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Inheritance

1

Autosomal recessive HP:0000007

Reported as homozygosity in consanguineous Tunisian and Moroccan families and as biallelic C-terminal alleles in the original DFNB31 kindreds.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:15841483 SUPPORT DIRECT Human Clinical

"in a consanguineous Tunisian family segregating congenital profound ARNSHL"

Recessive segregation of the DFNB31 locus in a consanguineous kindred.

PMID:37924449 SUPPORT DIRECT Human Clinical

"Exome sequencing in a consanguineous Moroccan patient with severe hearing loss identified a single homozygous mutation"

Independent homozygous WHRN variant in a second consanguineous family.

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Discussions and Knowledge Gaps

2

Whirlin-null mice have overt vestibular dysfunction and no published WHRN patient reports a vestibular deficit. Is human DFNB31 genuinely vestibular-sparing, or has vestibular function never been tested?

HUMAN MODEL MISMATCH dfnb31_vestibular_mouse_human_mismatch

Attached to

pathophysiology#Failure of Stereocilia Elongation and Bundle Organization

Whirlin is expressed in vestibular hair cells as well as cochlear ones, and the same stereocilia machinery builds both bundles, so a vestibular phenotype is what the mechanism predicts. The whirler mouse circles and head-bobs, and the mouse lacking both isoforms has profound deafness with vestibular dysfunction. Against that, the review summarising the published WHRN patients records that none of them self-reported a vestibular deficit - which is a statement about what patients volunteered, not about what testing showed. Whether DFNB31 spares the human vestibular system, or whether the deficit is present and compensated or simply unmeasured, changes what should be offered clinically: vestibular assessment and balance habilitation in a deaf child are not routine unless a deficit is suspected.

Proposed experiments

Formal vestibular testing of a DFNB31 cohort

exp_dfnb31_formal_vestibular_testing

Vestibular-evoked myogenic potentials, caloric testing and video head impulse testing in genotyped DFNB31 patients, with age-matched controls, rather than symptom questionnaires.

Would support

pathophysiology#Failure of Stereocilia Elongation and Bundle Organization

Would refute

pathophysiology#Failure of Stereocilia Elongation and Bundle Organization

Supporting outcome

Measurable vestibular hypofunction in DFNB31 patients would show that the murine phenotype translates and that the absence of self-reported symptoms reflects compensation rather than sparing.

Refuting outcome

Normal vestibular function on formal testing would establish a real cochlear-restricted phenotype in humans and make the mouse a poor model for this aspect of the disease.

Show evidence (3 references)

PMID:30831381 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"None of these aforementioned patients self-reported any vestibular deficits."

The human side of the mismatch, and the reason it is weak - self-report, not testing.

PMID:30831381 SUPPORT REVIEW SYNTHESIS Model Organism

"However, both Whrnneo and Whrnwi mice show similar severe to profound loss of linear vestibular evoked potential (VsEP) responses."

On objective testing both mouse alleles lose otolith responses, including the one without overt balance behaviour, so a deficit can be present where behaviour misses it. That is the case for formal testing rather than self-report in patients.

PMID:27117407 SUPPORT DIRECT Model Organism

"Lack of both isoforms causes abnormally short stereocilia and profound deafness and vestibular dysfunction."

The murine side of the mismatch.

Is the 5' / 3' positional rule - long-isoform-specific N-terminal alleles give Usher syndrome type 2D, C-terminal alleles give non-syndromic DFNB31 - actually a rule, or a pattern in a handful of families?

KNOWLEDGE GAP dfnb31_isoform_position_genotype_phenotype_rule

Attached to

genetic#WHRN variants

The rule is the entry's mechanistic account of why one gene gives two diseases, and it is doing real clinical work: it is what would decide whether a WHRN-positive deaf child is put under retinal surveillance. But it rests on two alleles in one German USH2 family set against the DFNB31 alleles known in 2007, and its authors stated it as a proposal. One later nonsyndromic report carries a homozygous missense change at residue 207, inside the long-isoform-specific region, without a reported retinal assessment. Until a genotype-stratified cohort with ophthalmological follow-up exists, the rule should not be used to withhold retinal surveillance.

Proposed experiments

Genotype-stratified retinal follow-up of WHRN-positive hearing loss

exp_dfnb31_genotype_stratified_retinal_followup

Assemble WHRN biallelic cases from hearing loss cohorts, classify alleles by whether they affect the long-isoform-specific exons, and follow retinal function longitudinally into the third decade.

Would support

genetic#WHRN variants

Would refute

genetic#WHRN variants

Supporting outcome

Retinitis pigmentosa confined to carriers of long-isoform-specific alleles would turn the proposal into a usable clinical rule.

Refuting outcome

Retinal degeneration in carriers of C-terminal alleles, or its absence in carriers of N-terminal ones, would show that isoform position does not determine the syndromic boundary.

Show evidence (1 reference)

PMID:17171570 SUPPORT INDIRECT Human Clinical

"We propose that mutations causing Usher syndrome are probably restricted to exons 1-6 that are specific for the long isoform and probably crucial for retinal function."

The proposal, in the authors' own hedged wording.

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Pathophysiology

4

Biallelic WHRN Loss of Function

Biallelic WHRN variants remove or truncate whirlin, a PDZ-domain scaffold with two N-terminal PDZ domains, a proline-rich region and a C-terminal PDZ. The gene has two major isoforms - a long form encoded by exons 1-13 and a short form from exons 6-13 lacking PDZ1 and PDZ2 - and the alleles reported in DFNB31 sit in the C-terminal half, so both isoforms lose their C-terminal PDZ. The first DFNB31 allele described is the exon 10 nonsense change R778X; a frameshift in exon 11, G808DfsX11, was reported next.

WHRN hgnc:16361

Genetic context variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Nonsense and frameshift alleles in the C-terminal half of the protein, reported homozygously in consanguineous families.

Downstream

Loss of Whirlin from the Stereocilia Tip Complex The truncated protein cannot serve as the tip scaffold; in the whirler mouse, which ablates both major isoforms, the tip pool is what is missing.

Show evidence (2 references)

PMID:12833159 SUPPORT DIRECT Human Clinical

"The gene encoding whirlin also underlies the human autosomal recessive deafness locus DFNB31."

Establishes WHRN as the DFNB31 gene in humans.

PMID:30831381 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The first WHRN mutation identified in DFNB31 patients is a cysteine to threonine substitution in exon 10, which changes the arginine codon to a stop codon (R778X)"

Names the founding DFNB31 allele and its position in the C-terminal half. Quoted from a review summarising the primary reports rather than from a primary report, hence REVIEW_SYNTHESIS.

Loss of Whirlin from the Stereocilia Tip Complex

Whirlin localizes to the tips of stereocilia, and its expression there is dynamic rather than static: it appears and fades out in an ordered sequence across the rows of the growing bundle, fading from inner hair cells before outer hair cells. At the tip the short isoform binds EPS8, and the pair are required together for normal length regulation. Losing whirlin therefore removes the scaffold that assembles the actin-regulatory machinery at the one place in the stereocilium where the actin core grows.

cochlear hair cell CL:0000202

stereocilium tip GO:0032426

Downstream

Failure of Stereocilia Elongation and Bundle Organization Without the tip scaffold the actin core is not elongated to its programmed length and the graded row heights are not established.

Show evidence (2 references)

PMID:15590699 SUPPORT DIRECT Model Organism

"We show that whirlin localizes at the tips of stereocilia."

Places whirlin at the stereocilium tip, which is where the lesion acts.

PMID:27117407 SUPPORT DIRECT Model Organism

"WHRN-S interacts with EPS8, and both are required at stereocilia tips for normal length regulation."

Identifies the tip complex whose loss produces the short-stereocilia phenotype.

Failure of Stereocilia Elongation and Bundle Organization

Hair bundles in whirlin-null mice are built from abnormally short stereocilia, in both inner and outer hair cells. The defect is in elongation and maintenance of the actin core and in the organization of the bundle, not in the presence of the stereocilia themselves. The isoforms divide the work: a mouse expressing the short isoform but not the long one keeps inner hair cell bundles close to normal and loses outer hair cell bundle morphology, organization and function, so the long isoform is doing something the short one does not - its localization midway along the shorter stereocilia coincides with the inter-stereociliary links.

cochlear hair cell CL:0000202

stereocilia elongation by actin polymerization GO:0030041 ↓ DECREASED auditory hair cell stereocilium organization GO:0060088 ⚠ ABNORMAL stereocilium maintenance GO:0120045 ↓ DECREASED

stereocilium bundle GO:0032421

Animal models

Whirler mouse (Whrn wi/wi) Mouse recapitulates Ultrastructural analysis of the organ of Corti in this mutant is the primary evidence that whirlin is required for stereocilia elongation and maintenance.

Whrn tm1b long-isoform-null mouse Mouse partially recapitulates Reproduces bundle disorganization, but only in outer hair cells, and with a milder auditory outcome than DFNB31.

AAV8-whirlin gene transfer in whirler mice Mouse rescues Restoring whirlin restores the bundle, which is the strongest available evidence that the bundle phenotype is a direct consequence of whirlin loss rather than a downstream or developmental side effect.

Downstream

Hair Bundle Mechanotransduction Failure A bundle of short, ungraded stereocilia cannot deflect and gate as a bundle of graded ones does, so sound no longer produces a normal receptor response.

Congenital Onset of Hearing Loss The bundle defect is developmental - the stereocilia never reach their programmed length - so the deficit is present from birth rather than acquired, which is how the one family with a reported onset is described.

Show evidence (4 references)

PMID:12833159 SUPPORT DIRECT Model Organism

"detailed ultrastructural analysis of sensory hair cells in the organ of Corti of the inner ear indicates that the whirler gene encodes a protein involved in the elongation and maintenance of stereocilia in both inner hair cells (IHCs) and outer hair cells (OHCs)"

Ultrastructural demonstration that the lesion is one of stereocilia elongation and maintenance.

PMID:12833159 SUPPORT INDIRECT Model Organism

"this novel PDZ domain-containing molecule acts as an organizer of submembranous molecular complexes that control the coordinated actin polymerization and membrane growth of stereocilia"

The authors' mechanistic account of how whirlin controls elongation. Graded INDIRECT because it is offered as a suggestion from the phenotype rather than a measurement.

PMID:27117407 SUPPORT DIRECT Model Organism

"Lack of both isoforms causes abnormally short stereocilia and profound deafness and vestibular dysfunction."

Links complete whirlin loss to short stereocilia and to profound deafness in the mouse.

+ 1 more reference

Hair Bundle Mechanotransduction Failure

With short, disordered bundles the hair cell cannot convert sound-induced deflection into a receptor potential, and the cochlea does not transmit. The transduction machinery itself is not the lesion in DFNB31 - the bundle architecture it depends on is - which is why the deficit is sensorineural and cochlear rather than retrocochlear.

cochlear hair cell CL:0000202

detection of mechanical stimulus involved in hearing GO:0050910 ↓ DECREASED

Downstream

Profound Sensorineural Hearing Impairment The clinical endpoint of the chain: a cochlear sensory deficit at the severe end of the range.

Show evidence (2 references)

PMID:27117407 SUPPORT INDIRECT Model Organism

"While the Whrnwi/wi mutant is profoundly deaf and exhibits circling and headbobbing behavior, we found that the Whrntm1b mutant shows only moderate to severe hearing loss"

Ties bundle state to auditory outcome across two mouse alleles. INDIRECT for the human claim because the measured outcome is murine auditory function.

PMID:30831381 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"USH2D patients have moderate sensorineural hearing loss and RP, while DFNB31 patients have profound sensorineural hearing loss and normal vision."

The human endpoint, and the contrast with the allelic syndromic disease.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

2

Profound Sensorineural Hearing Impairment Auditory HP:0011476

No frequency band is recorded. Profound hearing loss is the ascertainment criterion for every reported DFNB31 family, so any band computed from those reports would restate the inclusion criterion rather than measure penetrance.

Show evidence (2 references)

PMID:30831381 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"USH2D patients have moderate sensorineural hearing loss and RP, while DFNB31 patients have profound sensorineural hearing loss and normal vision."

States the DFNB31 auditory phenotype and its severity.

PMID:15841483 SUPPORT DIRECT Human Clinical

"in a consanguineous Tunisian family segregating congenital profound ARNSHL"

Primary report of congenital profound loss in a DFNB31-linked family.

Congenital Onset of Hearing Loss Auditory HP:0008527

Denominator is one family. No frequency band, for the same reason as the phenotype above.

Show evidence (1 reference)

PMID:15841483 SUPPORT DIRECT Human Clinical

"in a consanguineous Tunisian family segregating congenital profound ARNSHL"

The one report that states onset describes it as congenital.

🧬

Genetic Associations

1

WHRN variants (Causative)

Gene: WHRN hgnc:16361

Autosomal recessive

Show evidence (3 references)

PMID:17171570 SUPPORT DIRECT Human Clinical

"While mutations in the C-terminal half of whirlin have previously been reported in non-syndromic deafness (DFNB31), both alterations identified in our USH2 family affect the long protein isoform."

States the positional contrast between the DFNB31 and USH2D allele sets.

PMID:17171570 SUPPORT INDIRECT Human Clinical

"We propose that mutations causing Usher syndrome are probably restricted to exons 1-6 that are specific for the long isoform and probably crucial for retinal function."

The genotype-phenotype proposal itself. Graded INDIRECT because the authors offer it as a hypothesis from two alleles in one family plus the prior DFNB31 reports.

PMID:37924449 SUPPORT INDIRECT Human Clinical

"Exome sequencing in a consanguineous Moroccan patient with severe hearing loss identified a single homozygous mutation"

A homozygous WHRN variant at residue 207 - inside the region the positional rule assigns to Usher syndrome - reported in hearing loss. Recorded as a complication of that rule, and graded INDIRECT because the source does not report an ophthalmological assessment that would settle whether the case is syndromic.

💊

Medical Actions

2

Cochlear Implantation

Action: cochlear device implantation Ontology label: Surgical Procedure NCIT:C15329

Platform: Device

The standard intervention for congenital profound sensorineural hearing loss. The mechanism supports it in principle: the lesion is in the hair bundle, upstream of the spiral ganglion an implant stimulates, and no cochlear malformation is described in this disease. No outcome data exist for DFNB31 patients specifically.

Mechanism Target:

BYPASSES Hair Bundle Mechanotransduction Failure — Bypasses the failed transduction step by stimulating the auditory nerve directly.

Early Identification and Habilitation

Action: auditory habilitation Ontology label: Rehabilitation NCIT:C15315

Platform: Behavioral / lifestyle

Where the loss is congenital and profound, the modifiable outcome is spoken-language development and the modifier is how early it is identified and habilitated. Newborn hearing screening detects it.

📊

Prevalence

1

Tunisian families with autosomal recessive nonsyndromic hearing loss

Cases In Literature Not yet documented

No prevalence estimate exists. What is on record is a negative screen: after identifying the second DFNB31 family, the authors typed 62 further unrelated informative Tunisian ARNSHL families and found no linkage to the locus in any of them.

Show evidence (2 references)

PMID:15841483 SUPPORT DIRECT Human Clinical

"we performed linkage analysis in 62 unrelated informative families affected with ARNSHL. No linkage was found to this locus."

The negative linkage screen behind the rarity statement.

PMID:15841483 SUPPORT DIRECT Human Clinical

"we concluded that DFNB31/WHRN is most likely to be a rare cause of ARNSHL in the Tunisian population"

The authors' own rarity conclusion.

🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Autosomal Recessive Nonsyndromic Hearing Loss 31:

Usher syndrome type 2D

Overlapping Features The allelic syndromic disease, caused by variants in the same gene. It is the differential that matters here, because the distinction is not made on the audiogram alone: USH2D hearing loss is moderate rather than profound, and the discriminating feature is retinitis pigmentosa, which begins around the second decade. A child with WHRN-related hearing loss and a variant in the long-isoform-specific N terminus is therefore a candidate for retinal surveillance rather than a settled DFNB31 diagnosis.

Show evidence (2 references)

PMID:30831381 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"USH2D patients have moderate sensorineural hearing loss and RP, while DFNB31 patients have profound sensorineural hearing loss and normal vision."

The clinical discriminator between the two WHRN diseases.

PMID:17171570 SUPPORT DIRECT Human Clinical

"this is the first case of USH2 that is allelic to non-syndromic deafness"

Establishes that the two WHRN diseases are allelic, which is why this differential exists at all.

🐁

Animal Models

3

Whirler mouse (Whrn wi/wi)

The spontaneous mutant through which the gene was found. Whirler mice do not respond to sound and their inner and outer hair cells carry abnormally short stereocilia. Because the deletion removes both major isoforms, the model is the null end of the WHRN allelic series rather than a copy of any particular human allele.

Species

Mouse

Genotype

Whrn wi/wi - spontaneous deletion removing most of exons 6-10, ablating both major whirlin isoforms

Publication

PMID:12833159

Pathograph links

Failure of Stereocilia Elongation and Bundle Organization recapitulates fidelity: high observes: cellular Ultrastructural analysis of the organ of Corti in this mutant is the primary evidence that whirlin is required for stereocilia elongation and maintenance.

Limitations: The whirler deletion sits in the 3' region shared by both isoforms, which is where the human DFNB31 alleles fall, so it matches them in position; but it removes both isoforms outright rather than truncating them, so it may be more severe than the human lesion. The mutant also circles and head-bobs, a vestibular phenotype not reported in DFNB31 patients.

Readouts

Stereocilia length in inner and outer hair cells

Direction: DECREASED

Interpretation: Short stereocilia in both hair cell types is the structural correlate of this node.

Show evidence (1 reference)

PMID:12833159 SUPPORT Model Organism

"detailed ultrastructural analysis of sensory hair cells in the organ of Corti of the inner ear indicates that the whirler gene encodes a protein involved in the elongation and maintenance of stereocilia in both inner hair cells (IHCs) and outer hair cells (OHCs)"

The ultrastructural measurement behind this readout.

Show evidence (1 reference)

PMID:12833159 SUPPORT Model Organism

"The whirler mouse mutant (wi) does not respond to sound stimuli"

Establishes the model's auditory phenotype.

Whrn tm1b long-isoform-null mouse

The isoform-dissecting model. Retaining the short isoform alone leaves inner hair cell bundles close to normal, damages outer hair cell bundles, and produces moderate to severe rather than profound hearing loss with no overt vestibular dysfunction. It is the experimental basis for the proposal that isoform-specific loss explains the difference between DFNB31 and USH2D.

Species

Mouse

Genotype

Whrn tm1b(KOMP)Wtsi homozygote - exon 4 deleted, expresses WHRN-S but not WHRN-L

Publication

PMID:27117407

Pathograph links

Failure of Stereocilia Elongation and Bundle Organization partially recapitulates fidelity: moderate observes: cellular Reproduces bundle disorganization, but only in outer hair cells, and with a milder auditory outcome than DFNB31.

Limitations: This allele is the inverse of the human DFNB31 genotype: it removes the long isoform and spares the short one, whereas the reported DFNB31 alleles truncate the C terminus shared by both. It models the allelic contrast rather than the human disease.

Readouts

Outer hair cell bundle morphology and function

Direction: ALTERED

Interpretation: Isoform-restricted bundle damage, sparing inner hair cells.

Show evidence (1 reference)

PMID:27117407 SUPPORT Model Organism

"WHRN-S expression, however, is sufficient to maintain stereocilia bundle morphology and function in a subset of hair cells, resulting in some auditory response and no overt vestibular dysfunction."

The bundle and auditory readout in this allele.

AAV8-whirlin gene transfer in whirler mice

A rescue experiment rather than a disease model: delivering wild-type whirlin cDNA to neonatal whirler cochleas restored normal stereocilia length and bundle architecture in infected hair cells and increased inner hair cell survival relative to the untreated contralateral ear.

Species

Mouse

Genotype

Whrn wi/wi treated with AAV8 carrying wild-type whirlin cDNA by neonatal round-window injection

Publication

PMID:26307667

Pathograph links

Failure of Stereocilia Elongation and Bundle Organization rescues fidelity: moderate observes: cellular Restoring whirlin restores the bundle, which is the strongest available evidence that the bundle phenotype is a direct consequence of whirlin loss rather than a downstream or developmental side effect.

Limitations: Neonatal delivery in a mouse with a double-isoform-null allele. Round-window delivery partially lengthened inner but not outer hair cell stereocilia and did not restore hearing, so this experiment is a structural rescue without a functional one. That negative result is specific to the route: a later study delivering the same construct through the posterior semicircular canal reached more cochlear hair cells and partially improved both auditory and vestibular function. The claim that treating adult mice did not restore stereocilia comes from the deep-research report's reading of full text that could not be fetched and is not asserted here.

Readouts

Stereocilia length and bundle architecture after transduction

Direction: RESTORED

Interpretation: Structural rescue in transduced hair cells.

Show evidence (1 reference)

PMID:26307667 SUPPORT Model Organism

"whirlin expression was detected in infected hair cells (IHCs), and normal stereocilia length and bundle architecture were restored"

The structural rescue readout.

Hearing after round-window delivery

Direction: UNCHANGED

Interpretation: Hearing loss was not restored despite partial stereocilia lengthening in inner hair cells, so the structural rescue did not carry through to function by this route.

Show evidence (1 reference)

PMID:30831381 SUPPORT REVIEW SYNTHESIS Model Organism

"The cochlear round window delivery partially increases the stereocilia length in IHCs but not OHCs, and hearing loss in Whrnwi mice is not restored (Chien et al., 2015)."

The review's summary of the functional outcome of this experiment, which the primary paper's abstract does not report.

Show evidence (1 reference)

PMID:30831381 SUPPORT REVIEW SYNTHESIS Model Organism

"Posterior semicircular canal delivery of AAV-FL-whirlin was found to increase the stereociliary length in utricular hair cells as well as cochlear inner hair cells, and partially improve both the vestibular and auditory function of Whrnwi mice (Isgrig et al., 2017)."

A different delivery route partially restored function, so the round-window negative result reflects the route rather than a limit of whirlin replacement.

Show evidence (1 reference)

PMID:26307667 SUPPORT Model Organism

"Wild-type whirlin cDNA was delivered via adeno-associated virus (AAV8) by injection through the round window of the cochleas in neonatal whirler mice."

Describes the delivery route and construct.

{ }

Source YAML

click to show

name: Autosomal Recessive Nonsyndromic Hearing Loss 31
category: Mendelian
creation_date: "2026-09-16T00:00:00Z"
synonyms:
- DFNB31
- Deafness, autosomal recessive 31
- Autosomal recessive nonsyndromic deafness 31
- WHRN-associated nonsyndromic hearing loss
- Autosomal recessive nonsyndromic deafness caused by mutation in WHRN
description: >-
  DFNB31 is nonsyndromic sensorineural hearing loss caused by biallelic variants in WHRN,
  which encodes whirlin - a PDZ-domain scaffold protein at the tips of hair-cell stereocilia.
  It was identified through the whirler mouse, a spontaneous mutant that does not respond to
  sound and whose hair cells carry abnormally short stereocilia; transgene correction and
  mutation analysis identified whirlin, and the same gene was shown to underlie the human
  DFNB31 locus.

  The mechanism is a failure of stereocilia elongation and bundle organization rather than a
  defect in the mechanotransduction channel itself. Whirlin sits at the stereocilium tip, the
  site of actin polymerization, where it forms a complex with EPS8 that sets stereocilium
  length; its appearance and fade-out across the rows of a growing bundle is graded, and
  removing it leaves the bundle short and disordered. The transduction apparatus is not
  the lesion - the structure it needs is.

  What makes this entry more than a per-locus record is that the same gene also causes Usher
  syndrome type 2D, and the two are allelic. Clinically they are clearly different: DFNB31
  patients have profound hearing loss and normal vision, while USH2D patients have moderate
  hearing loss with retinitis pigmentosa. WHRN has two major isoforms, a long form encoded by
  exons 1-13 and a short form from exons 6-13 that lacks the N-terminal PDZ1 and PDZ2 domains.
  The reported human alleles line up with that split - the DFNB31 alleles fall in the
  C-terminal half, the USH2D alleles in the long-isoform-specific N terminus - and the
  proposal that mutations causing Usher syndrome are restricted to the long-isoform-specific
  exons is the mechanistic account of why one gene gives a syndromic and a non-syndromic
  disease. It remains a proposal drawn from a small number of clinical reports, not a
  validated rule, and at least one reported nonsyndromic case carries a missense variant
  inside the N-terminal region the rule would assign to Usher syndrome.

  DFNB31 is rare even among recessive nonsyndromic hearing loss. The Tunisian study that
  reported the second family screened 62 further unrelated ARNSHL families and found no
  linkage to the locus at all.
disease_term:
  preferred_term: autosomal recessive nonsyndromic hearing loss 31
  term:
    id: MONDO:0011767
    label: autosomal recessive nonsyndromic hearing loss 31
parents:
- Nonsyndromic Hearing Loss
notes: >-
  Identifiers. OMIM #607084 (DFNB31) is the OMIM key for this concept, and WHRN is
  hgnc:16361 at 9q32. They are recorded in prose because the schema's `mappings` block
  carries `mondo_mappings` only and has no slot for an OMIM identifier.

  Scope, and the entity next door. This entry is the non-syndromic disease only. WHRN also
  causes Usher syndrome type 2D, which is curated in `Usher_Syndrome.yaml` as a WHRN
  subtype; the allelic relationship between the two is curated here because it is what
  explains the DFNB31 phenotype, but USH2D itself is not re-curated. The other WHRN
  neighbour in the KB, `Autosomal_Recessive_Nonsyndromic_Hearing_Loss_48`, is a CIB2 entry
  that mentions whirlin only in mechanism prose and argues that CIB2's stereocilia role is
  not exercised through whirlin; it is not coverage of this disease.

  Evidence base and its shape. The human evidence for DFNB31 is thin, and worth stating
  plainly: the founding report (PMID:12833159) names the human locus but is largely a mouse
  paper, the second family (PMID:15841483) is one consanguineous Tunisian kindred, and a
  third (PMID:37924449) is one consanguineous Moroccan patient. The allele list this entry
  quotes - R778X in exon 10, G808DfsX11 in exon 11 - comes from a review (PMID:30831381)
  summarising those primary reports, and is graded `REVIEW_SYNTHESIS` accordingly. No
  frequency bands are recorded on the phenotypes, because with three reported families
  every band would be computed from an ascertainment criterion rather than from a cohort.

  Mechanism evidence is mouse and cell biology throughout, and is graded that way. Whirlin's
  tip localization and its dynamic gradation across stereocilia rows (PMID:15590699), the
  isoform-specific localization and the WHRN-S/EPS8 length-regulation complex
  (PMID:27117407), and the AAV8 rescue (PMID:26307667) are all mouse work. None of it is
  used as the sole support for a human phenotype.

  Two things this entry deliberately does not assert. First, it does not claim that DFNB31
  patients have been shown to have normal retinas by examination. The review states that
  DFNB31 patients have normal vision, and that is recorded as written, but no source read
  here reports a systematic ophthalmological assessment of a DFNB31 cohort. Second, it does
  not resolve vestibular involvement. The whirler mouse circles and head-bobs, and the
  double-isoform-null mouse has overt vestibular dysfunction, while the review records that
  none of the published WHRN patients self-reported a vestibular deficit - self-report, not
  testing. That disagreement is recorded as a HUMAN_MODEL_MISMATCH discussion rather than
  resolved.

  Bilaterality and progression are not curated. Neither "bilateral" nor a progression course
  is described for DFNB31 in the references read here. Recessive cochlear disease is
  bilateral in expectation, but expectation is not a source, so `HP:0008619` is not bound.

  Deep research. A Falcon deep-research report is committed alongside this entry. The query
  was seeded with a disambiguated disease name ("DFNB31 WHRN whirlin-related autosomal
  recessive nonsyndromic hearing loss") rather than the bare numbered locus name, because
  numbered loci are where providers substitute a different disease. It came back on topic:
  `just preflight-dr` passed against MONDO:0011767 with WHRN mentioned 66 times and the
  correct OMIM number (607084) present, and its own reference validation resolved 9 of 9
  citations with a confabulation rate of 0. It was used as a lead source only - every
  snippet in this entry is anchored to a PMID fetched into `references_cache/` and read
  directly - and it did not change any conclusion drawn from the primary literature.

  The report states that the AAV8 rescue restored stereocilia morphology but did **not**
  improve hearing, and that treating adult mice did not restore stereocilia at all. The
  first half is confirmed by the whirlin isoform review (PMID:30831381), which is cached in
  full and is cited on the AAV8 model's readout; the same review reports that posterior
  semicircular canal delivery partially improved hearing and balance, so the negative result
  is route-specific. The adult-treatment claim is attributed to the gene-therapy paper's full
  text, which is not cached (its abstract and DOI record do not contain it), so it is not
  asserted here.
references:
- reference: PMID:12833159
  title: "Defects in whirlin, a PDZ domain molecule involved in stereocilia elongation, cause deafness in the whirler mouse and families with DFNB31."
- reference: PMID:15841483
  title: Identification of a novel frameshift mutation in the DFNB31/WHRN gene in a Tunisian consanguineous family with hereditary non-syndromic recessive hearing loss.
- reference: PMID:17171570
  title: "A novel gene for Usher syndrome type 2: mutations in the long isoform of whirlin are associated with retinitis pigmentosa and sensorineural hearing loss."
- reference: PMID:30831381
  title: "Usher syndrome and non-syndromic deafness: Functions of different whirlin isoforms in the cochlea, vestibular organs, and retina."
- reference: PMID:15590699
  title: Mutant analysis reveals whirlin as a dynamic organizer in the growing hair cell stereocilium.
- reference: PMID:27117407
  title: Alternative Splice Forms Influence Functions of Whirlin in Mechanosensory Hair Cell Stereocilia.
- reference: PMID:26307667
  title: Gene Therapy Restores Hair Cell Stereocilia Morphology in Inner Ears of Deaf Whirler Mice.
- reference: PMID:37924449
  title: Novel pathogenic WHRN variant causing hearing loss in a moroccan family.
inheritance:
- name: Autosomal recessive
  description: >-
    Reported as homozygosity in consanguineous Tunisian and Moroccan families and as
    biallelic C-terminal alleles in the original DFNB31 kindreds.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:15841483
    reference_title: Identification of a novel frameshift mutation in the DFNB31/WHRN gene in a Tunisian consanguineous family with hereditary non-syndromic recessive hearing loss.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "in a consanguineous Tunisian family segregating congenital profound ARNSHL"
    explanation: Recessive segregation of the DFNB31 locus in a consanguineous kindred.
  - reference: PMID:37924449
    reference_title: Novel pathogenic WHRN variant causing hearing loss in a moroccan family.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome sequencing in a consanguineous Moroccan patient with severe hearing loss identified a single homozygous mutation"
    explanation: Independent homozygous WHRN variant in a second consanguineous family.
pathophysiology:
- name: Biallelic WHRN Loss of Function
  description: >-
    Biallelic WHRN variants remove or truncate whirlin, a PDZ-domain scaffold with two
    N-terminal PDZ domains, a proline-rich region and a C-terminal PDZ. The gene has two
    major isoforms - a long form encoded by exons 1-13 and a short form from exons 6-13
    lacking PDZ1 and PDZ2 - and the alleles reported in DFNB31 sit in the C-terminal half,
    so both isoforms lose their C-terminal PDZ. The first DFNB31 allele described is the
    exon 10 nonsense change R778X; a frameshift in exon 11, G808DfsX11, was reported next.
  role: trigger
  biological_scale: MOLECULAR
  genes:
  - preferred_term: WHRN
    term:
      id: hgnc:16361
      label: WHRN
  genetic_context:
    functional_impact_category: LOSS_OF_FUNCTION
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    description: >-
      Nonsense and frameshift alleles in the C-terminal half of the protein, reported
      homozygously in consanguineous families.
  downstream:
  - target: Loss of Whirlin from the Stereocilia Tip Complex
    description: >-
      The truncated protein cannot serve as the tip scaffold; in the whirler mouse, which
      ablates both major isoforms, the tip pool is what is missing.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:12833159
    reference_title: "Defects in whirlin, a PDZ domain molecule involved in stereocilia elongation, cause deafness in the whirler mouse and families with DFNB31."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The gene encoding whirlin also underlies the human autosomal recessive deafness locus DFNB31."
    explanation: Establishes WHRN as the DFNB31 gene in humans.
  - reference: PMID:30831381
    reference_title: "Usher syndrome and non-syndromic deafness: Functions of different whirlin isoforms in the cochlea, vestibular organs, and retina."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "The first WHRN mutation identified in DFNB31 patients is a cysteine to threonine substitution in exon 10, which changes the arginine codon to a stop codon (R778X)"
    explanation: >-
      Names the founding DFNB31 allele and its position in the C-terminal half. Quoted from
      a review summarising the primary reports rather than from a primary report, hence
      REVIEW_SYNTHESIS.
- name: Loss of Whirlin from the Stereocilia Tip Complex
  description: >-
    Whirlin localizes to the tips of stereocilia, and its expression there is dynamic rather
    than static: it appears and fades out in an ordered sequence across the rows of the
    growing bundle, fading from inner hair cells before outer hair cells. At the tip the
    short isoform binds EPS8, and the pair are required together for normal length
    regulation. Losing whirlin therefore removes the scaffold that assembles the
    actin-regulatory machinery at the one place in the stereocilium where the actin core
    grows.
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: cochlear hair cell
    term:
      id: CL:0000202
      label: auditory hair cell
  cellular_components:
  - preferred_term: stereocilium tip
    term:
      id: GO:0032426
      label: stereocilium tip
  downstream:
  - target: Failure of Stereocilia Elongation and Bundle Organization
    description: >-
      Without the tip scaffold the actin core is not elongated to its programmed length and
      the graded row heights are not established.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:15590699
    reference_title: Mutant analysis reveals whirlin as a dynamic organizer in the growing hair cell stereocilium.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "We show that whirlin localizes at the tips of stereocilia."
    explanation: Places whirlin at the stereocilium tip, which is where the lesion acts.
  - reference: PMID:27117407
    reference_title: Alternative Splice Forms Influence Functions of Whirlin in Mechanosensory Hair Cell Stereocilia.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "WHRN-S interacts with EPS8, and both are required at stereocilia tips for normal length regulation."
    explanation: Identifies the tip complex whose loss produces the short-stereocilia phenotype.
- name: Failure of Stereocilia Elongation and Bundle Organization
  description: >-
    Hair bundles in whirlin-null mice are built from abnormally short stereocilia, in both
    inner and outer hair cells. The defect is in elongation and maintenance of the actin
    core and in the organization of the bundle, not in the presence of the stereocilia
    themselves. The isoforms divide the work: a mouse expressing the short isoform but not
    the long one keeps inner hair cell bundles close to normal and loses outer hair cell
    bundle morphology, organization and function, so the long isoform is doing something
    the short one does not - its localization midway along the shorter stereocilia
    coincides with the inter-stereociliary links.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: cochlear hair cell
    term:
      id: CL:0000202
      label: auditory hair cell
  cellular_components:
  - preferred_term: stereocilium bundle
    term:
      id: GO:0032421
      label: stereocilium bundle
  biological_processes:
  - preferred_term: stereocilia elongation by actin polymerization
    modifier: DECREASED
    term:
      id: GO:0030041
      label: actin filament polymerization
  - preferred_term: auditory hair cell stereocilium organization
    modifier: ABNORMAL
    term:
      id: GO:0060088
      label: auditory receptor cell stereocilium organization
  - preferred_term: stereocilium maintenance
    modifier: DECREASED
    term:
      id: GO:0120045
      label: stereocilium maintenance
  downstream:
  - target: Hair Bundle Mechanotransduction Failure
    description: >-
      A bundle of short, ungraded stereocilia cannot deflect and gate as a bundle of graded
      ones does, so sound no longer produces a normal receptor response.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - loss of graded stereocilia row heights
    - loss of the inter-stereociliary link geometry that couples the rows, so tip-link
      tension is not developed normally on deflection
  - target: Congenital Onset of Hearing Loss
    description: >-
      The bundle defect is developmental - the stereocilia never reach their programmed
      length - so the deficit is present from birth rather than acquired, which is how the
      one family with a reported onset is described.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - failure of hair bundle maturation during cochlear development
  evidence:
  - reference: PMID:12833159
    reference_title: "Defects in whirlin, a PDZ domain molecule involved in stereocilia elongation, cause deafness in the whirler mouse and families with DFNB31."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "detailed ultrastructural analysis of sensory hair cells in the organ of Corti of the inner ear indicates that the whirler gene encodes a protein involved in the elongation and maintenance of stereocilia in both inner hair cells (IHCs) and outer hair cells (OHCs)"
    explanation: Ultrastructural demonstration that the lesion is one of stereocilia elongation and maintenance.
  - reference: PMID:12833159
    reference_title: "Defects in whirlin, a PDZ domain molecule involved in stereocilia elongation, cause deafness in the whirler mouse and families with DFNB31."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "this novel PDZ domain-containing molecule acts as an organizer of submembranous molecular complexes that control the coordinated actin polymerization and membrane growth of stereocilia"
    explanation: >-
      The authors' mechanistic account of how whirlin controls elongation. Graded INDIRECT
      because it is offered as a suggestion from the phenotype rather than a measurement.
  - reference: PMID:27117407
    reference_title: Alternative Splice Forms Influence Functions of Whirlin in Mechanosensory Hair Cell Stereocilia.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Lack of both isoforms causes abnormally short stereocilia and profound deafness and vestibular dysfunction."
    explanation: Links complete whirlin loss to short stereocilia and to profound deafness in the mouse.
  - reference: PMID:27117407
    reference_title: Alternative Splice Forms Influence Functions of Whirlin in Mechanosensory Hair Cell Stereocilia.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "WHRN-S expression, however, is sufficient to maintain stereocilia bundle morphology and function in a subset of hair cells, resulting in some auditory response and no overt vestibular dysfunction."
    explanation: >-
      Shows the two isoforms are not interchangeable, and that retaining the short isoform
      alone converts profound deafness into a milder loss in the mouse.
- name: Hair Bundle Mechanotransduction Failure
  description: >-
    With short, disordered bundles the hair cell cannot convert sound-induced deflection
    into a receptor potential, and the cochlea does not transmit. The transduction
    machinery itself is not the lesion in DFNB31 - the bundle architecture it depends on
    is - which is why the deficit is sensorineural and cochlear rather than retrocochlear.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: cochlear hair cell
    term:
      id: CL:0000202
      label: auditory hair cell
  biological_processes:
  - preferred_term: detection of mechanical stimulus involved in hearing
    modifier: DECREASED
    term:
      id: GO:0050910
      label: detection of mechanical stimulus involved in sensory perception of sound
  downstream:
  - target: Profound Sensorineural Hearing Impairment
    description: >-
      The clinical endpoint of the chain: a cochlear sensory deficit at the severe end of
      the range.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:27117407
    reference_title: Alternative Splice Forms Influence Functions of Whirlin in Mechanosensory Hair Cell Stereocilia.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "While the Whrnwi/wi mutant is profoundly deaf and exhibits circling and headbobbing behavior, we found that the Whrntm1b mutant shows only moderate to severe hearing loss"
    explanation: >-
      Ties bundle state to auditory outcome across two mouse alleles. INDIRECT for the human
      claim because the measured outcome is murine auditory function.
  - reference: PMID:30831381
    reference_title: "Usher syndrome and non-syndromic deafness: Functions of different whirlin isoforms in the cochlea, vestibular organs, and retina."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "USH2D patients have moderate sensorineural hearing loss and RP, while DFNB31 patients have profound sensorineural hearing loss and normal vision."
    explanation: The human endpoint, and the contrast with the allelic syndromic disease.
phenotypes:
- category: Auditory
  name: Profound Sensorineural Hearing Impairment
  description: >-
    Profound sensorineural hearing loss is the defining and, so far as the reported families
    go, the only clinical feature of DFNB31. The Tunisian kindred is described as congenital
    and profound; the review summarising the published patients records profound
    sensorineural loss with normal vision as what distinguishes DFNB31 from allelic USH2D.
  phenotype_term:
    preferred_term: Profound sensorineural hearing impairment
    term:
      id: HP:0011476
      label: Profound sensorineural hearing impairment
  notes: >-
    No frequency band is recorded. Profound hearing loss is the ascertainment criterion for
    every reported DFNB31 family, so any band computed from those reports would restate the
    inclusion criterion rather than measure penetrance.
  evidence:
  - reference: PMID:30831381
    reference_title: "Usher syndrome and non-syndromic deafness: Functions of different whirlin isoforms in the cochlea, vestibular organs, and retina."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "USH2D patients have moderate sensorineural hearing loss and RP, while DFNB31 patients have profound sensorineural hearing loss and normal vision."
    explanation: States the DFNB31 auditory phenotype and its severity.
  - reference: PMID:15841483
    reference_title: Identification of a novel frameshift mutation in the DFNB31/WHRN gene in a Tunisian consanguineous family with hereditary non-syndromic recessive hearing loss.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "in a consanguineous Tunisian family segregating congenital profound ARNSHL"
    explanation: Primary report of congenital profound loss in a DFNB31-linked family.
- category: Auditory
  name: Congenital Onset of Hearing Loss
  description: >-
    The loss is present at birth in the family where onset is reported. Only the Tunisian
    kindred is explicitly described as congenital; the other reports do not state onset, so
    this is recorded as a feature of the disease as reported rather than as an established
    universal.
  phenotype_term:
    preferred_term: Congenital sensorineural hearing impairment
    term:
      id: HP:0008527
      label: Congenital sensorineural hearing impairment
  notes: >-
    Denominator is one family. No frequency band, for the same reason as the phenotype
    above.
  evidence:
  - reference: PMID:15841483
    reference_title: Identification of a novel frameshift mutation in the DFNB31/WHRN gene in a Tunisian consanguineous family with hereditary non-syndromic recessive hearing loss.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "in a consanguineous Tunisian family segregating congenital profound ARNSHL"
    explanation: The one report that states onset describes it as congenital.
genetic:
- name: WHRN variants
  gene_term:
    preferred_term: WHRN
    term:
      id: hgnc:16361
      label: WHRN
  association: Causative
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  features: >-
    WHRN lies at 9q32 and encodes whirlin. The DFNB31 alleles reported so far are truncating
    and lie in the C-terminal half of the protein - R778X in exon 10 and the exon 11
    frameshift G808DfsX11 - while the alleles reported in Usher syndrome type 2D lie in the
    long-isoform-specific N terminus. That positional split is the proposed explanation for
    why one gene produces a syndromic and a non-syndromic disease, and it is a proposal from
    a handful of clinical reports rather than a validated rule. One reported nonsyndromic
    case complicates it: a homozygous missense change at residue 207, inside the
    long-isoform-specific region, in a consanguineous Moroccan patient with severe hearing
    loss. Whether that patient's retina was assessed is not stated in the source read here.
  evidence:
  - reference: PMID:17171570
    reference_title: "A novel gene for Usher syndrome type 2: mutations in the long isoform of whirlin are associated with retinitis pigmentosa and sensorineural hearing loss."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "While mutations in the C-terminal half of whirlin have previously been reported in non-syndromic deafness (DFNB31), both alterations identified in our USH2 family affect the long protein isoform."
    explanation: States the positional contrast between the DFNB31 and USH2D allele sets.
  - reference: PMID:17171570
    reference_title: "A novel gene for Usher syndrome type 2: mutations in the long isoform of whirlin are associated with retinitis pigmentosa and sensorineural hearing loss."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "We propose that mutations causing Usher syndrome are probably restricted to exons 1-6 that are specific for the long isoform and probably crucial for retinal function."
    explanation: >-
      The genotype-phenotype proposal itself. Graded INDIRECT because the authors offer it
      as a hypothesis from two alleles in one family plus the prior DFNB31 reports.
  - reference: PMID:37924449
    reference_title: Novel pathogenic WHRN variant causing hearing loss in a moroccan family.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome sequencing in a consanguineous Moroccan patient with severe hearing loss identified a single homozygous mutation"
    explanation: >-
      A homozygous WHRN variant at residue 207 - inside the region the positional rule
      assigns to Usher syndrome - reported in hearing loss. Recorded as a complication of
      that rule, and graded INDIRECT because the source does not report an ophthalmological
      assessment that would settle whether the case is syndromic.
prevalence:
- population: Tunisian families with autosomal recessive nonsyndromic hearing loss
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    No prevalence estimate exists. What is on record is a negative screen: after identifying
    the second DFNB31 family, the authors typed 62 further unrelated informative Tunisian
    ARNSHL families and found no linkage to the locus in any of them.
  evidence:
  - reference: PMID:15841483
    reference_title: Identification of a novel frameshift mutation in the DFNB31/WHRN gene in a Tunisian consanguineous family with hereditary non-syndromic recessive hearing loss.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "we performed linkage analysis in 62 unrelated informative families affected with ARNSHL. No linkage was found to this locus."
    explanation: The negative linkage screen behind the rarity statement.
  - reference: PMID:15841483
    reference_title: Identification of a novel frameshift mutation in the DFNB31/WHRN gene in a Tunisian consanguineous family with hereditary non-syndromic recessive hearing loss.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "we concluded that DFNB31/WHRN is most likely to be a rare cause of ARNSHL in the Tunisian population"
    explanation: The authors' own rarity conclusion.
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 standard intervention for congenital profound sensorineural hearing loss. The
    mechanism supports it in principle: the lesion is in the hair bundle, upstream of the
    spiral ganglion an implant stimulates, and no cochlear malformation is described in
    this disease. No outcome data exist for DFNB31 patients specifically.
  target_mechanisms:
  - target: Hair Bundle Mechanotransduction Failure
    treatment_effect: BYPASSES
    description: Bypasses the failed transduction step by stimulating the auditory nerve directly.
  notes: >-
    Carries no evidence item deliberately. The published WHRN literature reports no implant
    outcomes, and the rationale above is this entry's inference from the mechanism, 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 is
    attached as a qualifier instead.
- name: Early Identification and Habilitation
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: auditory habilitation
    term:
      id: NCIT:C15315
      label: Rehabilitation
  description: >-
    Where the loss is congenital and profound, the modifiable outcome is spoken-language
    development and the modifier is how early it is identified and habilitated. Newborn
    hearing screening detects it.
  notes: >-
    No evidence item. This is general practice for congenital profound deafness, not a
    DFNB31 finding.
animal_models:
- name: Whirler mouse (Whrn wi/wi)
  species: Mouse
  genotype: Whrn wi/wi - spontaneous deletion removing most of exons 6-10, ablating both major whirlin isoforms
  publication: PMID:12833159
  description: >-
    The spontaneous mutant through which the gene was found. Whirler mice do not respond to
    sound and their inner and outer hair cells carry abnormally short stereocilia. Because
    the deletion removes both major isoforms, the model is the null end of the WHRN allelic
    series rather than a copy of any particular human allele.
  modeled_mechanisms:
  - target: Failure of Stereocilia Elongation and Bundle Organization
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: >-
      Ultrastructural analysis of the organ of Corti in this mutant is the primary evidence
      that whirlin is required for stereocilia elongation and maintenance.
    limitations: >-
      The whirler deletion sits in the 3' region shared by both isoforms, which is where the
      human DFNB31 alleles fall, so it matches them in position; but it removes both
      isoforms outright rather than truncating them, so it may be more severe than the
      human lesion. The mutant also
      circles and head-bobs, a vestibular phenotype not reported in DFNB31 patients.
    readouts:
    - name: Stereocilia length in inner and outer hair cells
      target: Failure of Stereocilia Elongation and Bundle Organization
      direction: DECREASED
      interpretation: Short stereocilia in both hair cell types is the structural correlate of this node.
      evidence:
      - reference: PMID:12833159
        reference_title: "Defects in whirlin, a PDZ domain molecule involved in stereocilia elongation, cause deafness in the whirler mouse and families with DFNB31."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "detailed ultrastructural analysis of sensory hair cells in the organ of Corti of the inner ear indicates that the whirler gene encodes a protein involved in the elongation and maintenance of stereocilia in both inner hair cells (IHCs) and outer hair cells (OHCs)"
        explanation: The ultrastructural measurement behind this readout.
  evidence:
  - reference: PMID:12833159
    reference_title: "Defects in whirlin, a PDZ domain molecule involved in stereocilia elongation, cause deafness in the whirler mouse and families with DFNB31."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The whirler mouse mutant (wi) does not respond to sound stimuli"
    explanation: Establishes the model's auditory phenotype.
- name: Whrn tm1b long-isoform-null mouse
  species: Mouse
  genotype: Whrn tm1b(KOMP)Wtsi homozygote - exon 4 deleted, expresses WHRN-S but not WHRN-L
  publication: PMID:27117407
  description: >-
    The isoform-dissecting model. Retaining the short isoform alone leaves inner hair cell
    bundles close to normal, damages outer hair cell bundles, and produces moderate to
    severe rather than profound hearing loss with no overt vestibular dysfunction. It is
    the experimental basis for the proposal that isoform-specific loss explains the
    difference between DFNB31 and USH2D.
  modeled_mechanisms:
  - target: Failure of Stereocilia Elongation and Bundle Organization
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Reproduces bundle disorganization, but only in outer hair cells, and with a milder
      auditory outcome than DFNB31.
    limitations: >-
      This allele is the inverse of the human DFNB31 genotype: it removes the long isoform
      and spares the short one, whereas the reported DFNB31 alleles truncate the C terminus
      shared by both. It models the allelic contrast rather than the human disease.
    readouts:
    - name: Outer hair cell bundle morphology and function
      target: Failure of Stereocilia Elongation and Bundle Organization
      direction: ALTERED
      interpretation: Isoform-restricted bundle damage, sparing inner hair cells.
      evidence:
      - reference: PMID:27117407
        reference_title: Alternative Splice Forms Influence Functions of Whirlin in Mechanosensory Hair Cell Stereocilia.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "WHRN-S expression, however, is sufficient to maintain stereocilia bundle morphology and function in a subset of hair cells, resulting in some auditory response and no overt vestibular dysfunction."
        explanation: The bundle and auditory readout in this allele.
- name: AAV8-whirlin gene transfer in whirler mice
  species: Mouse
  genotype: Whrn wi/wi treated with AAV8 carrying wild-type whirlin cDNA by neonatal round-window injection
  publication: PMID:26307667
  description: >-
    A rescue experiment rather than a disease model: delivering wild-type whirlin cDNA to
    neonatal whirler cochleas restored normal stereocilia length and bundle architecture in
    infected hair cells and increased inner hair cell survival relative to the untreated
    contralateral ear.
  modeled_mechanisms:
  - target: Failure of Stereocilia Elongation and Bundle Organization
    relationship: RESCUES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Restoring whirlin restores the bundle, which is the strongest available evidence that
      the bundle phenotype is a direct consequence of whirlin loss rather than a downstream
      or developmental side effect.
    limitations: >-
      Neonatal delivery in a mouse with a double-isoform-null allele. Round-window delivery
      partially lengthened inner but not outer hair cell stereocilia and did not restore
      hearing, so this experiment is a structural rescue without a functional one. That
      negative result is specific to the route: a later study delivering the same construct
      through the posterior semicircular canal reached more cochlear hair cells and partially
      improved both auditory and vestibular function. The claim that treating adult mice did
      not restore stereocilia comes from the deep-research report's reading of full text
      that could not be fetched and is not asserted here.
    readouts:
    - name: Stereocilia length and bundle architecture after transduction
      target: Failure of Stereocilia Elongation and Bundle Organization
      direction: RESTORED
      interpretation: Structural rescue in transduced hair cells.
      evidence:
      - reference: PMID:26307667
        reference_title: Gene Therapy Restores Hair Cell Stereocilia Morphology in Inner Ears of Deaf Whirler Mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "whirlin expression was detected in infected hair cells (IHCs), and normal stereocilia length and bundle architecture were restored"
        explanation: The structural rescue readout.
    - name: Hearing after round-window delivery
      target: Failure of Stereocilia Elongation and Bundle Organization
      direction: UNCHANGED
      interpretation: >-
        Hearing loss was not restored despite partial stereocilia lengthening in inner hair
        cells, so the structural rescue did not carry through to function by this route.
      evidence:
      - reference: PMID:30831381
        reference_title: "Usher syndrome and non-syndromic deafness: Functions of different whirlin isoforms in the cochlea, vestibular organs, and retina."
        supports: SUPPORT
        quote_role: REVIEW_SYNTHESIS
        evidence_source: MODEL_ORGANISM
        snippet: "The cochlear round window delivery partially increases the stereocilia length in IHCs but not OHCs, and hearing loss in Whrnwi mice is not restored (Chien et al., 2015)."
        explanation: >-
          The review's summary of the functional outcome of this experiment, which the
          primary paper's abstract does not report.
    evidence:
    - reference: PMID:30831381
      reference_title: "Usher syndrome and non-syndromic deafness: Functions of different whirlin isoforms in the cochlea, vestibular organs, and retina."
      supports: SUPPORT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: MODEL_ORGANISM
      snippet: "Posterior semicircular canal delivery of AAV-FL-whirlin was found to increase the stereociliary length in utricular hair cells as well as cochlear inner hair cells, and partially improve both the vestibular and auditory function of Whrnwi mice (Isgrig et al., 2017)."
      explanation: >-
        A different delivery route partially restored function, so the round-window
        negative result reflects the route rather than a limit of whirlin replacement.
  evidence:
  - reference: PMID:26307667
    reference_title: Gene Therapy Restores Hair Cell Stereocilia Morphology in Inner Ears of Deaf Whirler Mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Wild-type whirlin cDNA was delivered via adeno-associated virus (AAV8) by injection through the round window of the cochleas in neonatal whirler mice."
    explanation: Describes the delivery route and construct.
differential_diagnoses:
- name: Usher syndrome type 2D
  description: >-
    The allelic syndromic disease, caused by variants in the same gene. It is the
    differential that matters here, because the distinction is not made on the audiogram
    alone: USH2D hearing loss is moderate rather than profound, and the discriminating
    feature is retinitis pigmentosa, which begins around the second decade. A child with
    WHRN-related hearing loss and a variant in the long-isoform-specific N terminus is
    therefore a candidate for retinal surveillance rather than a settled DFNB31 diagnosis.
  evidence:
  - reference: PMID:30831381
    reference_title: "Usher syndrome and non-syndromic deafness: Functions of different whirlin isoforms in the cochlea, vestibular organs, and retina."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "USH2D patients have moderate sensorineural hearing loss and RP, while DFNB31 patients have profound sensorineural hearing loss and normal vision."
    explanation: The clinical discriminator between the two WHRN diseases.
  - reference: PMID:17171570
    reference_title: "A novel gene for Usher syndrome type 2: mutations in the long isoform of whirlin are associated with retinitis pigmentosa and sensorineural hearing loss."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "this is the first case of USH2 that is allelic to non-syndromic deafness"
    explanation: Establishes that the two WHRN diseases are allelic, which is why this differential exists at all.
discussions:
- discussion_id: dfnb31_vestibular_mouse_human_mismatch
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Whirlin-null mice have overt vestibular dysfunction and no published WHRN patient
    reports a vestibular deficit. Is human DFNB31 genuinely vestibular-sparing, or has
    vestibular function never been tested?
  attaches_to:
  - pathophysiology#Failure of Stereocilia Elongation and Bundle Organization
  rationale: >-
    Whirlin is expressed in vestibular hair cells as well as cochlear ones, and the same
    stereocilia machinery builds both bundles, so a vestibular phenotype is what the
    mechanism predicts. The whirler mouse circles and head-bobs, and the mouse lacking both
    isoforms has profound deafness with vestibular dysfunction. Against that, the review
    summarising the published WHRN patients records that none of them self-reported a
    vestibular deficit - which is a statement about what patients volunteered, not about
    what testing showed. Whether DFNB31 spares the human vestibular system, or whether the
    deficit is present and compensated or simply unmeasured, changes what should be offered
    clinically: vestibular assessment and balance habilitation in a deaf child are not
    routine unless a deficit is suspected.
  proposed_experiments:
  - experiment_id: exp_dfnb31_formal_vestibular_testing
    name: Formal vestibular testing of a DFNB31 cohort
    description: >-
      Vestibular-evoked myogenic potentials, caloric testing and video head impulse testing
      in genotyped DFNB31 patients, with age-matched controls, rather than symptom
      questionnaires.
    would_support:
    - pathophysiology#Failure of Stereocilia Elongation and Bundle Organization
    supporting_outcome:
    - Measurable vestibular hypofunction in DFNB31 patients would show that the murine
      phenotype translates and that the absence of self-reported symptoms reflects
      compensation rather than sparing.
    would_refute:
    - pathophysiology#Failure of Stereocilia Elongation and Bundle Organization
    refuting_outcome:
    - Normal vestibular function on formal testing would establish a real
      cochlear-restricted phenotype in humans and make the mouse a poor model for this
      aspect of the disease.
  evidence:
  - reference: PMID:30831381
    reference_title: "Usher syndrome and non-syndromic deafness: Functions of different whirlin isoforms in the cochlea, vestibular organs, and retina."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "None of these aforementioned patients self-reported any vestibular deficits."
    explanation: The human side of the mismatch, and the reason it is weak - self-report, not testing.
  - reference: PMID:30831381
    reference_title: "Usher syndrome and non-syndromic deafness: Functions of different whirlin isoforms in the cochlea, vestibular organs, and retina."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: MODEL_ORGANISM
    snippet: "However, both Whrnneo and Whrnwi mice show similar severe to profound loss of linear vestibular evoked potential (VsEP) responses."
    explanation: >-
      On objective testing both mouse alleles lose otolith responses, including the one
      without overt balance behaviour, so a deficit can be present where behaviour misses it.
      That is the case for formal testing rather than self-report in patients.
  - reference: PMID:27117407
    reference_title: Alternative Splice Forms Influence Functions of Whirlin in Mechanosensory Hair Cell Stereocilia.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Lack of both isoforms causes abnormally short stereocilia and profound deafness and vestibular dysfunction."
    explanation: The murine side of the mismatch.
- discussion_id: dfnb31_isoform_position_genotype_phenotype_rule
  kind: KNOWLEDGE_GAP
  prompt: >-
    Is the 5' / 3' positional rule - long-isoform-specific N-terminal alleles give Usher
    syndrome type 2D, C-terminal alleles give non-syndromic DFNB31 - actually a rule, or a
    pattern in a handful of families?
  attaches_to:
  - genetic#WHRN variants
  rationale: >-
    The rule is the entry's mechanistic account of why one gene gives two diseases, and it
    is doing real clinical work: it is what would decide whether a WHRN-positive deaf child
    is put under retinal surveillance. But it rests on two alleles in one German USH2 family
    set against the DFNB31 alleles known in 2007, and its authors stated it as a proposal.
    One later nonsyndromic report carries a homozygous missense change at residue 207, inside
    the long-isoform-specific region, without a reported retinal assessment. Until a
    genotype-stratified cohort with ophthalmological follow-up exists, the rule should not be
    used to withhold retinal surveillance.
  proposed_experiments:
  - experiment_id: exp_dfnb31_genotype_stratified_retinal_followup
    name: Genotype-stratified retinal follow-up of WHRN-positive hearing loss
    description: >-
      Assemble WHRN biallelic cases from hearing loss cohorts, classify alleles by whether
      they affect the long-isoform-specific exons, and follow retinal function
      longitudinally into the third decade.
    would_support:
    - genetic#WHRN variants
    supporting_outcome:
    - Retinitis pigmentosa confined to carriers of long-isoform-specific alleles would turn
      the proposal into a usable clinical rule.
    would_refute:
    - genetic#WHRN variants
    refuting_outcome:
    - Retinal degeneration in carriers of C-terminal alleles, or its absence in carriers of
      N-terminal ones, would show that isoform position does not determine the syndromic
      boundary.
  evidence:
  - reference: PMID:17171570
    reference_title: "A novel gene for Usher syndrome type 2: mutations in the long isoform of whirlin are associated with retinitis pigmentosa and sensorineural hearing loss."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "We propose that mutations causing Usher syndrome are probably restricted to exons 1-6 that are specific for the long isoform and probably crucial for retinal function."
    explanation: The proposal, in the authors' own hedged wording.

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References & Deep Research

References

8

PMID:12833159

Defects in whirlin, a PDZ domain molecule involved in stereocilia elongation, cause deafness in the whirler mouse and families with DFNB31.