
- preferred_term: SPNS2
term:
id: hgnc:26992
label: SPNS2
allele_type: frameshift, nonsense, in-frame single-codon deletion and missense variants
variant_origin: GERMLINE
zygosity: COMPOUND_HETEROZYGOUS
functional_impact_category: LOSS_OF_FUNCTION
description: >-
Both published probands are compound heterozygous; no homozygous family has been
reported, which is unusual for a DFNB entity and is why the zygosity slot carries a
single unambiguous value.
notes: >-
LOSS_OF_FUNCTION is used for the block because FunctionalImpactEnum defines it as a
complete or partial reduction of normal gene product function, which covers the
truncating and the in-frame alleles alike. How much of that is measured differs by
allele and should not be flattened: for the truncating alleles loss is predicted, not
demonstrated, and for p.Ser319del and p.Asp163Asn the published support is in silico
prediction plus absence from population databases. The transport-ablating effect of
pathogenic SPNS2 substitutions has been shown structurally and in export assays, but
for other residues.
evidence:
- reference: PMID:36494063
reference_title: "Compound heterozygous variants in SPNS2 cause sensorineural hearing loss."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we identified two novel damaging variants of c.906G>A; p.(Trp302*) and c.487G>A; p.(Asp163Asn) in the SPNS2 gene in an eight-year-old female with bilateral sensorineural hearing loss"
explanation: The two alleles and the phenotype in the second reported proband.
- reference: PMID:36494063
reference_title: "Compound heterozygous variants in SPNS2 cause sensorineural hearing loss."
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: "in silico analysis by various tools predicted that these variants are damaging"
explanation: >-
The nature of the functional support for those two alleles. Graded COMPUTATIONAL
because prediction is what the quoted sentence describes; no assay was performed.
- reference: PMID:39820269
reference_title: "Transport and inhibition of the sphingosine-1-phosphate exporter SPNS2."
supports: SUPPORT
directness: INDIRECT
evidence_source: IN_VITRO
snippet: "we identify how pathogenic mutations ablate the protein's export activity and thereby lead to hearing loss"
explanation: >-
The structural and transport-assay demonstration that pathogenic SPNS2 substitutions
abolish export activity. Marked INDIRECT because the residues tested are not the four
alleles reported in DFNB115 patients, so this supports the mechanism class rather than
these specific variants.
downstream:
- target: Failure of Sphingosine-1-Phosphate Export
causal_link_type: DIRECT
- name: Failure of Sphingosine-1-Phosphate Export
biological_scale: MOLECULAR
description: >-
Sphingosine-1-phosphate is made inside the cell by the sphingosine kinases and has to be
exported to reach its G-protein-coupled receptors on the outside. SPNS2 is one of a
small set of plasma-membrane exporters that perform that step and is the principal one
in several tissues. Losing it leaves S1P stranded intracellularly, so downstream S1P
receptor signalling in the tissues that depend on SPNS2 for their local supply is lost
without S1P synthesis being touched.
molecular_functions:
- preferred_term: sphingosine-1-phosphate export across the plasma membrane
modifier: DECREASED
term:
id: GO:0046624
label: sphingolipid intramembrane carrier activity
biological_processes:
- preferred_term: sphingosine-1-phosphate receptor signaling pathway
modifier: DECREASED
term:
id: GO:0003376
label: sphingosine-1-phosphate receptor signaling pathway
- preferred_term: lipid transport
modifier: DECREASED
term:
id: GO:0006869
label: lipid transport
evidence:
- reference: PMID:25356849
reference_title: "Spinster homolog 2 (spns2) deficiency causes early onset progressive hearing loss."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: BACKGROUND
snippet: "Spinster homolog 2 (Spns2) acts as a Sphingosine-1-phosphate (S1P) transporter in zebrafish and mice, regulating heart development and lymphocyte trafficking respectively."
explanation: >-
The molecular identity of the gene product. Marked BACKGROUND because this is the
framing sentence of the paper rather than its own result, and MODEL_ORGANISM because
the transport role it states was established in zebrafish and mice.
- reference: PMID:39820269
reference_title: "Transport and inhibition of the sphingosine-1-phosphate exporter SPNS2."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Sphingosine-1-phosphate (S1P) is a signaling lysolipid critical to heart development, immunity, and hearing."
explanation: >-
That the exported lipid is itself the signalling molecule, and that hearing is one of
the processes it is required for.
downstream:
- target: Stria Vascularis Disorganization
causal_link_type: DIRECT
description: >-
Conditional ablation of Spns2 in the cochlea reproduces the auditory phenotype while
ablation in blood, platelets or endothelium does not, which places the relevant S1P
supply locally in the ear rather than in the circulation.
evidence:
- reference: PMID:25356849
reference_title: "Spinster homolog 2 (spns2) deficiency causes early onset progressive hearing loss."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Targeted inactivation of Spns2 in red blood cells, platelets, or lymphatic or vascular endothelial cells did not affect hearing, but targeted ablation of Spns2 in the cochlea using a Sox10-Cre allele produced a similar auditory phenotype to the original mutation, suggesting that local Spns2 expression is critical for hearing in mammals."
explanation: >-
The tissue-of-action experiment. Four cell-type-specific knockouts leave hearing
intact and the cochlear one does not, which is what makes this a local lesion rather
than a consequence of the systemic S1P defect.
- name: Stria Vascularis Disorganization
biological_scale: TISSUE
description: >-
The stria vascularis is the vascularised epithelium of the cochlear lateral wall that
generates the endocochlear potential. In Spns2 mutant mice the lateral wall shows
structural change at the marginal cell boundaries and in the strial capillaries. The
barrier itself is not leaky: permeability of the strial boundaries and capillaries was
normal, so this is a structural and functional derangement of the epithelium rather than
a breakdown of the blood-labyrinth barrier.
Nothing equivalent has been examined in a person with DFNB115. This node is
model-organism inference.
locations:
- preferred_term: stria vascularis of the cochlear duct
term:
id: UBERON:0002282
label: stria vascularis of cochlear duct
cell_types:
- preferred_term: strial marginal cell
term:
id: CL:0002492
label: strial marginal cell
evidence:
- reference: PMID:25356849
reference_title: "Spinster homolog 2 (spns2) deficiency causes early onset progressive hearing loss."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In the lateral wall of adult mutants, we observed structural changes of marginal cell boundaries and of strial capillaries"
explanation: The structural lesion in the lateral wall, and the two components it affects.
- reference: PMID:25356849
reference_title: "Spinster homolog 2 (spns2) deficiency causes early onset progressive hearing loss."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Permeability of the boundaries of the stria vascularis and of the strial capillaries appeared normal."
explanation: >-
The negative result that constrains the mechanism: the barrier is intact, so the
endocochlear potential is not lost through leakage.
- reference: PMID:39820269
reference_title: "Transport and inhibition of the sphingosine-1-phosphate exporter SPNS2."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: BACKGROUND
snippet: "loss of SPNS2 function leads to hearing defects in humans and mice due to disorganization of the stria vascularis and loss of the endocochlear potential"
explanation: >-
An independent group stating the accepted mechanism in one sentence. The two findings
this node needs from it - strial disorganization and loss of the endocochlear potential -
are the mouse half of that sentence, so evidence_source grades the quoted evidence as
MODEL_ORGANISM. quote_role BACKGROUND records that the citing paper is a primary
structural study restating other groups' in vivo work in its introduction, not the place
the finding came from.
downstream:
- target: Endocochlear Potential Collapse
causal_link_type: DIRECT
- target: Reduced Expression of Strial Ion-Transport Proteins
causal_link_type: DIRECT
- name: Reduced Expression of Strial Ion-Transport Proteins
biological_scale: MOLECULAR
description: >-
Kcnj10, Kcnq1, Gjb2 and Gjb6 - the potassium channel and gap junction proteins that
generate and recycle the endolymphatic potassium current - are expressed at reduced
levels in the lateral wall of adult Spns2 mutants. This node is drawn as a consequence
of the strial lesion and not as a cause of the endocochlear potential loss, because the
authors judge the change secondary and because it was measured in adults, after the
potential had already fallen at two to three weeks. It is curated at all because three
of these four genes are themselves causes of nonsyndromic deafness, so the convergence
is worth recording.
biological_processes:
- preferred_term: potassium ion transmembrane transport in the cochlear lateral wall
modifier: DECREASED
term:
id: GO:0071805
label: potassium ion transmembrane transport
evidence:
- reference: PMID:25356849
reference_title: "Spinster homolog 2 (spns2) deficiency causes early onset progressive hearing loss."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "reduced expression of several key proteins involved in the generation of the EP (Kcnj10, Kcnq1, Gjb2 and Gjb6), but these changes were likely to be secondary"
explanation: >-
The measured expression change together with the authors' own reading of its causal
position, which is why this node has no downstream edge to the endocochlear potential.
- name: Endocochlear Potential Collapse
biological_scale: TISSUE
description: >-
The endocochlear potential is the standing positive voltage of the endolymph that
supplies most of the driving force for mechanotransduction current through the hair
cells. In Spns2 mutant mice it falls between two and three weeks of age, in parallel
with auditory sensitivity, and it is the earliest defect found - earlier than any change
in the organ of Corti. That ordering is the load-bearing observation in this entry: it
is what makes the lateral wall the primary lesion and the hair cells a downstream
casualty.
biological_processes:
- preferred_term: sensory perception of sound
modifier: DECREASED
term:
id: GO:0007605
label: sensory perception of sound
evidence:
- reference: PMID:25356849
reference_title: "Spinster homolog 2 (spns2) deficiency causes early onset progressive hearing loss."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Spns2-deficient mice rapidly lost auditory sensitivity and endocochlear potential (EP) from 2 to 3 weeks old"
explanation: The loss itself and the age at which it happens.
- reference: PMID:25356849
reference_title: "Spinster homolog 2 (spns2) deficiency causes early onset progressive hearing loss."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "the earliest defect was a decline in the EP, suggesting that dysfunction of the lateral wall was the primary lesion"
explanation: >-
The temporal ordering that assigns the primary lesion to the lateral wall rather than
to the organ of Corti.
- reference: PMID:25356849
reference_title: "Spinster homolog 2 (spns2) deficiency causes early onset progressive hearing loss."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "These findings indicate that Spns2 is required for normal maintenance of the EP and hence for normal auditory function, and support a role for S1P signalling in hearing."
explanation: The conclusion the paper draws, which is the whole chain in one sentence.
downstream:
- target: Progressive Sensory Hair Cell Degeneration
causal_link_type: DIRECT
- target: Bilateral Sensorineural Hearing Impairment
causal_link_type: DIRECT
- target: Childhood Onset of Hearing Impairment
causal_link_type: DIRECT
- name: Progressive Sensory Hair Cell Degeneration
biological_scale: CELLULAR
description: >-
Sensory hair cells in the organ of Corti degenerate progressively in Spns2 mutants. The
evidence that this is secondary rather than primary is twofold: it is not the earliest
defect, and restoring Spns2 expression early enough protects the hair cells, which a
cell-autonomous hair cell lesion would not permit.
cell_types:
- preferred_term: cochlear outer hair cell
term:
id: CL:0000601
label: cochlear outer hair cell
- preferred_term: cochlear inner hair cell
term:
id: CL:0000589
label: cochlear inner hair cell
biological_processes:
- preferred_term: death of cochlear hair cells
modifier: INCREASED
term:
id: GO:0008219
label: cell death
notes: >-
The process was originally bound to GO:1905584 outer hair cell apoptotic process, which
asserted more than the source does in two directions at once. The only evidence here is
that hair cells degenerate; neither cited paper measures apoptosis, and the cached text of
PMID:25356849 contains no mention of apoptosis, TUNEL or caspase. The node also covers
inner as well as outer hair cells, so an outer-hair-cell-specific term was narrower than
the claim on the cell-type axis too. GO:0008219 cell death says what is observed - hair
cells are lost - without naming a death programme nobody has established.
evidence:
- reference: PMID:25356849
reference_title: "Spinster homolog 2 (spns2) deficiency causes early onset progressive hearing loss."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "We found progressive degeneration of sensory hair cells in the organ of Corti, but the earliest defect was a decline in the EP"
explanation: >-
Both halves of the claim in one sentence: the degeneration happens, and it is not what
starts the disease.
- reference: PMID:37552762
reference_title: "Reversal of an existing hearing loss by gene activation in Spns2 mutant mice."
supports: SUPPORT
directness: INDIRECT
evidence_source: MODEL_ORGANISM
snippet: "Early activation of Spns2 not only led to improvement in auditory function but also to protection of sensory hair cells from secondary degeneration."
explanation: >-
A rescue result cited as evidence for the causal ordering. INDIRECT because the claim
that degeneration is secondary follows from the rescue rather than being asserted by a
measurement of the degeneration itself. Note the authors use the word secondary.
downstream:
- target: Bilateral Sensorineural Hearing Impairment
causal_link_type: DIRECT
- target: Severe Hearing Impairment
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
phenotypes:
- name: Bilateral Sensorineural Hearing Impairment
category: Ear
description: >-
The defining feature, and in both reported probands the only one attributed to SPNS2.
Loss is bilateral and sensorineural; in the first proband bone conduction testing was
used to establish that it is sensorineural rather than conductive, and acoustic reflexes
were absent.
frequency: OBLIGATE
phenotype_term:
preferred_term: Bilateral sensorineural hearing impairment
term:
id: HP:0008619
label: Bilateral sensorineural hearing impairment
onset:
onset_category: CHILDHOOD
notes: >-
Both probands were impaired when first formally tested, at two and at eight years.
Neither report establishes whether the loss was present at birth, so CHILDHOOD rather
than CONGENITAL. This duplicates the separate Childhood Onset of Hearing Impairment
phenotype on purpose: the descriptor slot is the queryable form, and the phenotype is
kept because it is what carries the onset evidence and the causal edge.
notes: >-
OBLIGATE with a denominator of two probands. A nonsyndromic deafness entity is
ascertained through its hearing loss, so no unaffected biallelic carrier could have been
reported and the band carries no information about penetrance.
evidence:
- reference: PMID:36494063
reference_title: "Compound heterozygous variants in SPNS2 cause sensorineural hearing loss."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "an eight-year-old female with bilateral sensorineural hearing loss"
explanation: The phenotype and its laterality in the second proband.
- reference: PMID:30973865
reference_title: "Mouse screen reveals multiple new genes underlying mouse and human hearing loss."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: "Bone conduction testing indicated moderate-severe hearing loss at 2 kHz in the right ear, suggesting a sensorineural (not conductive) impairment, and acoustic reflexes were absent."
explanation: >-
The audiological argument that the loss in the first proband is sensorineural, which is
what distinguishes this from a conductive phenotype.
- name: Childhood Onset of Hearing Impairment
category: Ear
description: >-
Hearing loss is present in early childhood. The first proband was tested by visual
reinforcement audiometry at two years of age and was already impaired; the second was
reported at eight years. Neither report establishes whether the loss was present at
birth, so this is curated as childhood onset rather than congenital onset.
frequency: OBLIGATE
phenotype_term:
preferred_term: Childhood onset sensorineural hearing impairment
term:
id: HP:0011474
label: Childhood onset sensorineural hearing impairment
notes: >-
Denominator two probands. The distinction from congenital onset is deliberate and is a
real gap rather than a hedge: no newborn hearing screening result is reported for either
patient, and the mouse mutant hears normally at the onset of hearing and then
deteriorates over the following week, which would be consistent with a postnatal onset in
humans too.
evidence:
- reference: PMID:30973865
reference_title: "Mouse screen reveals multiple new genes underlying mouse and human hearing loss."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: "Visual reinforcement audiometry at two years old revealed moderate to moderately severe hearing loss between 250 Hz and 4 kHz with no response at 8 kHz in the right ear"
explanation: >-
The age at which the first proband was documented as impaired, and the audiogram at that
assessment.
- reference: PMID:30973865
reference_title: "Mouse screen reveals multiple new genes underlying mouse and human hearing loss."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Several of the genes were associated with the range of hearing thresholds in the human population and one, SPNS2, was involved in childhood deafness."
explanation: >-
The paper's own summary of the human finding, which is also the sentence OMIM cites in
designating DFNB115.
- name: Severe Hearing Impairment
category: Ear
description: >-
Severity reaches the severe range. In the first proband the left ear showed severe
hearing loss sloping to profound deafness from 500 Hz to 8 kHz, while the right ear was
moderate to moderately severe - so the loss is bilateral but markedly asymmetric. OMIM
characterises the entity as severe on the strength of that report.
frequency: FREQUENT
phenotype_term:
preferred_term: Severe sensorineural hearing impairment
term:
id: HP:0008625
label: Severe sensorineural hearing impairment
notes: >-
FREQUENT, one of two probands. The severity of the second proband is not stated beyond
bilateral sensorineural hearing loss, so the denominator for a severity band is really
one informative case and the band should not be read as a population estimate.
evidence:
- reference: PMID:30973865
reference_title: "Mouse screen reveals multiple new genes underlying mouse and human hearing loss."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: "and severe hearing loss sloping to profound deafness from 500 Hz to 8 kHz with no response at 4 and 8 kHz in the left ear"
explanation: >-
The severity and audiometric configuration in the more affected ear of the first
proband.
- reference: PMID:30973865
reference_title: "Mouse screen reveals multiple new genes underlying mouse and human hearing loss."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "The severe level of hearing impairment associated with predicted damaging SPNS2 variants is similar to our findings in the mouse Spns2 mutant"
explanation: >-
The authors' comparison of human severity with the mouse mutant. Marked INDIRECT because
it supports the severity claim by concordance with the animal model rather than by
measuring a further patient.
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
No prevalence estimate exists. Two unrelated probands have been published, one from a
United States clinic and one from Iran, in two papers seven years apart. No rate is given
because none has been reported.
One real denominator exists and is worth recording as a ceiling rather than a rate. A
South African and Cameroonian study screened 25 patients with nonsyndromic hearing
impairment, plus 40 exomes, specifically for the two SPNS2 alleles reported in the first
proband, and found neither. That is evidence those particular alleles are not a recurring
cause in those populations, not evidence about SPNS2 overall; the same study found one
novel heterozygous SPNS2 missense variant in a Cameroonian patient.
evidence:
- reference: PMID:32996353
reference_title: "Whole exome sequencing identifies rare coding variants in novel human-mouse ortholog genes in African individuals diagnosed with non-syndromic hearing impairment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The previously reported SPNS2 deletion mutations (c.1066_1067delCCinsT) and SPNS2 (c.955_957delTCC) were not identified in the WES data, neither were they found in the 25 NSHI patients, nor in the 26 matched controls that were Sanger sequenced."
explanation: >-
The one targeted screening denominator in the literature, and its negative result for
the two alleles reported in the index proband.
- reference: PMID:32996353
reference_title: "Whole exome sequencing identifies rare coding variants in novel human-mouse ortholog genes in African individuals diagnosed with non-syndromic hearing impairment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "One novel variant, SPNS2, c867C>A p.(Pro289Gln), was found in heterozygous state, in one Cameroonian patient."
explanation: >-
The single SPNS2 finding in that cohort. Heterozygous and therefore not a recessive
diagnosis, which is why it is recorded as ascertainment context and not as a third case.
progression:
- phase: Early childhood
notes: >-
Impairment is established by the time hearing is first formally tested in the reported
patients - two years in the first proband, eight in the second. Whether it was present at
birth is not known for either.
evidence:
- reference: PMID:30973865
reference_title: "Mouse screen reveals multiple new genes underlying mouse and human hearing loss."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: "Visual reinforcement audiometry at two years old revealed moderate to moderately severe hearing loss between 250 Hz and 4 kHz with no response at 8 kHz in the right ear"
explanation: The earliest documented audiological assessment in either proband.
- phase: Later course
notes: >-
Nothing is published. Neither proband has been followed longitudinally, so whether human
DFNB115 progresses is unknown. This is deliberately not filled in from the mouse, which
loses hearing rapidly between two and three weeks of age and then remains impaired; that
time course belongs to the animal model section, and reporting it here would present a
mouse result as a human natural history.
genetic:
- name: SPNS2
relationship_type: CAUSATIVE
variant_origin: GERMLINE
gene_term:
preferred_term: SPNS2
term:
id: hgnc:26992
label: SPNS2
features: >-
SPNS2 at 17p13.2 encodes the sphingosine-1-phosphate exporter. Four biallelic alleles
have been reported across two probands: c.1066_1067delCCinsT p.(Pro356Cysfs) and
c.955_957delTCC p.(Ser319del) in the first, and c.906G>A p.(Trp302Ter) and c.487G>A
p.(Asp163Asn) in the second. None was present in gnomAD or other public databases at the
time of reporting.
notes: >-
OMIM records the gene-phenotype relationship as provisional. NCBI mim2gene_medgen maps
OMIM:618457 to GeneID 124976 with source GeneMap and the comment `question`, which is the
marker for an OMIM gene-map phenotype carrying a leading question mark. This is recorded
because it changes how the entry should be read, not because the assignment looks wrong:
two unrelated probands, a concordant mouse mutant with a defined cochlear mechanism, and
a structural study of transport-ablating substitutions are a coherent case, but they are
not multi-family segregation.
evidence:
- reference: PMID:36494063
reference_title: "Compound heterozygous variants in SPNS2 cause sensorineural hearing loss."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "To date, these detected variants have not been reported in any of the existing public databases."
explanation: >-
Population-database absence for the two alleles in the second proband, which is part of
the pathogenicity argument in the absence of a functional assay.
- reference: PMID:36494063
reference_title: "Compound heterozygous variants in SPNS2 cause sensorineural hearing loss."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "SPNS2 is one of these genes that has been attributed to deafness in recent years."
explanation: >-
The state of the gene-disease claim as the authors describe it. BACKGROUND because it
restates the prior literature rather than reporting this paper's own finding, and the
hedged phrasing is itself informative about how settled the association was.
diagnosis:
- name: SPNS2 sequencing in unexplained childhood bilateral sensorineural hearing loss
description: >-
Both probands were found by exome sequencing performed for undiagnosed hearing loss, not
by a targeted test - in the first case through a clinical exome that was then matched
against a mouse screen result. The practical consequence is that SPNS2 belongs on
hearing-loss gene panels, and that a recessive exome reported as negative before 2019
does not exclude this diagnosis.
evidence:
- reference: PMID:30973865
reference_title: "Mouse screen reveals multiple new genes underlying mouse and human hearing loss."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
snippet: "The hearing-impaired child was ascertained through the Kaiser Permanente clinic, testing was performed at Ambry Genetics, and the mutations were identified in SPNS2 by sequencing of candidate genes as part of clinical whole exome analysis."
explanation: >-
The route to diagnosis in the index proband: a clinical exome ordered for undiagnosed
hearing loss, with SPNS2 read out of it as a candidate gene rather than tested for
directly.
- reference: PMID:32996353
reference_title: "Whole exome sequencing identifies rare coding variants in novel human-mouse ortholog genes in African individuals diagnosed with non-syndromic hearing impairment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we used the Sanger sequencing technique to screen for the two deletion mutations (c.1066_1067delCCinsT and c.955_957delTCC) associated with childhood HI in the SPNS2 human-mouse ortholog genes previously reported."
explanation: >-
The one published example of targeted SPNS2 testing, showing what a directed screen for
the known alleles looks like and, by its negative result, why panel-wide sequencing is
the right approach rather than allele-specific testing.
treatments:
- name: Genetic Counselling and Cascade Testing
description: >-
Counselling for a recessive condition with a 25 percent sibling recurrence risk. Both
probands are compound heterozygous rather than homozygous, and in the first the two
alleles were shown to come one from each parent, so carrier testing of parents and
siblings is informative in a way that a homozygous consanguineous pedigree does not
require. Counselling does not act on the mechanism; it is curated because it is the only
intervention the genotype itself indicates.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: genetic counseling
term:
id: NCIT:C15240
label: Genetic Counseling
evidence:
- reference: PMID:36494063
reference_title: "Compound heterozygous variants in SPNS2 cause sensorineural hearing loss."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Sanger sequencing confirmed that the variants are compound heterozygote."
explanation: >-
The segregation result that carrier testing and recurrence counselling act on.
notes: >-
No treatment of any kind is reported for either published proband - not a hearing aid,
not a cochlear implant, not audiological follow-up beyond the diagnostic assessment. This
entry therefore curates no amplification or implantation treatment. Both are standard
care for childhood sensorineural hearing loss and would look right here, and one proband
reaches the severe-to-profound range in one ear where implantation is normally
considered; but attributing either to these patients would be importing an indication
recorded only in other people. Spns2 gene reactivation, which does act on the mechanism,
is curated under animal_models rather than here, because it has been done only in mice.
animal_models:
- name: Spns2 knockout mouse
species: Mouse
genotype: Spns2 tm1a and related null alleles, homozygous
publication: PMID:25356849
description: >-
The model in which the whole cochlear mechanism was worked out. Homozygotes lose auditory
sensitivity and endocochlear potential between two and three weeks of age, show lateral
wall structural change and secondary hair cell degeneration, and are rescued by cochlear
but not by haematopoietic or endothelial Spns2 expression.
modeled_mechanisms:
- target: Endocochlear Potential Collapse
relationship: RECAPITULATES
fidelity: HIGH
model_scale: TISSUE
description: >-
The endocochlear potential is measured directly in this model, at the scale the node
describes.
limitations: >-
No endocochlear potential has ever been measured in a person with DFNB115, so the
human counterpart of this node is unverified. Mouse alleles are engineered nulls while
both human probands are compound heterozygous, one allele of each being in-frame.
readouts:
- name: Endocochlear potential
target: Endocochlear Potential Collapse
direction: DECREASED
interpretation: The direct measurement of the node.
evidence:
- reference: PMID:25356849
reference_title: "Spinster homolog 2 (spns2) deficiency causes early onset progressive hearing loss."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Spns2-deficient mice rapidly lost auditory sensitivity and endocochlear potential (EP) from 2 to 3 weeks old"
explanation: The measurement and its direction.
evidence:
- reference: PMID:25356849
reference_title: "Spinster homolog 2 (spns2) deficiency causes early onset progressive hearing loss."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "the earliest defect was a decline in the EP, suggesting that dysfunction of the lateral wall was the primary lesion"
explanation: >-
Why this model is informative for this node specifically: it is where the ordering of
events was established.
- target: Stria Vascularis Disorganization
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: TISSUE
description: >-
Lateral wall histology and capillary structure are the model's direct observations.
limitations: >-
Fidelity is graded MODERATE rather than HIGH because the structural changes were
characterised in adult mutants, after the functional loss, and because no human
cochlear tissue exists to compare against.
evidence:
- reference: PMID:25356849
reference_title: "Spinster homolog 2 (spns2) deficiency causes early onset progressive hearing loss."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In the lateral wall of adult mutants, we observed structural changes of marginal cell boundaries and of strial capillaries"
explanation: The histological observation underlying this link.
- target: Progressive Sensory Hair Cell Degeneration
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: CELLULAR
description: Hair cell counts in the organ of Corti fall progressively in mutants.
limitations: >-
Hair cell loss has not been examined in a person with DFNB115 and cannot be, short of
post-mortem temporal bone study, so the human correspondence of this node is inferred
from the shared audiological phenotype alone.
evidence:
- reference: PMID:25356849
reference_title: "Spinster homolog 2 (spns2) deficiency causes early onset progressive hearing loss."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "We found progressive degeneration of sensory hair cells in the organ of Corti, but the earliest defect was a decline in the EP"
explanation: The degeneration, and its position in the sequence.
notes: >-
The mouse also shows focal retinal degeneration, retinal capillary anomalies and anterior
eye defects. That has no reported human counterpart - both probands are described as
having nonsyndromic hearing loss - and is recorded as a human-model mismatch in
discussions rather than as a phenotype of the disease.
- name: Spns2 reactivation mouse
species: Mouse
genotype: Spns2 tm1a conditional allele, transcription restored after onset of hearing loss
publication: PMID:37552762
description: >-
A rescue rather than a disease model. The tm1a allele is reverted at chosen ages after
hearing has already been lost, which asks whether the pathology is fixed or recoverable.
modeled_mechanisms:
- target: Endocochlear Potential Collapse
relationship: RESCUES
fidelity: HIGH
model_scale: ORGANISM
description: >-
Restoring Spns2 transcription after onset returns auditory brainstem response
thresholds to close to normal at low and mid frequencies, and the benefit shrinks the
longer restoration is delayed.
limitations: >-
The intervention is genetic reactivation of an engineered allele, not a deliverable
therapy, and recovery was partial - close to normal only at low to mid frequencies.
Nothing equivalent has been attempted in humans, so the existence of a human critical
window is a hypothesis rather than a finding.
readouts:
- name: Auditory brainstem response threshold
target: Endocochlear Potential Collapse
direction: RESTORED
interpretation: >-
The functional readout of the rescue, and the measure in which the critical window
appears.
evidence:
- reference: PMID:37552762
reference_title: "Reversal of an existing hearing loss by gene activation in Spns2 mutant mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "we found that an existing auditory impairment can be reversed to give close to normal thresholds for an auditory brainstem response (ABR), at least at low to mid stimulus frequencies"
explanation: The rescue result, with the frequency limitation the authors state.
- reference: PMID:37552762
reference_title: "Reversal of an existing hearing loss by gene activation in Spns2 mutant mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Delaying the activation of Spns2 led to less effective recovery of ABR thresholds, suggesting that there is a critical period for intervention."
explanation: The time-dependence of the rescue, which is the critical-window claim.
evidence:
- reference: PMID:37552762
reference_title: "Reversal of an existing hearing loss by gene activation in Spns2 mutant mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "one common form involves a failure to maintain the local ionic environment of the sensory hair cells reflected in a reduced endocochlear potential"
explanation: >-
The authors' statement of which pathology this model addresses, which is what makes
the rescue informative for this node.
discussions:
- discussion_id: dfnb115_eye_involvement_species_mismatch
kind: HUMAN_MODEL_MISMATCH
status: OPEN
prompt: >-
Does the eye involvement seen in Spns2 mutant mice have any counterpart in people with
biallelic SPNS2 variants, or is DFNB115 genuinely nonsyndromic?
attaches_to:
- phenotypes#
rationale: >-
Spns2 mutant mice have focal retinal degeneration, retinal capillary anomalies and
anterior eye defects alongside the hearing loss, and S1P signalling is required for
vascular maturation generally, so a retinal phenotype is mechanistically plausible rather
than incidental. Both human probands are nonetheless described as nonsyndromic. The
mismatch matters because it decides whether a person with DFNB115 should have
ophthalmological surveillance. Two readings are open and the reports cannot separate
them: humans may be genuinely spared, or the eye may not have been examined. Neither
publication states that a dilated fundus examination was performed, and neither states
that it was not.
proposed_experiments:
- experiment_id: dfnb115_ophthalmological_assessment
name: Ophthalmological assessment of reported and future SPNS2 biallelic patients
description: >-
Fundus photography, optical coherence tomography and fluorescein angiography in
individuals with biallelic SPNS2 variants, reported whether normal or abnormal.
readouts:
- name: Retinal structure on optical coherence tomography
target: disease#Autosomal Recessive Nonsyndromic Hearing Loss 115
interpretation: >-
Retinal thinning or capillary abnormality would make DFNB115 a syndromic entity and
change its surveillance; a normal result in several patients would establish a real
species difference in the tissue dependence on SPNS2.
- discussion_id: dfnb115_human_progression_and_critical_window
kind: KNOWLEDGE_GAP
status: OPEN
prompt: >-
Is the hearing loss of human DFNB115 progressive, and is there a human counterpart of the
critical window in which restoring SPNS2 rescues hearing in mice?
attaches_to:
- progression#Later course
- pathophysiology#Endocochlear Potential Collapse
rationale: >-
The mouse result is the strongest therapeutic claim in this entity: hearing already lost
can be recovered by restoring Spns2, and the recovery shrinks with delay. Whether that
translates depends on two unknowns on the human side. Neither published proband has
longitudinal audiometry, so it is not known whether human thresholds are stable or
deteriorating, and no cochlear implant or hearing aid outcome has been reported that
might indirectly indicate how much residual strial function remains. Without a human
natural history there is no way to identify who would be inside such a window.
proposed_experiments:
- experiment_id: dfnb115_longitudinal_audiometry
name: Longitudinal audiometry in a SPNS2 biallelic cohort
description: >-
Serial pure-tone and auditory brainstem response thresholds in identified SPNS2
biallelic patients over several years, with distortion-product otoacoustic emissions to
separate outer hair cell function from threshold.
readouts:
- name: Change in pure-tone average over time
target: phenotypes#Bilateral Sensorineural Hearing Impairment
direction: DECREASED
interpretation: >-
Stable thresholds would argue the human lesion completes early, which is a different
disease course from the mouse and would narrow any therapeutic window. Progressive
loss would argue there is ongoing strial failure to intervene against.
external_assertions:
- name: OMIM deafness, autosomal recessive 115 record
source: OMIM
assertion_type: disease_record
external_id: OMIM:618457
url: https://omim.org/entry/618457
description: >-
The OMIM phenotype record under which DFNB115 was designated, based on the SPNS2 proband
reported in the mouse screen paper. Recorded here rather than under mappings because the
DiseaseMappings class carries only ICD-10-CM, ICD-11, MONDO and NCIT slots. NCBI
mim2gene_medgen maps this MIM number to GeneID 124976 (SPNS2) with source GeneMap and the
comment `question`, marking the gene-phenotype relationship as provisional in OMIM.
evidence:
- reference: PMID:30973865
reference_title: "Mouse screen reveals multiple new genes underlying mouse and human hearing loss."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Several of the genes were associated with the range of hearing thresholds in the human population and one, SPNS2, was involved in childhood deafness."
explanation: >-
The human finding on which the OMIM designation rests, stated by the paper OMIM cites.
notes: >-
Scope decision: curated as a DISEASE. One gene, one proximal lesion - failure of S1P export
from the cochlear lateral wall - and one clinical picture. There are no member diseases to
unite and this is not a subtype of any curated entry. Its MONDO parent, MONDO:0019588
hearing loss, autosomal recessive, is an ontology grouping of dozens of unrelated DFNB loci
and is not a dismech entry. The stub is deleted by this change.
Identity resolution, since the stub and MONDO both record no causal gene: MONDO:0032762
cross-references OMIM:618457, and NCBI mim2gene_medgen maps OMIM:618457 to GeneID 124976,
which is SPNS2 at 17p13.2. That is the opposite outcome from the DFNB46 ruling in #11978,
where the same lookup returned GeneID `-` and the concept was placed out of scope as a
mapped locus. A search of `kb/` for SPNS2 and for DFNB115 before writing found no existing
coverage under any name.
Evidence balance worth stating explicitly: the clinical picture is human and the mechanism
is almost entirely mouse. Every pathophysiology node below the gene carries MODEL_ORGANISM
evidence, and the two nodes that are pure mouse inference - the strial lesion and the
endocochlear potential - say so in their own descriptions as well as in their evidence
grading. No human cochlear tissue, endocochlear potential measurement or hair cell count
exists for this entity.
The entry name uses the repository's Autosomal Recessive Nonsyndromic Hearing Loss NNN
convention, which the disease_term preferred_term follows. The bound MONDO label is
different - "hearing loss, autosomal recessive 115" - because that is what MONDO calls the
term and term labels are copied from the ontology, not composed. MONDO has no
"autosomal recessive nonsyndromic hearing loss 115" term.