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Classifications

Harrison's Part

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Inheritance

1

Autosomal dominant inheritance HP:0000006

DDOD is transmitted as an autosomal dominant trait. Most molecularly solved probands carry a de novo heterozygous ATP6V1B2 p.Arg506* variant with unaffected parents, but vertical transmission through three generations has been documented in two independent families, confirming dominant inheritance rather than exclusively sporadic de novo occurrence.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:24421866 SUPPORT Human Clinical

"We present here three male family members in three generations with sensori-neural deafness, onychodystrophy and brachydactyly inherited via autosomal dominant transmission."

Documents vertical autosomal dominant transmission across three generations.

PMID:24913193 SUPPORT Human Clinical

"An identical heterozygous de novo c.1516 C>T (p.Arg506X) mutation in ATP6V1B2 was verified in two probands"

Establishes the heterozygous de novo origin in simplex probands.

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Discussions and Knowledge Gaps

5

Does the DDOD p.Arg506* allele act by haploinsufficiency or by a dominant-negative effect of the expressed truncated B2 subunit?

KNOWLEDGE GAP ddod_haploinsufficiency_vs_dominant_negative

Attached to

pathophysiology#ATP6V1B2 C-Terminal Truncation and Weakened V-ATPase Subunit Interaction

The distinction is not cosmetic. The mutant transcript escapes nonsense-mediated decay, so a truncated subunit is expressed and can be incorporated into V-ATPase complexes; the observed weakening of the V1B2 to V1E interaction is consistent with a poisoned complex rather than with simple dosage reduction. Yuan et al. concluded haploinsufficiency from a transfection dose-response, but a later review of the same allele stated only that it causes loss of function and left the route open. The answer determines whether allele-specific knockdown would be therapeutic, or whether gene augmentation of the kind demonstrated in the hair-cell knockout mouse is the right strategy for patients. It is also why this entry records `functional_impact_category: LOSS_OF_FUNCTION` rather than the more specific DOMINANT_NEGATIVE.

Proposed experiments

Allele-specific dosage versus poisoning test in patient iPSC-derived cells

ddod_exp_allele_dosage_vs_poisoning

Compare endolysosomal pH, V-ATPase assembly and autophagic flux across the patient iPSC line, its isogenic corrected control, and a heterozygous null created in the corrected background. If the patient line is worse than the heterozygous null, the truncated subunit is dominant negative; if the two are equivalent, the mechanism is haploinsufficiency.

Show evidence (2 references)

PMID:37628590 SUPPORT Model Organism

"Altogether, these results indicates that the p.R506* variant causes a loss of function either as a result of a dominant negative effect or haploinsufficiency."

States the unresolved alternative directly.

PMID:24913193 SUPPORT In Vitro

"Taken together, these results suggest that ATP6V1B2 c.1516 C>T mutation is a haploinsufficient mutation."

The competing haploinsufficiency reading, offered as a suggestion from transfection data rather than as a settled result.

Why do the DDOD truncating allele and the ZLS2 missense alleles move lysosomal pH in opposite directions while producing an overlapping clinical continuum?

KNOWLEDGE GAP ddod_bidirectional_lysosomal_ph

Attached to

pathophysiology#Impaired Endolysosomal Acidification

This is the central unresolved problem of the dominant ATP6V1B2 spectrum, and it is easy to curate away by mistake. For the DDOD p.Arg506* allele, lysosomal acidification is reduced, with transfected cells showing raised lysosomal pH and cochlear tissue showing reduced V-ATPase and cathepsin-D activity. For the ZLS2-associated missense alleles, patient fibroblasts show the reverse, a hyperactive pump and significantly more acidic lysosomes, and the authors proposed increased acidification as the driver of the whole spectrum. Critically, p.Arg506* was not among the alleles tested in that hyperactivity series, so the two results do not directly contradict each other; they were simply never measured side by side. The DDOD side has since been replicated in isogenic CRISPR-engineered p.Arg506* cells, which removes the overexpression caveat attaching to the original transfection result and makes the divergence harder to explain away as an artefact of method. Until the alleles are compared directly, a unifying claim that the spectrum is driven by V-ATPase upregulation should not be imported into this entry, and conformance to `lysosomal_substrate_accumulation` is deliberately not declared here because the cholesterol and ceramide storage data come from the missense lines, not from DDOD cells.

Proposed experiments

Side-by-side lysosomal pH panel across the ATP6V1B2 allelic series

ddod_exp_allelic_series_ph_panel

Measure intraorganellar pH, substrate storage and autophagic flux in one laboratory, using one protocol, across patient-derived fibroblasts or isogenic iPSC lines carrying p.Arg506*, p.Arg485Pro and the ADP/ATP-site missense cluster, with shared controls. This is the experiment that would establish whether the continuum is one mechanism with a bidirectional readout or two distinct mechanisms converging on overlapping phenotypes.

Show evidence (3 references)

PMID:24913193 SUPPORT In Vitro

"A statistically significant difference in lysosomal pH was detected between ATP6V1B2 WT- and c.1516 C>T mutant-transfected cells (LSD test, p = 0.02, Supplementary information, Figure S1E), indicating the reduced acidification caused by c.1516 C>T mutation."

The DDOD-allele result showing reduced acidification.

PMID:39210597 REFUTE In Vitro

"We observed a significant higher acidity of lysosomes in all patients’ cell lines compared with control cells, indicating a hyperactive behavior of the proton pumps assembling the mutant B2/C1 subunits."

The opposing result from the missense alleles of the same gene; REFUTE because it contradicts the reduced-acidification direction, though it was measured on different alleles.

PMID:41896517 SUPPORT In Vitro

"Isogenic HEK293T models (ATP6V1B2R506X/+ and ATP6V1B2R506X/R506X) were generated using CRISPR/Cas9 for dynamic lysosomal pH monitoring via ratiometric RpH-LAMP1-3×flag imaging to evaluate pathophysiological mechanisms."

Independent isogenic replication of the DDOD-allele direction without transient overexpression. Note that these heterozygous and homozygous lines are close to the design proposed under the haploinsufficiency-versus-dominant-negative discussion, so that gap may now be partly addressable from published data.

By what route does impaired V-ATPase function in nail-matrix keratinocytes and developing digits produce onychodystrophy and terminal phalangeal hypoplasia?

KNOWLEDGE GAP ddod_nail_matrix_mechanism_unmeasured

Attached to

pathophysiology#Impaired Nail Matrix and Distal Digit Development

Onychodystrophy is one of the two obligate features of DDOD, yet every mechanistic study of the gene to date has been done in the cochlea or in fibroblasts. There is no published measurement of lysosomal pH, autophagic flux or apoptosis in nail matrix or in the developing autopod for any ATP6V1B2 allele, so the nail arm of this entry rests on clinical observation alone. The digit-selective pattern, with the thumb and fifth finger most affected and the second to fourth digits relatively spared, is itself unexplained and suggests an interaction with limb patterning rather than a uniform keratinocyte defect.

Proposed experiments

Endolysosomal profiling of DDOD nail-matrix and autopod tissue

ddod_exp_nail_autopod_endolysosomal_profiling

Differentiate the patient iPSC line and its isogenic control towards keratinocyte and limb-bud mesenchymal fates, and assay lysosomal pH, cathepsin activity and autophagic flux. Complement with conditional Atp6v1b2 deletion in nail-matrix and autopod lineages in mouse to test whether the digit-selective pattern is reproduced.

Show evidence (1 reference)

PMID:39210597 SUPPORT Human Clinical

"Specifically, individuals with DDOD syndrome primarily share sensorineural deafness and onychodystrophy with digital anomalies characterized by bulbous fingertips of digits, and finger-like thumbs/triphalangeal thumb."

Establishes the nail and digit phenotype whose mechanism is unmeasured.

Is cognition genuinely spared in DDOD, or is there subtle learning and memory involvement that routine assessment of a congenitally deaf child cannot detect?

KNOWLEDGE GAP ddod_subtle_cns_involvement

Attached to

pathophysiology#Impaired Endolysosomal Acidification

"Normal development and cognition" is the axis this entry uses to separate DDOD from the DOORS and ZLS2 poles, so any softness in it matters. The claim is well supported at the level of frank intellectual disability, and the original probands achieved oral-language rehabilitation after implantation. But follow-up of implanted DDOD patients found language rehabilitation unsatisfactory despite a well-functioning device on standard mapping indicators, which the reporting group attributed to learning and memory problems, and the same group described a DDOD pedigree with mild intellectual impairment. The p.Arg506* knock-in mouse independently shows cognitive deficits with an impaired hippocampal CA1 region. The honest reading is that DDOD lacks the frank intellectual disability of DOORS and ZLS2, not that the CNS is demonstrably uninvolved. The gap is partly methodological: systematic CNS evaluation in these patients is unavailable, because mild deficits are hard to assess in early childhood against severe congenital deafness, and resting-state fMRI cannot be performed once a cochlear implant is in place.

Proposed experiments

Deafness-matched cognitive phenotyping of molecularly confirmed DDOD patients

ddod_exp_systematic_cognitive_phenotyping

Assess learning and memory in p.Arg506* carriers using instruments validated for congenitally deaf children, against deaf controls with non-syndromic hearing loss matched for implantation age and device performance. A deafness-matched control arm is what separates a real DDOD-specific cognitive effect from the general effect of congenital deafness on these measures.

Show evidence (3 references)

PMID:31257146 SUPPORT Human Clinical

"Clinical follow-up of DDOD syndrome patients with cochlear implantation revealed the language rehabilitation was unsatisfactory although the implanted cochlea worked well, which indicates there might be learning and memory problems in DDOD syndrome patients."

The clinical observation that raises the question, and the reason this entry does not state cognitive sparing more strongly than it does.

PMID:31257146 SUPPORT Model Organism

"Additionally, the impaired hippocampal CA1 region may be the pathological basis of the behavioral defects seen in Atp6v1b2Arg506X/Arg506X mice."

Independent model-organism support for a CNS arm of the same allele, from the same study.

PMID:39210597 SUPPORT Human Clinical

"Individuals with DDOD syndrome usually show normal development and cognitive function, while those with DOORS syndrome and ZLS present with intellectual disability (ID), with or without seizures."

The competing reading. Note the hedge "usually", which is what leaves room for the subtler involvement above; PARTIAL because it supports cognitive sparing as the norm without excluding subclinical involvement.

Do the Atp6v1b2 p.Arg506* knock-in mice model human DDOD deafness, given that their hearing loss is late-onset while the human phenotype is congenital and profound?

HUMAN MODEL MISMATCH ddod_mouse_hearing_onset_mismatch

Attached to

pathophysiology#Apoptotic Degeneration of Spiral Ganglion Neurons and Hair Cells

Both published knock-in lines have essentially normal early hearing. Auditory brainstem responses were normal at 14 weeks in the IMPC-phenotyped line, and the cochlear-pathology line showed only hidden hearing loss early with late-onset threshold shifts. The proposed explanation is compensatory upregulation of the paralogue Atp6v1b1 in hair cells, a species-level rescue with no evidence of a human counterpart. The mismatch matters for interpretation in both directions. Mechanistic findings about spiral ganglion apoptosis are drawn from a system where the insult is milder than in patients, and any therapeutic rescue demonstrated in these mice starts from a less severe baseline and within a postnatal window that has no human equivalent, because human DDOD deafness is already established at birth.

Proposed experiments

Test whether ATP6V1B1 compensation occurs in human cochlear cells

ddod_exp_human_atp6v1b1_compensation

Quantify ATP6V1B1 transcript and protein in human iPSC-derived otic and hair-cell-like cells carrying p.Arg506* against the isogenic corrected control. Absence of compensation would confirm the paralogue rescue as the species difference and would explain the severity gap directly.

Adult-onset rescue window test

ddod_exp_adult_onset_rescue_window

Deliver AAV-mediated Atp6v1b2 augmentation to knock-in mice after hearing loss is established, rather than at postnatal days 0 to 2, to determine whether rescue is possible outside a developmental window that human patients have already passed at diagnosis.

Show evidence (2 references)

PMID:37628590 SUPPORT Model Organism

"The auditory brainstem response (ABR) confirmed proper auditory function at 14 weeks of age"

Documents preserved hearing in the knock-in mouse, the core of the mismatch.

PMID:34746137 SUPPORT Model Organism

"We observed increased transcription of Atp6v1b1 in hair cells of Atp6v1b2Arg506*/Arg506* mice and inferred that Atp6v1b1 compensated for the Atp6v1b2 dysfunction by increasing its own transcription level. Genetic compensation in hair cells explains the milder hearing impairment in..."

Gives the proposed species-specific compensation mechanism behind the mismatch.

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Pathophysiology

5

ATP6V1B2 C-Terminal Truncation and Weakened V-ATPase Subunit Interaction

The recurrent heterozygous c.1516C>T (p.Arg506*) variant inserts a premature stop codon that removes the last six, highly conserved residues of the ATP6V1B2 B2 subunit. Because the transcript is stable and escapes nonsense-mediated decay, the truncated subunit is produced and incorporated into the pump rather than being absent. The truncation weakens the interaction between the V1B2 and V1E subunits and ATP hydrolysis by the complex falls. The node is deliberately named for the weakened subunit interaction rather than for failed assembly: the V-ATPase complex still assembles with the truncated subunit, so this is a defective pump rather than an absent one, which is exactly why the dominant-negative reading remains live.

Genetic context ATP6V1B2 hgnc:854 allele_type: nonsense single-nucleotide variant variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Heterozygous germline NM_001693.4:c.1516C>T (p.Arg506*), recurrent and usually de novo, removing the C-terminal six residues of the B2 subunit.

LOSS_OF_FUNCTION is chosen deliberately as the superordinate call the literature actually supports, not as a default. Yuan et al. measured reduced ATPase hydrolysis activity and reduced lysosomal acidification for the p.Arg506* allele and called it haploinsufficient; a later review of the same allele concluded only that it acts by loss of function, and explicitly left dominant-negative versus haploinsufficiency open, which is recorded as a KNOWLEDGE_GAP discussion on this entry. The finer FunctionalImpactEnum values DOMINANT_NEGATIVE and PARTIAL_LOSS_OF_FUNCTION are therefore deliberately NOT used here.

V-ATPase proton transmembrane transporter activity GO:0015078 ↓ DECREASED

Downstream

Impaired Endolysosomal Acidification Reduced V1 domain assembly and ATP hydrolysis lower proton pumping into the lysosomal lumen.

Show evidence (3 references)

PMID:24913193 SUPPORT In Vitro

"We found that the ATPase hydrolysis activity significantly decreased in the transfected cells when the ratio of the mutant/WT increased."

Directly measures reduced ATPase hydrolysis activity attributable to the DDOD allele.

PMID:34746137 SUPPORT Model Organism

"The interaction between the V1B2 and V1E subunits was found to be weaker in Atp6v1b2Arg506*/Arg506*mice than in wild-type (WT) mice, indicating that the assembly of V-ATPase was affected by the mutation"

Provides the subunit-interaction defect that links the truncation to reduced pump function.

PMID:31257146 SUPPORT Model Organism

"The molecular mechanism underlying V-ATPases dysfunction involves a weak interaction between the E and B2 subunits, although the assembly of V-ATPases can still take place."

Qualifies the preceding item. Assembly of the complex is not abolished, so the lesion is a weakened subunit interaction within an assembled pump rather than failure to assemble; PARTIAL because it supports the interaction defect while constraining how strongly the assembly claim may be stated.

Impaired Endolysosomal Acidification

Reduced V-ATPase proton pumping raises lysosomal luminal pH. In cells expressing the DDOD allele, and in cochlear tissue from the corresponding mouse models, lysosomal acidification is reduced, cathepsin-D activity falls and lysosomal membrane and ion-channel proteins are upregulated, consistent with failure of the acidic compartment to support hydrolase activity. This node is the disease's rate-limiting molecular lesion.

Spiral ganglion neuron CL:0011113 Cochlear hair cell CL:0000202

Lysosomal lumen acidification GO:0007042 ↓ DECREASED Vacuolar acidification GO:0007035 ↓ DECREASED

Animal models

Cochlea-specific Atp6v1b2 morpholino knockdown mouse Mouse recapitulates Cochlear knockdown reproduces the reduction in V-ATPase activity and lysosomal acidification that underlies the human disease, measured in cochlear tissue rather than in a heterologous cell line.

Downstream

Autophagic Flux Blockade Lysosomes that cannot acidify cannot complete degradation of autophagosomal cargo, so autophagic flux stalls.

Show evidence (3 references)

PMID:24913193 SUPPORT In Vitro

"A statistically significant difference in lysosomal pH was detected between ATP6V1B2 WT- and c.1516 C>T mutant-transfected cells (LSD test, p = 0.02, Supplementary information, Figure S1E), indicating the reduced acidification caused by c.1516 C>T mutation."

Measures the raised lysosomal pH produced by the DDOD allele.

PMID:41995948 SUPPORT Model Organism

"Mechanistically, cochlear V-ATPase and Cath-D activities were significantly reduced, while lysosomal membrane proteins (LAMP1, LAMP2) and ion channel proteins (TPC1, TPC2) were upregulated, suggesting lysosomal acidification dysfunction."

Confirms the acidification defect in cochlear tissue of a DDOD model rather than only in transfected cells.

PMID:41896517 SUPPORT In Vitro

"Cellular studies demonstrated significant increase of lysosomal pH in mutant cells compared to wild-type control."

Independent replication of the raised lysosomal pH in isogenic CRISPR-engineered p.Arg506* cells, which is the cleanest genetic control for this direction of effect and does not depend on transient overexpression.

Autophagic Flux Blockade

Undegraded autophagosomes accumulate because fusion-competent, acidified lysosomes are not available to complete cargo breakdown. In cochlear tissue this manifests as accumulation of large autophagosomes together with the lysosomal morphological abnormalities seen in the mouse models.

Autophagosome maturation GO:0097352 ↓ DECREASED Autophagy GO:0006914 ↓ DECREASED

Downstream

Apoptotic Degeneration of Spiral Ganglion Neurons and Hair Cells Persistent autophagic blockade activates the intrinsic apoptotic program in cochlear neurons and sensory cells.

Show evidence (1 reference)

PMID:34746137 SUPPORT Model Organism

"Apoptosis activated by lysosomal dysfunction and the subsequent blockade of autophagic flux induced the degeneration of spiral ganglion neurons and further impaired the hearing."

States the lysosomal dysfunction to autophagic blockade to neurodegeneration sequence in the p.Arg506* mouse.

Apoptotic Degeneration of Spiral Ganglion Neurons and Hair Cells

Autophagosome accumulation shifts the Bcl-2 to Bax ratio, permeabilizing the mitochondrial outer membrane and releasing cytochrome c, which activates caspase-3. The resulting apoptosis produces loss of spiral ganglion neurons and, in the hair-cell-specific knockout model, hair cell degeneration. In the knock-in mouse the earliest cochlear lesion is demyelination of auditory nerve fibres, followed by fibre and spiral ganglion cell body loss, with the organ of Corti morphologically normal, so the degeneration in that model is neural rather than sensory. Atp6v1b2 is expressed in exactly these compartments, which is what makes the cochlea the tissue that fails first. This node is the DDOD-specific instance of the conserved spiral-ganglion arm of the sensorineural hearing loss module. It attaches at the spiral ganglion node rather than the module's upstream `#Hair Cell Mechanotransduction Failure and Death` node because the p.Arg506* evidence describes apoptotic neurodegeneration downstream of lysosomal failure, not a primary mechanotransduction defect.

Spiral ganglion neuron CL:0011113 Cochlear hair cell CL:0000202

Neuron apoptotic process GO:0051402 ↑ INCREASED Apoptotic process GO:0006915 ↑ INCREASED

Animal models

Atp6v1b2 p.Arg506* knock-in mouse Mouse partially recapitulates The knock-in reproduces apoptotic spiral ganglion neuron degeneration downstream of lysosomal dysfunction and autophagic blockade, which is the human mechanism, but on a delayed timescale.

Hair-cell-specific Atp6v1b2 conditional knockout mouse Mouse rescues A single postnatal administration of AAV-ie-Eh3-mAtp6v1b2 into the scala media prevented hair cell degeneration and restored lysosome morphology and auditory and vestibular function, providing the strongest available causal test that the cochlear degeneration node is Atp6v1b2-dependent and in principle reversible.

Downstream

Congenital Sensorineural Hearing Loss Loss of cochlear sensory cells and their afferent neurons abolishes auditory transduction and transmission.

Show evidence (5 references)

PMID:24913193 SUPPORT Model Organism

"Immunostaining of mouse cochlear sections and cultured cochlear tissues showed Atp6v1b2 expression mainly in the organ of Corti and spiral ganglion neurons"

Establishes that the affected compartments express the gene, grounding cochlear tissue selectivity.

PMID:41995948 SUPPORT Model Organism

"In DDOD model mice, ATP6V1B2 mRNA and protein levels were significantly reduced in the inner ear, with decreased localization in key auditory regions such as cochlear hair cells and spiral ganglion neurons (SGNs), which was accompanied by SGN loss."

Directly reports spiral ganglion neuron loss in a DDOD model.

PMID:40068100 SUPPORT Model Organism

"The study generates a hair cell-specific knockout mouse (Atp6v1b2fl/fl;Atoh1Cre/+) recapitulating the human phenotypes, with pathological features including hair cell loss and abnormal lysosomal morphology and function."

Adds the hair-cell arm of cochlear degeneration alongside spiral ganglion loss.

+ 2 more references

Impaired Nail Matrix and Distal Digit Development

The second obligate arm of DDOD is failure of nail-plate formation with associated hypoplasia of the terminal and middle phalanges, giving absent or hypoplastic nails, bulbous fingertips and triphalangeal or finger-like thumbs. Nail-matrix keratinocytes are a highly differentiating, keratinisation-dependent lineage in which endolysosomal proteolysis is required, which is the plausible route from the same V-ATPase lesion to the integumentary and distal skeletal phenotype. This node is deliberately curated without a mechanistic evidence item for the acidification-to-nail step. The observation that DDOD patients have onychodystrophy is well-evidenced, but no study has yet demonstrated the lysosomal mechanism in nail matrix or developing digit, which is recorded as a KNOWLEDGE_GAP.

Nail matrix keratinocyte CL:0000312

Downstream

Onychodystrophy Failure of nail-matrix differentiation produces the absent or hypoplastic nails that define the disorder's second arm.

Show evidence (1 reference)

PMID:24913193 SUPPORT Human Clinical

"The probands displayed identical phenotypes including severe congenital sensorineural hearing loss, absence of nails and aplasia of the middle phalanx in the fifth fingers"

Establishes the paired nail and terminal-phalanx involvement in DDOD probands.

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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

11

Head and Neck 2

Dental Anomalies OCCASIONAL Oligodontia HP:0000677

Show evidence (2 references)

PMID:39210597 SUPPORT Human Clinical

"Some affected individuals may also show tooth abnormalities (e.g., oligodontia, conical teeth, and late dentition)."

States that dental anomalies affect only some individuals, supporting the OCCASIONAL band.

PMID:24421866 SUPPORT Human Clinical

"The proband had late dentition and his father a history of late dentition, but otherwise the teeth appeared normal."

Documents delayed dentition in two members of a DDOD family with otherwise normal teeth.

Enamel Hypoplasia HP:0006297

Show evidence (1 reference)

PMID:41777697 SUPPORT Human Clinical

"We describe an eight-year-old female with congenital deafness, nail dysplasia, enamel hypoplasia, and recurrent episodes of hypokalemia-induced muscle weakness."

Documents enamel hypoplasia in a molecularly confirmed DDOD patient alongside the defining deafness and nail findings.

Integument 1

Onychodystrophy VERY_FREQUENT Nail dystrophy HP:0008404

Show evidence (2 references)

PMID:39210597 SUPPORT Human Clinical

"sensorineural hearing loss and onychodystrophy appear to invariably occur in individuals carrying the recurrent truncating variant (p.Arg506∗) in ATP6V1B2, with or without neurodevelopmental involvement"

States that onychodystrophy occurs invariably in p.Arg506* carriers, supporting the VERY_FREQUENT band.

PMID:21998865 SUPPORT Human Clinical

"In the feet,there were hypoplastic great toenails and absent nails on second to fifth toes."

Documents the characteristic digit-selective pattern of nail involvement.

Limbs 1

Triphalangeal Thumb FREQUENT HP:0001199

Show evidence (2 references)

PMID:39210597 SUPPORT Human Clinical

"Specifically, individuals with DDOD syndrome primarily share sensorineural deafness and onychodystrophy with digital anomalies characterized by bulbous fingertips of digits, and finger-like thumbs/triphalangeal thumb."

Names triphalangeal or finger-like thumbs as a primary shared DDOD feature.

PMID:28396750 SUPPORT Human Clinical

"He has a high forehead with dolichocephaly, bilateral triphalangeal thumbs without nails, hypoplastic fingernails from second to fifth fingers, flat feet with absent toenails (Fig. 1)."

Documents bilateral triphalangeal thumbs in a molecularly confirmed DDOD proband.

Nervous System 1

Seizures HP:0001250

Show evidence (2 references)

PMID:37628590 SUPPORT Human Clinical

"Some but not all individuals with this truncating variant have intellectual disability and/or epilepsy, suggesting incomplete penetrance and/or variable expressivity."

Supports occasional seizures among p.Arg506* carriers with incomplete penetrance; PARTIAL because the statement spans the DDOD and DOORS labels rather than DDOD alone.

PMID:21998865 SUPPORT Human Clinical

"In addition to deafness and onychodystrophy, other features in this family included subtle facial dysmorphism in two individuals, cutis aplasia in one individual, epilepsy in one individual, and sudden infant death in two family members, one of whom had deafness and onychodystrophy and one who did not."

Documents epilepsy in one member of a family otherwise fitting classic DDOD.

Other 6

Congenital Sensorineural Hearing Loss VERY_FREQUENT Congenital sensorineural hearing impairment HP:0008527

Severity: SEVERE

Show evidence (2 references)

PMID:39210597 SUPPORT Human Clinical

"sensorineural hearing loss and onychodystrophy appear to invariably occur in individuals carrying the recurrent truncating variant (p.Arg506∗) in ATP6V1B2, with or without neurodevelopmental involvement"

States that hearing loss occurs invariably in p.Arg506* carriers, supporting the VERY_FREQUENT band.

PMID:28396750 SUPPORT Human Clinical

"Audiological examination by auditory brainstem responses (ABR) at 1 year of age indicated profound bilateral sensorineural hearing impairment."

Documents congenital profound bilateral sensorineural hearing loss in a molecularly confirmed DDOD proband.

Absent Fingernails HP:0001817

Show evidence (1 reference)

PMID:21998865 SUPPORT Human Clinical

"We report on a three-generation family with three affected members with absent finger and toenails, finger-like thumbs, and severe sensorineural deafness."

Documents absent fingernails in affected family members.

Hypoplastic Fingernails HP:0001804

Show evidence (1 reference)

PMID:28396750 SUPPORT Human Clinical

"He has a high forehead with dolichocephaly, bilateral triphalangeal thumbs without nails, hypoplastic fingernails from second to fifth fingers, flat feet with absent toenails (Fig. 1)."

Documents hypoplastic fingernails alongside absent thumb and toenails.

Hypoplastic Toenails HP:0001800

Show evidence (1 reference)

PMID:21998865 SUPPORT Human Clinical

"In the feet,there were hypoplastic great toenails and absent nails on second to fifth toes."

Documents hypoplastic great toenails in DDOD.

Bulbous Fingertips Broad fingertip HP:0011300

Show evidence (2 references)

PMID:39210597 SUPPORT Human Clinical

"Specifically, individuals with DDOD syndrome primarily share sensorineural deafness and onychodystrophy with digital anomalies characterized by bulbous fingertips of digits, and finger-like thumbs/triphalangeal thumb."

Names bulbous fingertips as a primary shared DDOD digital anomaly.

PMID:21998865 SUPPORT Human Clinical

"In the hands, the first and fifth digits had absent nails and bulbous swelling of the distal phalanx."

Documents bulbous distal phalangeal swelling of the affected digits.

Middle and Distal Phalangeal Hypoplasia Short middle phalanx of the 5th finger HP:0004220

Show evidence (1 reference)

PMID:24913193 SUPPORT Human Clinical

"The probands displayed identical phenotypes including severe congenital sensorineural hearing loss, absence of nails and aplasia of the middle phalanx in the fifth fingers"

Documents aplasia of the fifth-finger middle phalanx in all three original probands.

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Genetic Associations

1

ATP6V1B2 (Causative)

Gene: ATP6V1B2 hgnc:854 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (4 references)

PMID:24913193 SUPPORT Human Clinical

"The identification of ATP6V1B2 c.1516 C>T mutation in three independently identified DDOD patients provides evidence that defect in ATP6V1B2 is the genetic etiology for DDOD syndrome."

Establishes ATP6V1B2 as the DDOD disease gene.

PMID:24913193 SUPPORT Human Clinical

"The p.Arg506X mutation in ATP6V1B2 inserts a premature stop codon and results in a truncated protein."

Describes the molecular consequence of the recurrent allele.

PMID:24913193 SUPPORT Human Clinical

"Expression analysis performed by quantitative real-time PCR on total RNA isolated from leukocytes in pedigree 3 showed that the average expression level of ATP6V1B2 in case 3 was comparable to that in her parent controls, indicating that the mutant ATP6V1B2 mRNA is stable."

The transcript escapes nonsense-mediated decay, so a truncated protein is expressed rather than simply lost.

+ 1 more reference

Variants (1)

ATP6V1B2 p.Arg506* Pathogenic

NM_001693.4:c.1516C>T; p.Arg506* recurrent de novo truncating variant removing the C-terminal six residues.

Show evidence (2 references)

PMID:24913193 SUPPORT Human Clinical

"An identical heterozygous de novo c.1516 C>T (p.Arg506X) mutation in ATP6V1B2 was verified in two probands"

Identifies the variant as recurrent and de novo in unrelated DDOD probands.

PMID:24913193 SUPPORT Human Clinical

"The mutation was not detected in the normal-hearing population"

Absence from 1053 ethnically matched normal-hearing controls, supporting the pathogenic classification.

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Medical Actions

3

Cochlear Implantation

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

Cochlear implantation is the principal intervention for the congenital severe-to-profound sensorineural hearing loss of DDOD. Device-level and auditory outcomes are consistently good: successful oral-language rehabilitation was reported in the original probands implanted between 2 and 18 years of age, and a child receiving bilateral sequential implants showed continued gains in auditory and communication performance. Language outcome is less uniformly good than auditory outcome, and this should be stated plainly rather than smoothed over. Follow-up of implanted DDOD patients has documented unsatisfactory language rehabilitation despite a well-functioning implant on standard cochlear-mapping indicators, which the reporting group attributed to subtle learning and memory problems. Molecular diagnosis is therefore prognostically useful in syndromic congenital hearing loss, but it should not be presented to families as a guarantee of language outcome.

Mechanism Target:

RESTORES Congenital Sensorineural Hearing Loss — The implant bypasses the degenerated cochlear sensory apparatus and stimulates surviving auditory neurons directly, restoring auditory input without correcting the underlying lysosomal defect.

Show evidence (1 reference)

PMID:40164508 SUPPORT Human Clinical

"Children with DDOD syndrome (ATP6V1B2 c.1516C > T) receiving bilateral CIs can enhance aural and communication skills."

Reports auditory and communication benefit from bilateral implantation in genetically confirmed DDOD.

Show evidence (3 references)

PMID:24913193 SUPPORT Human Clinical

"All three individuals had unilateral cochlea implantation at the ages of 2.5, 2 and 18 years, respectively."

Documents cochlear implantation as the intervention received by the original DDOD cohort.

PMID:42361897 SUPPORT Human Clinical

"We describe two clinical cases of the deafness and onychodystrophy (DOD) spectrum and the benefit of molecular diagnosis to underline the importance of genetic testing when evaluating potential CI outcomes in syndromic congenital SNHL."

Supports molecular diagnosis as prognostically informative for cochlear implant outcome in this spectrum.

PMID:31257146 SUPPORT Human Clinical

"Clinical follow-up of DDOD syndrome patients with cochlear implantation revealed the language rehabilitation was unsatisfactory although the implanted cochlea worked well, which indicates there might be learning and memory problems in DDOD syndrome patients."

Qualifies the otherwise favourable implant outcomes. The device works but language rehabilitation may still disappoint, which is why this entry does not present implantation as a guaranteed language outcome; PARTIAL because it reports a limitation of the intervention rather than supporting or refuting its use.

CPT-cAMP Lysosomal Reacidification (preclinical)

Action: Pharmacotherapy NCIT:C15986

Agent: CPT-cAMP (8-(4-chlorophenylthio)adenosine 3',5'-cyclic monophosphate)

The one mechanism-directed candidate for this disorder rather than a supportive measure. CPT-cAMP is a membrane-permeable cAMP analogue that restored lysosomal acidification in a concentration-dependent manner in isogenic p.Arg506* cells, crosses the blood-brain barrier, and in Atp6v1b2 p.Arg506* mice reduced seizure frequency, improved cognitive performance, and resolved autophagosome accumulation. It is therefore aimed squarely at the rate-limiting node of this entry rather than at a downstream consequence. NOT an available therapy: this is proof-of-concept work in cells and mice with no human data, and the reported benefits are on the neurological and cognitive arm, which is precisely the arm that classic DDOD largely lacks, so the read-across to DDOD patients is an inference rather than a demonstrated result.

Mechanism Target:

RESTORES Impaired Endolysosomal Acidification — Raises cAMP signalling to drive V-ATPase-dependent reacidification, correcting the elevated lysosomal pH caused by the truncated B2 subunit rather than compensating for a downstream consequence of it.

Show evidence (1 reference)

PMID:41896517 SUPPORT In Vitro

"Remarkably, treatment with the cAMP analog CPT-cAMP restored lysosomal acidification in a concentration-dependent manner."

Demonstrates correction of the entry's rate-limiting node by this agent in isogenic mutant cells.

Show evidence (2 references)

PMID:41896517 SUPPORT Model Organism

"Intraperitoneal CPT-cAMP administration (20 mg/kg) exerted triple therapeutic effects: (1) significant reduction in seizure frequency, (2) improved cognitive performance in behavioral paradigms, and (3) restoration of autophagic flux through resolution of autophagosome accumulation."

Reports the in vivo effects in the p.Arg506* mouse, all on the neurological and autophagic arms.

PMID:41896517 SUPPORT INDIRECT Other

"These findings establish proof-of-concept for cAMP-mediated lysosomal pH modulation as a viable therapeutic strategy."

The authors' own framing as proof-of-concept, which is why this is curated as preclinical rather than as an available treatment; INDIRECT because it supports the strategy without establishing clinical efficacy.

Genetic Counseling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Counselling addresses the autosomal dominant recurrence risk. Most probands carry a de novo p.Arg506* variant with a correspondingly low sibling recurrence risk, but documented three-generation transmission means an affected individual carries a 50 percent transmission risk, and the variable penetrance of intellectual disability and seizures within the same allele must be conveyed as genuine uncertainty rather than as a predictable outcome.

Show evidence (2 references)

PMID:37628590 SUPPORT Human Clinical

"Some but not all individuals with this truncating variant have intellectual disability and/or epilepsy, suggesting incomplete penetrance and/or variable expressivity."

Establishes the penetrance uncertainty that must be communicated during counselling.

PMID:24421866 SUPPORT Human Clinical

"We present here three male family members in three generations with sensori-neural deafness, onychodystrophy and brachydactyly inherited via autosomal dominant transmission."

Documents dominant transmission, which sets the recurrence risk for an affected individual's offspring.

🔬

Diagnosis

3

ATP6V1B2 molecular testing

Molecular confirmation is definitive and is the only test that separates DDOD from its phenotypic neighbours, because the clinical triad of congenital sensorineural deafness, onychodystrophy and digital anomaly is shared across the ATP6V1B2 continuum. In practice this means finding the recurrent heterozygous NM_001693.4:c.1516C>T (p.Arg506*), which accounts for essentially every reported case; most probands are de novo, so parental testing is informative. Note the important limit: the identical allele also causes ATP6V1B2-related DOORS syndrome, so a positive result establishes the gene and the allele but does not by itself assign the DDOD label. That assignment rests on the absence of osteodystrophy, intellectual disability and seizures.

Results: Heterozygous ATP6V1B2 NM_001693.4:c.1516C>T (p.Arg506*), typically de novo.

Show evidence (2 references)

PMID:34746137 SUPPORT Human Clinical

"ATP6V1B2 c.1516 C > T, p.Arg506∗, was identified in all families with DDOD syndrome"

Establishes that testing for this single recurrent allele is effectively diagnostic at the gene level.

PMID:34232384 SUPPORT Human Clinical

"Pathogenic variants in four genes, ATP6V1B2, TBC1D24, KCNH1 and KCNN3, have been shown to be associated with deafness and onychodystrophy syndromes."

Defines the four-gene panel a deafness-plus-onychodystrophy presentation should be tested against, which is the differential this diagnosis sits inside.

Auditory brainstem response testing

ABR establishes the severity and sensorineural character of the hearing loss in infancy, before behavioural audiometry is reliable, and is the measurement on which the timing of cochlear implantation depends.

Results: Profound bilateral sensorineural hearing impairment, detectable in the first year of life.

Show evidence (1 reference)

PMID:28396750 SUPPORT Human Clinical

"Audiological examination by auditory brainstem responses (ABR) at 1 year of age indicated profound bilateral sensorineural hearing impairment."

Documents ABR as the modality establishing the hearing phenotype in infancy.

Temporal bone imaging

Imaging is performed to exclude a structural cause of congenital sensorineural hearing loss and to plan implantation. In DDOD it is characteristically normal. This is a useful negative: the deafness is cellular and neural rather than malformative, which is consistent with the spiral ganglion degeneration mechanism and means normal imaging does not argue against the diagnosis.

Results: No inner ear malformation.

Show evidence (1 reference)

PMID:24913193 SUPPORT Human Clinical

"None showed inner ear malformation and intellectual disability."

Records absence of inner ear malformation in the original DDOD probands.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Dominant Deafness-Onychodystrophy Syndrome:

Zimmermann-Laband syndrome type 2 Not Yet Curated MONDO:0014646

Overlapping Features ZLS2 is caused by dominant ATP6V1B2 missense variants, most characteristically p.Arg485Pro, and is an allelic differential within the same dominant V-ATPase clinical continuum rather than an unrelated disorder. The practical discriminators are gingival hypertrophy and hypertrichosis, which are characteristic of ZLS2 and only very rarely reported in DDOD, and intellectual disability, which is usual in ZLS2 and atypical in DDOD. Conversely, the DDOD pole is marked by the constancy of congenital sensorineural deafness plus onychodystrophy with bulbous fingertips and triphalangeal thumbs.

Distinguishing Features

Gingival hypertrophy and hypertrichosis favor ZLS2; they are not usually reported in DDOD.
Intellectual disability is usual in ZLS2 and atypical in DDOD.
Predominant congenital sensorineural deafness with onychodystrophy, bulbous fingertips, and triphalangeal thumbs favors DDOD.
The allele class differs, in that DDOD is essentially always the truncating p.Arg506* whereas ZLS2 arises from missense substitutions such as p.Arg485Pro.
Genotype and phenotype should be read as a continuum rather than an absolute boundary.

Show evidence (3 references)

PMID:39210597 SUPPORT Human Clinical

"Facial features of DOORS syndrome have a significant overlap with ZLS, a condition also associated with organomegaly, gingival hypertrophy, and hypertrichosis, which are not usually reported in DDOD and DOORS syndromes."

Supports gingival hypertrophy and hypertrichosis as ZLS-favoring discriminators against DDOD.

PMID:39210597 SUPPORT Human Clinical

"The present findings further support these observations, documenting the presence of a phenotypic continuum among these disorders."

Supports reading DDOD and ZLS2 as poles of a continuum rather than as absolutely separate entities.

PMID:28396750 SUPPORT Human Clinical

"He does not have gingival hyperplasia, hypertrichosis, organomegaly, or joint hyperextensibility."

A molecularly confirmed DDOD proband explicitly lacks the ZLS-defining features.

DOORS syndrome MONDO:0009079

Overlapping Features DOORS syndrome shares congenital sensorineural deafness, onychodystrophy and triphalangeal thumbs with DDOD, and the ATP6V1B2-related form of DOORS is caused by the very same recurrent p.Arg506* allele. The discriminators are therefore not molecular but clinical. Osteodystrophy beyond the digits, intellectual disability and seizures define the DOORS pole and are absent or exceptional in DDOD. The larger share of DOORS cases is caused by biallelic TBC1D24 variants, which is a genuinely different genotype and mode of inheritance.

Distinguishing Features

Osteodystrophy, intellectual disability, and seizures define DOORS and are absent or exceptional in DDOD.
The recurrent ATP6V1B2 p.Arg506* allele is shared, so molecular testing alone cannot separate ATP6V1B2-related DOORS from DDOD.
Biallelic TBC1D24 variants cause the majority of DOORS and are recessive, unlike the dominant ATP6V1B2 mechanism.

Show evidence (2 references)

PMID:37628590 SUPPORT Human Clinical

"The autosomal dominant ATP6V1B2 p.Arg506* variant can cause both congenital deafness with onychodystrophy, autosomal dominant (DDOD) and deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures syndromes (DOORS)."

Establishes that the same allele underlies both labels, so the differential rests on clinical features.

PMID:39210597 SUPPORT Human Clinical

"Individuals with DDOD syndrome usually show normal development and cognitive function, while those with DOORS syndrome and ZLS present with intellectual disability (ID), with or without seizures."

States the cognitive and seizure axis that separates DDOD from DOORS.

🧫

Experimental Models

1

DDOD patient-derived iPSC line CPGHi002-A IPSC_DERIVED_MODEL

Induced pluripotent stem cell line reprogrammed from a 10-month-old female DDOD patient heterozygous for the recurrent ATP6V1B2 c.1516C>T variant, with an isogenic gene-corrected counterpart, CPGHi002-A-1, generated from it. Together they provide a patient-genotype, isogenic-control platform for studying the DDOD allele in human cells, which is the gap the mouse models leave open.

Show evidence (2 references)

PMID:32961450 SUPPORT In Vitro

"The induced pluripotent stem cell (iPSC) line was generated using the non-integrating episomal vector method from peripheral blood mononuclear cells (PBMCs) of a 10-month-old female DDOD patient with heterozygous ATP6V1B2 c.1516 C > T variant."

Establishes the provenance and genotype of the patient-derived iPSC line.

PMID:33714068 SUPPORT In Vitro

"Here we genetically corrected the c.1516 C>T mutation in the ATP6V1B2 gene using CRISPR/Cas9 technology to generate an isogenic control, CPGHi002-A-1."

Establishes the availability of an isogenic gene-corrected control line, which is what makes the pair usable for the proposed experiments.

🐁

Animal Models

3

Atp6v1b2 p.Arg506* knock-in mouse

CRISPR-generated knock-in of the human DDOD allele. Two independent lines exist, one characterised for cochlear pathology and one phenotyped through the IMPC pipeline with EEG. Together they establish the lysosomal to autophagic to apoptotic chain in spiral ganglion neurons, and they also demonstrate the model's key limitation, namely that the hearing loss is late-onset rather than congenital.

Species

Mouse

Genotype

Atp6v1b2 c.1516C>T (p.Arg506*) knock-in, heterozygous and homozygous

Publication

PMID:34746137

Pathograph links

Apoptotic Degeneration of Spiral Ganglion Neurons and Hair Cells partially recapitulates fidelity: moderate The knock-in reproduces apoptotic spiral ganglion neuron degeneration downstream of lysosomal dysfunction and autophagic blockade, which is the human mechanism, but on a delayed timescale.

Limitations: Hearing loss in the mouse is late-onset and preceded by hidden hearing loss, whereas human DDOD deafness is congenital and severe to profound. Compensatory upregulation of the paralogue Atp6v1b1 in hair cells blunts the murine phenotype, and much of the characterisation used homozygotes rather than the heterozygous state that models patients.

Readouts

Spiral ganglion neuron degeneration

Direction: INCREASED

Interpretation: Histological correlate of the cochlear degeneration node.

Show evidence (1 reference)

PMID:34746137 SUPPORT Model Organism

"Apoptosis activated by lysosomal dysfunction and the subsequent blockade of autophagic flux induced the degeneration of spiral ganglion neurons and further impaired the hearing."

Reports the apoptotic spiral ganglion degeneration measured in this model.

Show evidence (1 reference)

PMID:34746137 SUPPORT Model Organism

"The Atp6v1b2Arg506*/Arg506* mice showed hidden hearing loss (HHL) at early stages and developed late-onset hearing loss."

Establishes the model as informative for the cochlear node while naming its temporal mismatch.

Show evidence (1 reference)

PMID:37628590 SUPPORT Model Organism

"EEG analyses indicate that Atp6v1b2emR506* mutant mice have interictal epileptic activity and that both heterozygous (like patients) and homozygous mice have reduced seizure thresholds to pentylenetetrazol."

Establishes the knock-in as a model of the seizure-susceptibility arm of the p.Arg506* spectrum.

Cochlea-specific Atp6v1b2 morpholino knockdown mouse

Acute knockdown of Atp6v1b2 in the cochlea by microinjection of a splice-blocking morpholino into the scala media before postnatal day 3. This was the original demonstration that Atp6v1b2 deficiency alone is sufficient to cause sensorineural hearing loss, and the same approach was later used to profile the lysosomal and autophagic changes in cochlear tissue.

Species

Mouse

Genotype

Wild-type mouse with intracochlear Atp6v1b2 splice-blocking morpholino

Publication

PMID:24913193

Pathograph links

Impaired Endolysosomal Acidification recapitulates fidelity: moderate Cochlear knockdown reproduces the reduction in V-ATPase activity and lysosomal acidification that underlies the human disease, measured in cochlear tissue rather than in a heterologous cell line.

Limitations: Morpholino knockdown reduces wild-type transcript rather than expressing the truncated p.Arg506* subunit, so it models a pure dose reduction and cannot distinguish haploinsufficiency from a dominant-negative effect of the truncated protein. The effect is also acute and postnatal rather than developmental.

Readouts

Cochlear V-ATPase and cathepsin-D activity

Direction: DECREASED

Interpretation: Biochemical correlate of the acidification node in cochlear tissue.

Show evidence (1 reference)

PMID:41995948 SUPPORT Model Organism

"Mechanistically, cochlear V-ATPase and Cath-D activities were significantly reduced, while lysosomal membrane proteins (LAMP1, LAMP2) and ion channel proteins (TPC1, TPC2) were upregulated, suggesting lysosomal acidification dysfunction."

Reports the enzyme-activity measurements behind this readout.

Show evidence (1 reference)

PMID:41995948 SUPPORT Model Organism

"A DDOD syndrome mouse model was established via cochlear microinjection of ATP6V1B2-specific morpholino, while control mice injected with a scramble morpholino."

Establishes the model and its use for the cochlear acidification question.

Show evidence (1 reference)

PMID:24913193 SUPPORT Model Organism

"We generated a cochlea-specific Atp6v1b2-knockdown mouse model and found that Atp6v1b2 deficiency leads to severe sensorineural hearing loss."

Establishes that cochlear Atp6v1b2 deficiency is sufficient for sensorineural hearing loss.

Hair-cell-specific Atp6v1b2 conditional knockout mouse

Conditional deletion of Atp6v1b2 in cochlear hair cells, generated to provide a tractable platform for inner-ear gene therapy. It reproduces hair cell loss and abnormal lysosomal morphology, and a single intracochlear dose of an AAV vector carrying wild-type Atp6v1b2 rescued both.

Species

Mouse

Genotype

Atp6v1b2 fl/fl; Atoh1-Cre/+ conditional knockout

Publication

PMID:40068100

Pathograph links

Apoptotic Degeneration of Spiral Ganglion Neurons and Hair Cells rescues fidelity: moderate A single postnatal administration of AAV-ie-Eh3-mAtp6v1b2 into the scala media prevented hair cell degeneration and restored lysosome morphology and auditory and vestibular function, providing the strongest available causal test that the cochlear degeneration node is Atp6v1b2-dependent and in principle reversible.

Limitations: The model is a hair-cell-restricted complete knockout, not the heterozygous truncating genotype of human DDOD, and it does not address the spiral ganglion neuron compartment. Rescue was delivered at postnatal days 0 to 2, a developmental window with no direct human equivalent given that DDOD deafness is already present at birth. This is a preclinical result, not an available therapy.

Readouts

Auditory and vestibular function after AAV gene transfer

Direction: RESTORED

Interpretation: Functional rescue confirming the node is Atp6v1b2-dependent.

Show evidence (1 reference)

PMID:40068100 SUPPORT Model Organism

"A single administration of AAV-ie-Eh3-mAtp6v1b2 into the scala media at postnatal days 0-2, prevented hair cell degeneration, restored lysosome morphology, and robustly rescued auditory and vestibular function for at least 24 weeks."

Reports the functional and histological rescue measured in this model.

Show evidence (1 reference)

PMID:40068100 SUPPORT Model Organism

"The study generates a hair cell-specific knockout mouse (Atp6v1b2fl/fl;Atoh1Cre/+) recapitulating the human phenotypes, with pathological features including hair cell loss and abnormal lysosomal morphology and function."

Establishes the model as informative for the cochlear degeneration node.

{ }

Source YAML

click to show

name: Dominant Deafness-Onychodystrophy Syndrome
category: Mendelian
creation_date: "2026-08-21T00:00:00Z"
synonyms:
- DDOD
- DDOD syndrome
- autosomal dominant deafness-onychodystrophy syndrome
- deafness, congenital, with onychodystrophy, autosomal dominant
- Robinson-Miller-Bensimon syndrome
description: >
  Dominant deafness-onychodystrophy (DDOD) syndrome is a rare autosomal dominant
  disorder that pairs congenital severe-to-profound sensorineural hearing loss
  with onychodystrophy (hypoplastic or absent finger- and toenails) and
  characteristic distal digital anomalies, most notably triphalangeal or
  finger-like thumbs, bulbous fingertips, and hypoplasia of the terminal or
  middle phalanges. Development and cognition are characteristically normal,
  which is the main clinical feature separating DDOD from the neighbouring
  ATP6V1B2 phenotypes, though subtle learning and memory involvement has been
  reported in implanted patients and has never been systematically excluded.
  Almost every molecularly solved case carries the same
  recurrent heterozygous truncating variant in ATP6V1B2,
  NM_001693.4:c.1516C>T (p.Arg506*), usually arising de novo but also
  transmitted through multi-generation families. ATP6V1B2 encodes the B2 subunit
  of the V1 domain of the vacuolar H+-ATPase, so the mechanistic spine of the
  disorder runs through defective endolysosomal acidification, blocked
  autophagic flux, and apoptotic degeneration of cochlear spiral ganglion
  neurons and hair cells. DDOD sits at one end of a dominant ATP6V1B2 clinical
  continuum whose other poles are Zimmermann-Laband syndrome type 2 and the
  ATP6V1B2-related form of DOORS syndrome; the same p.Arg506* allele causes both
  DDOD and DOORS, with intellectual disability and seizures showing incomplete
  penetrance and variable expressivity.
disease_term:
  preferred_term: dominant deafness-onychodystrophy syndrome
  term:
    id: MONDO:0007420
    label: autosomal dominant deafness - onychodystrophy syndrome
parents:
- autosomal dominant disease
classifications:
  harrisons_chapter:
  - classification_value: DISORDER_OF_EAR
    notes: >-
      Congenital sensorineural hearing loss is the constant and clinically
      dominant feature, and cochlear implantation is the principal
      intervention.
    evidence:
    - reference: PMID:40164508
      reference_title: "Clinical Insights into Bilateral Cochlear Implantation for a Child with Dominant Deafness-Onychodystrophy Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Dominant deafness-onychodystrophy (DDOD) syndrome is a rare genetic disorder characterized by sensorineural hearing loss and the absence or hypoplasia of nails, associated with defects in the ATP6V1B2 gene."
      explanation: Frames DDOD as a sensorineural hearing disorder, supporting placement in the ear Part.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      Monogenic autosomal dominant disorder caused by a recurrent heterozygous
      ATP6V1B2 truncating variant.
    evidence:
    - reference: PMID:24913193
      reference_title: De novo mutation in ATP6V1B2 impairs lysosome acidification and causes dominant deafness-onychodystrophy syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "An identical heterozygous de novo c.1516 C>T (p.Arg506X) mutation in ATP6V1B2 was verified in two probands"
      explanation: Establishes DDOD as a Mendelian disorder with a defined causal variant.
  - classification_value: DERMATOLOGY
    notes: >-
      Onychodystrophy is the second obligate feature and places the entry under
      the integumentary parent MONDO:0002051 as well.
    evidence:
    - reference: PMID:24913193
      reference_title: De novo mutation in ATP6V1B2 impairs lysosome acidification and causes dominant deafness-onychodystrophy syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Dominant deafness-onychodystrophy syndrome (DDOD syndrome; MIM 124480) is characterized mainly by congenital sensorineural hearing loss accompanied by dystrophic or absent nails."
      explanation: States the nail-dystrophy component of the defining phenotype pair.
notes: >-
  Nosological scope. DDOD, Zimmermann-Laband syndrome type 2 (ZLS2) and the
  ATP6V1B2-related form of DOORS syndrome are increasingly described as a single
  dominant V-ATPase phenotypic continuum rather than three separate diseases,
  and the recurrent p.Arg506* allele is shared between DDOD and DOORS. dismech
  nevertheless keeps DDOD as its own Disease entry, consistent with the existing
  separate Zimmermann_Laband_Syndrome and DOORS_Syndrome entries and with
  MONDO:0007420 being a distinct leaf term with its own OMIM identity
  (MIM 124480). The continuum is modelled explicitly rather than left implicit.
  See the `differential_diagnoses` block, which curates the axes that separate
  the poles, and the `discussions` block, which records what is genuinely
  unresolved about the shared mechanism. Curators extending this entry should
  not silently import ZLS2 or DOORS findings as DDOD findings, because the
  functional data behind the two poles were generated on different alleles and
  point in opposite directions.

  Normal development and cognition are deliberately NOT curated as a
  `phenotypes` entry. The only available HPO binding would be HP:0001249
  Intellectual disability carrying REFUTE evidence, which renders as though the
  disease had intellectual disability. The claim is instead carried in the
  description above and in the DOORS and ZLS2 differential blocks, where it is
  the discriminating axis rather than a feature of the disease.
inheritance:
- name: Autosomal dominant inheritance
  description: >-
    DDOD is transmitted as an autosomal dominant trait. Most molecularly solved
    probands carry a de novo heterozygous ATP6V1B2 p.Arg506* variant with
    unaffected parents, but vertical transmission through three generations has
    been documented in two independent families, confirming dominant
    inheritance rather than exclusively sporadic de novo occurrence.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:24421866
    reference_title: A Danish family with dominant deafness-onychodystrophy syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We present here three male family members in three generations with sensori-neural deafness, onychodystrophy and brachydactyly inherited via autosomal dominant transmission."
    explanation: Documents vertical autosomal dominant transmission across three generations.
  - reference: PMID:24913193
    reference_title: De novo mutation in ATP6V1B2 impairs lysosome acidification and causes dominant deafness-onychodystrophy syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An identical heterozygous de novo c.1516 C>T (p.Arg506X) mutation in ATP6V1B2 was verified in two probands"
    explanation: Establishes the heterozygous de novo origin in simplex probands.
genetic:
- name: ATP6V1B2
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: ATP6V1B2
    term:
      id: hgnc:854
      label: ATP6V1B2
  notes: >-
    ATP6V1B2 encodes the B2 subunit of the cytosolic V1 domain of the vacuolar
    H+-ATPase. Essentially all molecularly confirmed DDOD probands reported to
    date carry the same recurrent nonsense variant NM_001693.4:c.1516C>T
    (p.Arg506*), which removes the last six highly conserved residues. The
    mutant transcript escapes nonsense-mediated decay, so the truncated subunit
    is expressed rather than absent, which is why the mechanism is described as
    loss of function without the route (dominant negative versus
    haploinsufficiency) being settled. The variant's structured allele and
    functional-impact annotation is carried by the `genetic_context` block on
    the ATP6V1B2 truncation pathophysiology node. The very same allele is also
    reported in ATP6V1B2-related DOORS syndrome; different missense alleles in
    the same gene cause Zimmermann-Laband syndrome type 2.
  variants:
  - name: ATP6V1B2 p.Arg506*
    description: "NM_001693.4:c.1516C>T; p.Arg506* recurrent de novo truncating variant removing the C-terminal six residues."
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:24913193
      reference_title: De novo mutation in ATP6V1B2 impairs lysosome acidification and causes dominant deafness-onychodystrophy syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "An identical heterozygous de novo c.1516 C>T (p.Arg506X) mutation in ATP6V1B2 was verified in two probands"
      explanation: Identifies the variant as recurrent and de novo in unrelated DDOD probands.
    - reference: PMID:24913193
      reference_title: De novo mutation in ATP6V1B2 impairs lysosome acidification and causes dominant deafness-onychodystrophy syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The mutation was not detected in the normal-hearing population"
      explanation: Absence from 1053 ethnically matched normal-hearing controls, supporting the pathogenic classification.
  evidence:
  - reference: PMID:24913193
    reference_title: De novo mutation in ATP6V1B2 impairs lysosome acidification and causes dominant deafness-onychodystrophy syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The identification of ATP6V1B2 c.1516 C>T mutation in three independently identified DDOD patients provides evidence that defect in ATP6V1B2 is the genetic etiology for DDOD syndrome."
    explanation: Establishes ATP6V1B2 as the DDOD disease gene.
  - reference: PMID:24913193
    reference_title: De novo mutation in ATP6V1B2 impairs lysosome acidification and causes dominant deafness-onychodystrophy syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The p.Arg506X mutation in ATP6V1B2 inserts a premature stop codon and results in a truncated protein."
    explanation: Describes the molecular consequence of the recurrent allele.
  - reference: PMID:24913193
    reference_title: De novo mutation in ATP6V1B2 impairs lysosome acidification and causes dominant deafness-onychodystrophy syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Expression analysis performed by quantitative real-time PCR on total RNA isolated from leukocytes in pedigree 3 showed that the average expression level of ATP6V1B2 in case 3 was comparable to that in her parent controls, indicating that the mutant ATP6V1B2 mRNA is stable."
    explanation: The transcript escapes nonsense-mediated decay, so a truncated protein is expressed rather than simply lost.
  - reference: PMID:34746137
    reference_title: Syndromic Deafness Gene ATP6V1B2 Controls Degeneration of Spiral Ganglion Neurons Through Modulating Proton Flux.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ATP6V1B2 c.1516 C > T, p.Arg506∗, was identified in all families with DDOD syndrome"
    explanation: Establishes the recurrent allele as essentially the sole reported DDOD genotype.
pathophysiology:
- name: ATP6V1B2 C-Terminal Truncation and Weakened V-ATPase Subunit Interaction
  biological_scale: MOLECULAR
  description: >
    The recurrent heterozygous c.1516C>T (p.Arg506*) variant inserts a premature
    stop codon that removes the last six, highly conserved residues of the
    ATP6V1B2 B2 subunit. Because the transcript is stable and escapes
    nonsense-mediated decay, the truncated subunit is produced and incorporated
    into the pump rather than being absent. The truncation weakens the
    interaction between the V1B2 and V1E subunits and ATP hydrolysis by the
    complex falls. The node is deliberately named for the weakened subunit
    interaction rather than for failed assembly: the V-ATPase complex still
    assembles with the truncated subunit, so this is a defective pump rather
    than an absent one, which is exactly why the dominant-negative reading
    remains live.
  genetic_context:
    allele_type: nonsense single-nucleotide variant
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    genes:
    - preferred_term: ATP6V1B2
      term:
        id: hgnc:854
        label: ATP6V1B2
    description: >-
      Heterozygous germline NM_001693.4:c.1516C>T (p.Arg506*), recurrent and
      usually de novo, removing the C-terminal six residues of the B2 subunit.
    notes: >-
      LOSS_OF_FUNCTION is chosen deliberately as the superordinate call the
      literature actually supports, not as a default. Yuan et al. measured
      reduced ATPase hydrolysis activity and reduced lysosomal acidification for
      the p.Arg506* allele and called it haploinsufficient; a later review of
      the same allele concluded only that it acts by loss of function, and
      explicitly left dominant-negative versus haploinsufficiency open, which is
      recorded as a KNOWLEDGE_GAP discussion on this entry. The finer
      FunctionalImpactEnum values DOMINANT_NEGATIVE and
      PARTIAL_LOSS_OF_FUNCTION are therefore deliberately NOT used here.
  molecular_functions:
  - preferred_term: V-ATPase proton transmembrane transporter activity
    term:
      id: GO:0015078
      label: proton transmembrane transporter activity
    modifier: DECREASED
  evidence:
  - reference: PMID:24913193
    reference_title: De novo mutation in ATP6V1B2 impairs lysosome acidification and causes dominant deafness-onychodystrophy syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We found that the ATPase hydrolysis activity significantly decreased in the transfected cells when the ratio of the mutant/WT increased."
    explanation: Directly measures reduced ATPase hydrolysis activity attributable to the DDOD allele.
  - reference: PMID:34746137
    reference_title: Syndromic Deafness Gene ATP6V1B2 Controls Degeneration of Spiral Ganglion Neurons Through Modulating Proton Flux.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The interaction between the V1B2 and V1E subunits was found to be weaker in Atp6v1b2Arg506*/Arg506*mice than in wild-type (WT) mice, indicating that the assembly of V-ATPase was affected by the mutation"
    explanation: Provides the subunit-interaction defect that links the truncation to reduced pump function.
  - reference: PMID:31257146
    reference_title: A subunit of V-ATPases, ATP6V1B2, underlies the pathology of intellectual disability.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The molecular mechanism underlying V-ATPases dysfunction involves a weak interaction between the E and B2 subunits, although the assembly of V-ATPases can still take place."
    explanation: Qualifies the preceding item. Assembly of the complex is not abolished, so the lesion is a weakened subunit interaction within an assembled pump rather than failure to assemble; PARTIAL because it supports the interaction defect while constraining how strongly the assembly claim may be stated.
  downstream:
  - target: Impaired Endolysosomal Acidification
    causal_link_type: DIRECT
    description: >-
      Reduced V1 domain assembly and ATP hydrolysis lower proton pumping into
      the lysosomal lumen.
    evidence:
    - reference: PMID:24913193
      reference_title: De novo mutation in ATP6V1B2 impairs lysosome acidification and causes dominant deafness-onychodystrophy syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "In vitro pathogenic evaluation showed that the ATP6V1B2 p.Arg506X is a haploinsufficient mutation and resulted in abnormal acidification in lysosomes."
      explanation: Links the variant's effect on the pump to the acidification defect.
- name: Impaired Endolysosomal Acidification
  biological_scale: CELLULAR
  description: >
    Reduced V-ATPase proton pumping raises lysosomal luminal pH. In cells
    expressing the DDOD allele, and in cochlear tissue from the corresponding
    mouse models, lysosomal acidification is reduced, cathepsin-D activity falls
    and lysosomal membrane and ion-channel proteins are upregulated, consistent
    with failure of the acidic compartment to support hydrolase activity. This
    node is the disease's rate-limiting molecular lesion.
  cell_types:
  - preferred_term: Spiral ganglion neuron
    term:
      id: CL:0011113
      label: spiral ganglion neuron
  - preferred_term: Cochlear hair cell
    term:
      id: CL:0000202
      label: auditory hair cell
  biological_processes:
  - preferred_term: Lysosomal lumen acidification
    term:
      id: GO:0007042
      label: lysosomal lumen acidification
    modifier: DECREASED
  - preferred_term: Vacuolar acidification
    term:
      id: GO:0007035
      label: vacuolar acidification
    modifier: DECREASED
  evidence:
  - reference: PMID:24913193
    reference_title: De novo mutation in ATP6V1B2 impairs lysosome acidification and causes dominant deafness-onychodystrophy syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "A statistically significant difference in lysosomal pH was detected between ATP6V1B2 WT- and c.1516 C>T mutant-transfected cells (LSD test, p = 0.02, Supplementary information, Figure S1E), indicating the reduced acidification caused by c.1516 C>T mutation."
    explanation: Measures the raised lysosomal pH produced by the DDOD allele.
  - reference: PMID:41995948
    reference_title: ATP6V1B2 Regulating Autophagy Flux To Affect Abnormal Auditory Development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mechanistically, cochlear V-ATPase and Cath-D activities were significantly reduced, while lysosomal membrane proteins (LAMP1, LAMP2) and ion channel proteins (TPC1, TPC2) were upregulated, suggesting lysosomal acidification dysfunction."
    explanation: Confirms the acidification defect in cochlear tissue of a DDOD model rather than only in transfected cells.
  - reference: PMID:41896517
    reference_title: Therapeutic potential of cAMP-mediated lysosomal pH modulation in ATP6V1B2-related neuropathology.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Cellular studies demonstrated significant increase of lysosomal pH in mutant cells compared to wild-type control."
    explanation: Independent replication of the raised lysosomal pH in isogenic CRISPR-engineered p.Arg506* cells, which is the cleanest genetic control for this direction of effect and does not depend on transient overexpression.
  downstream:
  - target: Autophagic Flux Blockade
    causal_link_type: DIRECT
    description: >-
      Lysosomes that cannot acidify cannot complete degradation of
      autophagosomal cargo, so autophagic flux stalls.
    evidence:
    - reference: PMID:41995948
      reference_title: ATP6V1B2 Regulating Autophagy Flux To Affect Abnormal Auditory Development.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "In HEI-OC1 cells, ATP6V1B2 knockdown led to autophagosome accumulation, increased expression of pro-apoptotic proteins (Bax, Caspase-3), decreased anti-apoptotic Bcl-2, elevated early apoptosis rates, and altered ROS levels."
      explanation: Connects reduced ATP6V1B2 to autophagosome accumulation in a cochlear cell line.
- name: Autophagic Flux Blockade
  biological_scale: CELLULAR
  description: >
    Undegraded autophagosomes accumulate because fusion-competent, acidified
    lysosomes are not available to complete cargo breakdown. In cochlear tissue
    this manifests as accumulation of large autophagosomes together with the
    lysosomal morphological abnormalities seen in the mouse models.
  biological_processes:
  - preferred_term: Autophagosome maturation
    term:
      id: GO:0097352
      label: autophagosome maturation
    modifier: DECREASED
  - preferred_term: Autophagy
    term:
      id: GO:0006914
      label: autophagy
    modifier: DECREASED
  evidence:
  - reference: PMID:34746137
    reference_title: Syndromic Deafness Gene ATP6V1B2 Controls Degeneration of Spiral Ganglion Neurons Through Modulating Proton Flux.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Apoptosis activated by lysosomal dysfunction and the subsequent blockade of autophagic flux induced the degeneration of spiral ganglion neurons and further impaired the hearing."
    explanation: States the lysosomal dysfunction to autophagic blockade to neurodegeneration sequence in the p.Arg506* mouse.
  downstream:
  - target: Apoptotic Degeneration of Spiral Ganglion Neurons and Hair Cells
    causal_link_type: DIRECT
    description: >-
      Persistent autophagic blockade activates the intrinsic apoptotic program
      in cochlear neurons and sensory cells.
    evidence:
    - reference: PMID:41995948
      reference_title: ATP6V1B2 Regulating Autophagy Flux To Affect Abnormal Auditory Development.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "ATP6V1B2 downregulation impairs cochlear lysosomal acidification by reducing V-ATPase activity, leading to autophagic flux blockade, apoptosis activation, and mitochondrial dysfunction, ultimately contributing to SGN degeneration and progressive hearing loss."
      explanation: States the full chain from acidification failure through autophagic blockade to apoptosis and SGN degeneration.
- name: Apoptotic Degeneration of Spiral Ganglion Neurons and Hair Cells
  biological_scale: TISSUE
  conforms_to: "sensorineural_hair_cell_loss#Cochlear Amplification Loss and Spiral Ganglion Neuron Degeneration"
  description: >
    Autophagosome accumulation shifts the Bcl-2 to Bax ratio, permeabilizing the
    mitochondrial outer membrane and releasing cytochrome c, which activates
    caspase-3. The resulting apoptosis produces loss of spiral ganglion neurons
    and, in the hair-cell-specific knockout model, hair cell degeneration. In the
    knock-in mouse the earliest cochlear lesion is demyelination of auditory
    nerve fibres, followed by fibre and spiral ganglion cell body loss, with the
    organ of Corti morphologically normal, so the degeneration in that model is
    neural rather than sensory. Atp6v1b2 is expressed in exactly these
    compartments, which is what makes the cochlea the tissue that fails first.
    This node is the DDOD-specific instance of the conserved
    spiral-ganglion arm of the sensorineural hearing loss module. It attaches at
    the spiral ganglion node rather than the module's upstream
    `#Hair Cell Mechanotransduction Failure and Death` node because the
    p.Arg506* evidence describes apoptotic neurodegeneration downstream of
    lysosomal failure, not a primary mechanotransduction defect.
  cell_types:
  - preferred_term: Spiral ganglion neuron
    term:
      id: CL:0011113
      label: spiral ganglion neuron
  - preferred_term: Cochlear hair cell
    term:
      id: CL:0000202
      label: auditory hair cell
  biological_processes:
  - preferred_term: Neuron apoptotic process
    term:
      id: GO:0051402
      label: neuron apoptotic process
    modifier: INCREASED
  - preferred_term: Apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:24913193
    reference_title: De novo mutation in ATP6V1B2 impairs lysosome acidification and causes dominant deafness-onychodystrophy syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Immunostaining of mouse cochlear sections and cultured cochlear tissues showed Atp6v1b2 expression mainly in the organ of Corti and spiral ganglion neurons"
    explanation: Establishes that the affected compartments express the gene, grounding cochlear tissue selectivity.
  - reference: PMID:41995948
    reference_title: ATP6V1B2 Regulating Autophagy Flux To Affect Abnormal Auditory Development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In DDOD model mice, ATP6V1B2 mRNA and protein levels were significantly reduced in the inner ear, with decreased localization in key auditory regions such as cochlear hair cells and spiral ganglion neurons (SGNs), which was accompanied by SGN loss."
    explanation: Directly reports spiral ganglion neuron loss in a DDOD model.
  - reference: PMID:40068100
    reference_title: Single Administration of AAV-mAtp6v1b2 Gene Therapy Rescues Hearing and Vestibular Disorders Caused by Atp6v1b2-Induced Lysosomal Dysfunction in Hair Cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The study generates a hair cell-specific knockout mouse (Atp6v1b2fl/fl;Atoh1Cre/+) recapitulating the human phenotypes, with pathological features including hair cell loss and abnormal lysosomal morphology and function."
    explanation: Adds the hair-cell arm of cochlear degeneration alongside spiral ganglion loss.
  - reference: PMID:34746137
    reference_title: Syndromic Deafness Gene ATP6V1B2 Controls Degeneration of Spiral Ganglion Neurons Through Modulating Proton Flux.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In this study, Atp6v1b2Arg506*/Arg506* mice developed demyelination of nerve fibers, followed by loss of nerve fibers and SGN cell bodies."
    explanation: Establishes auditory nerve fibre demyelination as the earliest cochlear lesion, preceding spiral ganglion cell body loss.
  - reference: PMID:34746137
    reference_title: Syndromic Deafness Gene ATP6V1B2 Controls Degeneration of Spiral Ganglion Neurons Through Modulating Proton Flux.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the Bcl-2 family detects abnormal lysosome autophagy and then induces the release of cytochrome C from the mitochondria; and (4) apoptosis occurs in SGNs, affecting hearing function"
    explanation: Provides the mitochondrial permeabilization and cytochrome c release step linking autophagic blockade to spiral ganglion apoptosis.
  downstream:
  - target: Congenital Sensorineural Hearing Loss
    causal_link_type: DIRECT
    description: >-
      Loss of cochlear sensory cells and their afferent neurons abolishes
      auditory transduction and transmission.
    evidence:
    - reference: PMID:34746137
      reference_title: Syndromic Deafness Gene ATP6V1B2 Controls Degeneration of Spiral Ganglion Neurons Through Modulating Proton Flux.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Apoptosis activated by lysosomal dysfunction and the subsequent blockade of autophagic flux induced the degeneration of spiral ganglion neurons and further impaired the hearing."
      explanation: Links the cochlear degeneration node to the hearing phenotype.
- name: Impaired Nail Matrix and Distal Digit Development
  biological_scale: TISSUE
  description: >
    The second obligate arm of DDOD is failure of nail-plate formation with
    associated hypoplasia of the terminal and middle phalanges, giving absent or
    hypoplastic nails, bulbous fingertips and triphalangeal or finger-like
    thumbs. Nail-matrix keratinocytes are a highly differentiating,
    keratinisation-dependent lineage in which endolysosomal proteolysis is
    required, which is the plausible route from the same V-ATPase lesion to the
    integumentary and distal skeletal phenotype. This node is deliberately
    curated without a mechanistic evidence item for the acidification-to-nail
    step. The observation that DDOD patients have onychodystrophy is
    well-evidenced, but no study has yet demonstrated the lysosomal mechanism in
    nail matrix or developing digit, which is recorded as a KNOWLEDGE_GAP.
  cell_types:
  - preferred_term: Nail matrix keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  evidence:
  - reference: PMID:24913193
    reference_title: De novo mutation in ATP6V1B2 impairs lysosome acidification and causes dominant deafness-onychodystrophy syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The probands displayed identical phenotypes including severe congenital sensorineural hearing loss, absence of nails and aplasia of the middle phalanx in the fifth fingers"
    explanation: Establishes the paired nail and terminal-phalanx involvement in DDOD probands.
  downstream:
  - target: Onychodystrophy
    causal_link_type: DIRECT
    description: >-
      Failure of nail-matrix differentiation produces the absent or hypoplastic
      nails that define the disorder's second arm.
    evidence:
    - reference: PMID:21998865
      reference_title: Report of a further family with dominant deafness-onychodystrophy (DDOD) syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In the hands, the first and fifth digits had absent nails and bulbous swelling of the distal phalanx."
      explanation: Describes the nail and distal phalanx findings that constitute the phenotype.
phenotypes:
- category: Auditory
  name: Congenital Sensorineural Hearing Loss
  description: >
    Bilateral severe-to-profound sensorineural hearing loss present from birth
    and detected on auditory brainstem response testing in infancy. It is the
    single most consistent feature of DDOD and is present in essentially all
    reported individuals with the p.Arg506* allele.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Congenital sensorineural hearing impairment
    term:
      id: HP:0008527
      label: Congenital sensorineural hearing impairment
    severity: SEVERE
  evidence:
  - reference: PMID:39210597
    reference_title: Dominantly acting variants in ATP6V1C1 and ATP6V1B2 cause a multisystem phenotypic spectrum by altering lysosomal and/or autophagosome function.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "sensorineural hearing loss and onychodystrophy appear to invariably occur in individuals carrying the recurrent truncating variant (p.Arg506∗) in ATP6V1B2, with or without neurodevelopmental involvement"
    explanation: States that hearing loss occurs invariably in p.Arg506* carriers, supporting the VERY_FREQUENT band.
  - reference: PMID:28396750
    reference_title: Dominant deafness-onychodystrophy syndrome caused by an ATP6V1B2 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Audiological examination by auditory brainstem responses (ABR) at 1 year of age indicated profound bilateral sensorineural hearing impairment."
    explanation: Documents congenital profound bilateral sensorineural hearing loss in a molecularly confirmed DDOD proband.
- category: Integumentary
  name: Onychodystrophy
  description: >
    Absent or hypoplastic finger- and toenails. Involvement is characteristically
    patterned rather than uniform. The thumb and fifth finger are most severely
    affected in the hands, with relative sparing of the second to fourth digits,
    while in the feet the great toenail is hypoplastic and the second to fifth
    toenails are typically absent.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Nail dystrophy
    term:
      id: HP:0008404
      label: Nail dystrophy
  evidence:
  - reference: PMID:39210597
    reference_title: Dominantly acting variants in ATP6V1C1 and ATP6V1B2 cause a multisystem phenotypic spectrum by altering lysosomal and/or autophagosome function.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "sensorineural hearing loss and onychodystrophy appear to invariably occur in individuals carrying the recurrent truncating variant (p.Arg506∗) in ATP6V1B2, with or without neurodevelopmental involvement"
    explanation: States that onychodystrophy occurs invariably in p.Arg506* carriers, supporting the VERY_FREQUENT band.
  - reference: PMID:21998865
    reference_title: Report of a further family with dominant deafness-onychodystrophy (DDOD) syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the feet,there were hypoplastic great toenails and absent nails on second to fifth toes."
    explanation: Documents the characteristic digit-selective pattern of nail involvement.
- category: Integumentary
  name: Absent Fingernails
  description: >
    Complete absence of nails on affected digits, most consistently the thumb
    and fifth finger, is the severe end of the onychodystrophy spectrum and was
    present in all three probands of the original gene-discovery cohort.
  phenotype_term:
    preferred_term: Absent fingernail
    term:
      id: HP:0001817
      label: Absent fingernail
  evidence:
  - reference: PMID:21998865
    reference_title: Report of a further family with dominant deafness-onychodystrophy (DDOD) syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report on a three-generation family with three affected members with absent finger and toenails, finger-like thumbs, and severe sensorineural deafness."
    explanation: Documents absent fingernails in affected family members.
- category: Integumentary
  name: Hypoplastic Fingernails
  description: >
    Fingernails that are present but small and dysplastic, typically on the
    second to fifth digits where nail loss is incomplete.
  phenotype_term:
    preferred_term: Hypoplastic fingernail
    term:
      id: HP:0001804
      label: Hypoplastic fingernail
  evidence:
  - reference: PMID:28396750
    reference_title: Dominant deafness-onychodystrophy syndrome caused by an ATP6V1B2 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He has a high forehead with dolichocephaly, bilateral triphalangeal thumbs without nails, hypoplastic fingernails from second to fifth fingers, flat feet with absent toenails (Fig. 1)."
    explanation: Documents hypoplastic fingernails alongside absent thumb and toenails.
- category: Integumentary
  name: Hypoplastic Toenails
  description: >
    Small or dysplastic toenails, characteristically affecting the great toe
    where the nail is hypoplastic rather than absent.
  phenotype_term:
    preferred_term: Hypoplastic toenails
    term:
      id: HP:0001800
      label: Hypoplastic toenails
  evidence:
  - reference: PMID:21998865
    reference_title: Report of a further family with dominant deafness-onychodystrophy (DDOD) syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the feet,there were hypoplastic great toenails and absent nails on second to fifth toes."
    explanation: Documents hypoplastic great toenails in DDOD.
- category: Skeletal
  name: Triphalangeal Thumb
  description: >
    A thumb containing three phalanges rather than two, giving the
    characteristic finger-like thumb. Together with bulbous fingertips this is
    the digital anomaly that most reliably marks the DDOD pole of the ATP6V1B2
    continuum.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Triphalangeal thumb
    term:
      id: HP:0001199
      label: Triphalangeal thumb
  evidence:
  - reference: PMID:39210597
    reference_title: Dominantly acting variants in ATP6V1C1 and ATP6V1B2 cause a multisystem phenotypic spectrum by altering lysosomal and/or autophagosome function.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Specifically, individuals with DDOD syndrome primarily share sensorineural deafness and onychodystrophy with digital anomalies characterized by bulbous fingertips of digits, and finger-like thumbs/triphalangeal thumb."
    explanation: Names triphalangeal or finger-like thumbs as a primary shared DDOD feature.
  - reference: PMID:28396750
    reference_title: Dominant deafness-onychodystrophy syndrome caused by an ATP6V1B2 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He has a high forehead with dolichocephaly, bilateral triphalangeal thumbs without nails, hypoplastic fingernails from second to fifth fingers, flat feet with absent toenails (Fig. 1)."
    explanation: Documents bilateral triphalangeal thumbs in a molecularly confirmed DDOD proband.
- category: Skeletal
  name: Bulbous Fingertips
  description: >
    Broad, bulbous swelling of the distal phalanges of affected digits,
    accompanying the nail defect.
  phenotype_term:
    preferred_term: Broad fingertip
    term:
      id: HP:0011300
      label: Broad fingertip
  evidence:
  - reference: PMID:39210597
    reference_title: Dominantly acting variants in ATP6V1C1 and ATP6V1B2 cause a multisystem phenotypic spectrum by altering lysosomal and/or autophagosome function.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Specifically, individuals with DDOD syndrome primarily share sensorineural deafness and onychodystrophy with digital anomalies characterized by bulbous fingertips of digits, and finger-like thumbs/triphalangeal thumb."
    explanation: Names bulbous fingertips as a primary shared DDOD digital anomaly.
  - reference: PMID:21998865
    reference_title: Report of a further family with dominant deafness-onychodystrophy (DDOD) syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the hands, the first and fifth digits had absent nails and bulbous swelling of the distal phalanx."
    explanation: Documents bulbous distal phalangeal swelling of the affected digits.
- category: Skeletal
  name: Middle and Distal Phalangeal Hypoplasia
  description: >
    Aplasia or hypoplasia of the middle phalanx, classically of the fifth
    finger, and hypoplasia of the terminal phalanges underlying the nail defect.
    Radiographic osteodystrophy beyond the digits, which characterises DOORS
    syndrome, is not a feature of DDOD.
  phenotype_term:
    preferred_term: Short middle phalanx of the 5th finger
    term:
      id: HP:0004220
      label: Short middle phalanx of the 5th finger
  evidence:
  - reference: PMID:24913193
    reference_title: De novo mutation in ATP6V1B2 impairs lysosome acidification and causes dominant deafness-onychodystrophy syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The probands displayed identical phenotypes including severe congenital sensorineural hearing loss, absence of nails and aplasia of the middle phalanx in the fifth fingers"
    explanation: Documents aplasia of the fifth-finger middle phalanx in all three original probands.
- category: Dental
  name: Dental Anomalies
  description: >
    A minority of individuals show tooth abnormalities including oligodontia,
    conical teeth and delayed dentition. These are variable and not required for
    the diagnosis.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Oligodontia
    term:
      id: HP:0000677
      label: Oligodontia
  evidence:
  - reference: PMID:39210597
    reference_title: Dominantly acting variants in ATP6V1C1 and ATP6V1B2 cause a multisystem phenotypic spectrum by altering lysosomal and/or autophagosome function.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Some affected individuals may also show tooth abnormalities (e.g., oligodontia, conical teeth, and late dentition)."
    explanation: States that dental anomalies affect only some individuals, supporting the OCCASIONAL band.
  - reference: PMID:24421866
    reference_title: A Danish family with dominant deafness-onychodystrophy syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proband had late dentition and his father a history of late dentition, but otherwise the teeth appeared normal."
    explanation: Documents delayed dentition in two members of a DDOD family with otherwise normal teeth.
- category: Dental
  name: Enamel Hypoplasia
  description: >
    Defective enamel formation, reported alongside the nail defect as part of the
    ectodermal involvement in DDOD. Documented in a molecularly confirmed
    p.Arg506* patient who also carried an unrelated CACNA1S variant, so the
    dental finding is attributable to the DDOD arm of a dual diagnosis rather
    than to a single unblended phenotype.
  phenotype_term:
    preferred_term: Enamel hypoplasia
    term:
      id: HP:0006297
      label: Enamel hypoplasia
  evidence:
  - reference: PMID:41777697
    reference_title: "Case Report: Dominant deafness-onychodystrophy syndrome and hypokalemic periodic paralysis in a single patient: a rare syndromic overlap."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe an eight-year-old female with congenital deafness, nail dysplasia, enamel hypoplasia, and recurrent episodes of hypokalemia-induced muscle weakness."
    explanation: Documents enamel hypoplasia in a molecularly confirmed DDOD patient alongside the defining deafness and nail findings.
- category: Neurologic
  name: Seizures
  description: >
    Seizures are not part of the classic DDOD phenotype, and their presence
    shifts the clinical label towards ATP6V1B2-related DOORS syndrome. They are
    nevertheless reported in a minority of p.Arg506* carriers and in one member
    of a family otherwise fitting classic DDOD, which is the observation behind
    the incomplete-penetrance reading of the continuum. No frequency band is
    asserted here, because the published proportion (7 of 20) is drawn from a
    pooled p.Arg506* cohort spanning both the DDOD and DOORS labels and so does
    not estimate seizure frequency within DDOD specifically.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:37628590
    reference_title: The ATP6V1B2 DDOD/DOORS-Associated p.Arg506* Variant Causes Hyperactivity and Seizures in Mice.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Some but not all individuals with this truncating variant have intellectual disability and/or epilepsy, suggesting incomplete penetrance and/or variable expressivity."
    explanation: Supports occasional seizures among p.Arg506* carriers with incomplete penetrance; PARTIAL because the statement spans the DDOD and DOORS labels rather than DDOD alone.
  - reference: PMID:21998865
    reference_title: Report of a further family with dominant deafness-onychodystrophy (DDOD) syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition to deafness and onychodystrophy, other features in this family included subtle facial dysmorphism in two individuals, cutis aplasia in one individual, epilepsy in one individual, and sudden infant death in two family members, one of whom had deafness and onychodystrophy and one who did not."
    explanation: Documents epilepsy in one member of a family otherwise fitting classic DDOD.
diagnosis:
- name: ATP6V1B2 molecular testing
  description: >
    Molecular confirmation is definitive and is the only test that separates
    DDOD from its phenotypic neighbours, because the clinical triad of
    congenital sensorineural deafness, onychodystrophy and digital anomaly is
    shared across the ATP6V1B2 continuum. In practice this means finding the
    recurrent heterozygous NM_001693.4:c.1516C>T (p.Arg506*), which accounts for
    essentially every reported case; most probands are de novo, so parental
    testing is informative. Note the important limit: the identical allele also
    causes ATP6V1B2-related DOORS syndrome, so a positive result establishes the
    gene and the allele but does not by itself assign the DDOD label. That
    assignment rests on the absence of osteodystrophy, intellectual disability
    and seizures.
  results: >-
    Heterozygous ATP6V1B2 NM_001693.4:c.1516C>T (p.Arg506*), typically de novo.
  evidence:
  - reference: PMID:34746137
    reference_title: Syndromic Deafness Gene ATP6V1B2 Controls Degeneration of Spiral Ganglion Neurons Through Modulating Proton Flux.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ATP6V1B2 c.1516 C > T, p.Arg506∗, was identified in all families with DDOD syndrome"
    explanation: Establishes that testing for this single recurrent allele is effectively diagnostic at the gene level.
  - reference: PMID:34232384
    reference_title: Genetic architecture and phenotypic landscape of deafness and onychodystrophy syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pathogenic variants in four genes, ATP6V1B2, TBC1D24, KCNH1 and KCNN3, have been shown to be associated with deafness and onychodystrophy syndromes."
    explanation: Defines the four-gene panel a deafness-plus-onychodystrophy presentation should be tested against, which is the differential this diagnosis sits inside.
- name: Auditory brainstem response testing
  description: >
    ABR establishes the severity and sensorineural character of the hearing loss
    in infancy, before behavioural audiometry is reliable, and is the
    measurement on which the timing of cochlear implantation depends.
  results: >-
    Profound bilateral sensorineural hearing impairment, detectable in the first
    year of life.
  evidence:
  - reference: PMID:28396750
    reference_title: Dominant deafness-onychodystrophy syndrome caused by an ATP6V1B2 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Audiological examination by auditory brainstem responses (ABR) at 1 year of age indicated profound bilateral sensorineural hearing impairment."
    explanation: Documents ABR as the modality establishing the hearing phenotype in infancy.
- name: Temporal bone imaging
  description: >
    Imaging is performed to exclude a structural cause of congenital
    sensorineural hearing loss and to plan implantation. In DDOD it is
    characteristically normal. This is a useful negative: the deafness is
    cellular and neural rather than malformative, which is consistent with the
    spiral ganglion degeneration mechanism and means normal imaging does not
    argue against the diagnosis.
  results: >-
    No inner ear malformation.
  evidence:
  - reference: PMID:24913193
    reference_title: De novo mutation in ATP6V1B2 impairs lysosome acidification and causes dominant deafness-onychodystrophy syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "None showed inner ear malformation and intellectual disability."
    explanation: Records absence of inner ear malformation in the original DDOD probands.
differential_diagnoses:
- name: Zimmermann-Laband syndrome type 2
  description: >
    ZLS2 is caused by dominant ATP6V1B2 missense variants, most characteristically
    p.Arg485Pro, and is an allelic differential within the same dominant
    V-ATPase clinical continuum rather than an unrelated disorder. The practical
    discriminators are gingival hypertrophy and hypertrichosis, which are
    characteristic of ZLS2 and only very rarely reported in DDOD, and
    intellectual disability, which is usual in ZLS2 and atypical in DDOD.
    Conversely, the DDOD pole is marked by the constancy of congenital
    sensorineural deafness plus onychodystrophy with bulbous fingertips and
    triphalangeal thumbs.
  disease_term:
    preferred_term: Zimmermann-Laband syndrome 2
    term:
      id: MONDO:0014646
      label: Zimmermann-Laband syndrome 2
  distinguishing_features:
  - Gingival hypertrophy and hypertrichosis favor ZLS2; they are not usually reported in DDOD.
  - Intellectual disability is usual in ZLS2 and atypical in DDOD.
  - Predominant congenital sensorineural deafness with onychodystrophy, bulbous fingertips, and triphalangeal thumbs favors DDOD.
  - The allele class differs, in that DDOD is essentially always the truncating p.Arg506* whereas ZLS2 arises from missense substitutions such as p.Arg485Pro.
  - Genotype and phenotype should be read as a continuum rather than an absolute boundary.
  evidence:
  - reference: PMID:39210597
    reference_title: Dominantly acting variants in ATP6V1C1 and ATP6V1B2 cause a multisystem phenotypic spectrum by altering lysosomal and/or autophagosome function.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Facial features of DOORS syndrome have a significant overlap with ZLS, a condition also associated with organomegaly, gingival hypertrophy, and hypertrichosis, which are not usually reported in DDOD and DOORS syndromes."
    explanation: Supports gingival hypertrophy and hypertrichosis as ZLS-favoring discriminators against DDOD.
  - reference: PMID:39210597
    reference_title: Dominantly acting variants in ATP6V1C1 and ATP6V1B2 cause a multisystem phenotypic spectrum by altering lysosomal and/or autophagosome function.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The present findings further support these observations, documenting the presence of a phenotypic continuum among these disorders."
    explanation: Supports reading DDOD and ZLS2 as poles of a continuum rather than as absolutely separate entities.
  - reference: PMID:28396750
    reference_title: Dominant deafness-onychodystrophy syndrome caused by an ATP6V1B2 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He does not have gingival hyperplasia, hypertrichosis, organomegaly, or joint hyperextensibility."
    explanation: A molecularly confirmed DDOD proband explicitly lacks the ZLS-defining features.
- name: DOORS syndrome
  description: >
    DOORS syndrome shares congenital sensorineural deafness, onychodystrophy and
    triphalangeal thumbs with DDOD, and the ATP6V1B2-related form of DOORS is
    caused by the very same recurrent p.Arg506* allele. The discriminators are
    therefore not molecular but clinical. Osteodystrophy beyond the digits,
    intellectual disability and seizures define the DOORS pole and are absent or
    exceptional in DDOD. The larger share of DOORS cases is caused by biallelic
    TBC1D24 variants, which is a genuinely different genotype and mode of
    inheritance.
  disease_term:
    preferred_term: DOORS syndrome
    term:
      id: MONDO:0009079
      label: DOORS syndrome
  distinguishing_features:
  - Osteodystrophy, intellectual disability, and seizures define DOORS and are absent or exceptional in DDOD.
  - The recurrent ATP6V1B2 p.Arg506* allele is shared, so molecular testing alone cannot separate ATP6V1B2-related DOORS from DDOD.
  - Biallelic TBC1D24 variants cause the majority of DOORS and are recessive, unlike the dominant ATP6V1B2 mechanism.
  evidence:
  - reference: PMID:37628590
    reference_title: The ATP6V1B2 DDOD/DOORS-Associated p.Arg506* Variant Causes Hyperactivity and Seizures in Mice.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The autosomal dominant ATP6V1B2 p.Arg506* variant can cause both congenital deafness with onychodystrophy, autosomal dominant (DDOD) and deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures syndromes (DOORS)."
    explanation: Establishes that the same allele underlies both labels, so the differential rests on clinical features.
  - reference: PMID:39210597
    reference_title: Dominantly acting variants in ATP6V1C1 and ATP6V1B2 cause a multisystem phenotypic spectrum by altering lysosomal and/or autophagosome function.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals with DDOD syndrome usually show normal development and cognitive function, while those with DOORS syndrome and ZLS present with intellectual disability (ID), with or without seizures."
    explanation: States the cognitive and seizure axis that separates DDOD from DOORS.
treatments:
- name: Cochlear Implantation
  description: >
    Cochlear implantation is the principal intervention for the congenital
    severe-to-profound sensorineural hearing loss of DDOD. Device-level and
    auditory outcomes are consistently good: successful oral-language
    rehabilitation was reported in the original probands implanted between 2 and
    18 years of age, and a child receiving bilateral sequential implants showed
    continued gains in auditory and communication performance. Language outcome
    is less uniformly good than auditory outcome, and this should be stated
    plainly rather than smoothed over. Follow-up of implanted DDOD patients has
    documented unsatisfactory language rehabilitation despite a well-functioning
    implant on standard cochlear-mapping indicators, which the reporting group
    attributed to subtle learning and memory problems. Molecular diagnosis is
    therefore prognostically useful in syndromic congenital hearing loss, but it
    should not be presented to families as a guarantee of language outcome.
  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
  notes: >-
    NCIT:C157820 `Cochlear Implant` exists but denotes the device, not a clinical
    action, and is not reachable from NCIT:C25218, so it fails the TreatmentActionTerm
    dynamic enum. The specificity is carried by `preferred_term`. The generic action
    bound here is the surgical one, which is what implantation is; an earlier version
    used NCIT:C15315 Rehabilitation and cited CAPOS_Syndrome as precedent, but CAPOS
    binds NCIT:C15329.
  target_mechanisms:
  - target: Congenital Sensorineural Hearing Loss
    treatment_effect: RESTORES
    description: >-
      The implant bypasses the degenerated cochlear sensory apparatus and
      stimulates surviving auditory neurons directly, restoring auditory input
      without correcting the underlying lysosomal defect.
    evidence:
    - reference: PMID:40164508
      reference_title: "Clinical Insights into Bilateral Cochlear Implantation for a Child with Dominant Deafness-Onychodystrophy Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Children with DDOD syndrome (ATP6V1B2 c.1516C > T) receiving bilateral CIs can enhance aural and communication skills."
      explanation: Reports auditory and communication benefit from bilateral implantation in genetically confirmed DDOD.
  evidence:
  - reference: PMID:24913193
    reference_title: De novo mutation in ATP6V1B2 impairs lysosome acidification and causes dominant deafness-onychodystrophy syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All three individuals had unilateral cochlea implantation at the ages of 2.5, 2 and 18 years, respectively."
    explanation: Documents cochlear implantation as the intervention received by the original DDOD cohort.
  - reference: PMID:42361897
    reference_title: "Hearing outcomes after cochlear implantation in two patients with ATP6V1B2-related deafness and onychodystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe two clinical cases of the deafness and onychodystrophy (DOD) spectrum and the benefit of molecular diagnosis to underline the importance of genetic testing when evaluating potential CI outcomes in syndromic congenital SNHL."
    explanation: Supports molecular diagnosis as prognostically informative for cochlear implant outcome in this spectrum.
  - reference: PMID:31257146
    reference_title: A subunit of V-ATPases, ATP6V1B2, underlies the pathology of intellectual disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical follow-up of DDOD syndrome patients with cochlear implantation revealed the language rehabilitation was unsatisfactory although the implanted cochlea worked well, which indicates there might be learning and memory problems in DDOD syndrome patients."
    explanation: Qualifies the otherwise favourable implant outcomes. The device works but language rehabilitation may still disappoint, which is why this entry does not present implantation as a guaranteed language outcome; PARTIAL because it reports a limitation of the intervention rather than supporting or refuting its use.
- name: CPT-cAMP Lysosomal Reacidification (preclinical)
  description: >
    The one mechanism-directed candidate for this disorder rather than a
    supportive measure. CPT-cAMP is a membrane-permeable cAMP analogue that
    restored lysosomal acidification in a concentration-dependent manner in
    isogenic p.Arg506* cells, crosses the blood-brain barrier, and in
    Atp6v1b2 p.Arg506* mice reduced seizure frequency, improved cognitive
    performance, and resolved autophagosome accumulation. It is therefore aimed
    squarely at the rate-limiting node of this entry rather than at a downstream
    consequence. NOT an available therapy: this is proof-of-concept work in
    cells and mice with no human data, and the reported benefits are on the
    neurological and cognitive arm, which is precisely the arm that classic DDOD
    largely lacks, so the read-across to DDOD patients is an inference rather
    than a demonstrated result.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: CPT-cAMP (8-(4-chlorophenylthio)adenosine 3',5'-cyclic monophosphate)
  notes: >-
    No `therapeutic_agent` `term:` is bound. CPT-cAMP has no CHEBI or NCIT
    clinical-agent term that validates against the schema's dynamic enums, and
    per the terms guidance no term is preferred over a wrong one, so the agent
    identity is carried by `preferred_term` alone.
  target_mechanisms:
  - target: Impaired Endolysosomal Acidification
    treatment_effect: RESTORES
    description: >-
      Raises cAMP signalling to drive V-ATPase-dependent reacidification,
      correcting the elevated lysosomal pH caused by the truncated B2 subunit
      rather than compensating for a downstream consequence of it.
    evidence:
    - reference: PMID:41896517
      reference_title: Therapeutic potential of cAMP-mediated lysosomal pH modulation in ATP6V1B2-related neuropathology.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Remarkably, treatment with the cAMP analog CPT-cAMP restored lysosomal acidification in a concentration-dependent manner."
      explanation: Demonstrates correction of the entry's rate-limiting node by this agent in isogenic mutant cells.
  evidence:
  - reference: PMID:41896517
    reference_title: Therapeutic potential of cAMP-mediated lysosomal pH modulation in ATP6V1B2-related neuropathology.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Intraperitoneal CPT-cAMP administration (20 mg/kg) exerted triple therapeutic effects: (1) significant reduction in seizure frequency, (2) improved cognitive performance in behavioral paradigms, and (3) restoration of autophagic flux through resolution of autophagosome accumulation."
    explanation: Reports the in vivo effects in the p.Arg506* mouse, all on the neurological and autophagic arms.
  - reference: PMID:41896517
    reference_title: Therapeutic potential of cAMP-mediated lysosomal pH modulation in ATP6V1B2-related neuropathology.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "These findings establish proof-of-concept for cAMP-mediated lysosomal pH modulation as a viable therapeutic strategy."
    explanation: The authors' own framing as proof-of-concept, which is why this is curated as preclinical rather than as an available treatment; INDIRECT because it supports the strategy without establishing clinical efficacy.
- name: Genetic Counseling
  description: >
    Counselling addresses the autosomal dominant recurrence risk. Most probands
    carry a de novo p.Arg506* variant with a correspondingly low sibling
    recurrence risk, but documented three-generation transmission means an
    affected individual carries a 50 percent transmission risk, and the variable
    penetrance of intellectual disability and seizures within the same allele
    must be conveyed as genuine uncertainty rather than as a predictable
    outcome.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:37628590
    reference_title: The ATP6V1B2 DDOD/DOORS-Associated p.Arg506* Variant Causes Hyperactivity and Seizures in Mice.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Some but not all individuals with this truncating variant have intellectual disability and/or epilepsy, suggesting incomplete penetrance and/or variable expressivity."
    explanation: Establishes the penetrance uncertainty that must be communicated during counselling.
  - reference: PMID:24421866
    reference_title: A Danish family with dominant deafness-onychodystrophy syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We present here three male family members in three generations with sensori-neural deafness, onychodystrophy and brachydactyly inherited via autosomal dominant transmission."
    explanation: Documents dominant transmission, which sets the recurrence risk for an affected individual's offspring.
animal_models:
- name: Atp6v1b2 p.Arg506* knock-in mouse
  species: Mouse
  genotype: Atp6v1b2 c.1516C>T (p.Arg506*) knock-in, heterozygous and homozygous
  publication: PMID:34746137
  description: >
    CRISPR-generated knock-in of the human DDOD allele. Two independent lines
    exist, one characterised for cochlear pathology and one phenotyped through
    the IMPC pipeline with EEG. Together they establish the lysosomal to
    autophagic to apoptotic chain in spiral ganglion neurons, and they also
    demonstrate the model's key limitation, namely that the hearing loss is
    late-onset rather than congenital.
  modeled_mechanisms:
  - target: Apoptotic Degeneration of Spiral Ganglion Neurons and Hair Cells
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      The knock-in reproduces apoptotic spiral ganglion neuron degeneration
      downstream of lysosomal dysfunction and autophagic blockade, which is the
      human mechanism, but on a delayed timescale.
    limitations: >-
      Hearing loss in the mouse is late-onset and preceded by hidden hearing
      loss, whereas human DDOD deafness is congenital and severe to profound.
      Compensatory upregulation of the paralogue Atp6v1b1 in hair cells blunts
      the murine phenotype, and much of the characterisation used homozygotes
      rather than the heterozygous state that models patients.
    readouts:
    - name: Spiral ganglion neuron degeneration
      target: Apoptotic Degeneration of Spiral Ganglion Neurons and Hair Cells
      direction: INCREASED
      interpretation: Histological correlate of the cochlear degeneration node.
      evidence:
      - reference: PMID:34746137
        reference_title: Syndromic Deafness Gene ATP6V1B2 Controls Degeneration of Spiral Ganglion Neurons Through Modulating Proton Flux.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Apoptosis activated by lysosomal dysfunction and the subsequent blockade of autophagic flux induced the degeneration of spiral ganglion neurons and further impaired the hearing."
        explanation: Reports the apoptotic spiral ganglion degeneration measured in this model.
    evidence:
    - reference: PMID:34746137
      reference_title: Syndromic Deafness Gene ATP6V1B2 Controls Degeneration of Spiral Ganglion Neurons Through Modulating Proton Flux.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The Atp6v1b2Arg506*/Arg506* mice showed hidden hearing loss (HHL) at early stages and developed late-onset hearing loss."
      explanation: Establishes the model as informative for the cochlear node while naming its temporal mismatch.
  - target: Congenital Sensorineural Hearing Loss
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      Neither knock-in line reproduces the congenital severe-to-profound
      deafness that defines human DDOD.
    limitations: >-
      In the IMPC-phenotyped line, auditory brainstem responses were normal at
      14 weeks of age. In the cochlear-pathology line, hearing loss appeared
      only late and was attributed to compensatory Atp6v1b1 upregulation in hair
      cells. Any therapeutic inference drawn from restored hearing in these mice
      therefore starts from a milder baseline than the human disease.
    evidence:
    - reference: PMID:37628590
      reference_title: The ATP6V1B2 DDOD/DOORS-Associated p.Arg506* Variant Causes Hyperactivity and Seizures in Mice.
      supports: REFUTE
      evidence_source: MODEL_ORGANISM
      snippet: "The auditory brainstem response (ABR) confirmed proper auditory function at 14 weeks of age"
      explanation: A negative result, in that the knock-in mouse has normal hearing at an age by which human DDOD is profoundly deaf.
    - reference: PMID:34746137
      reference_title: Syndromic Deafness Gene ATP6V1B2 Controls Degeneration of Spiral Ganglion Neurons Through Modulating Proton Flux.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We observed increased transcription of Atp6v1b1 in hair cells of Atp6v1b2Arg506*/Arg506* mice and inferred that Atp6v1b1 compensated for the Atp6v1b2 dysfunction by increasing its own transcription level. Genetic compensation in hair cells explains the milder hearing impairment in Atp6v1b2Arg506*/Arg506* mice."
      explanation: Gives the species-specific mechanism, paralogue compensation, behind the failure to recapitulate.
  evidence:
  - reference: PMID:37628590
    reference_title: The ATP6V1B2 DDOD/DOORS-Associated p.Arg506* Variant Causes Hyperactivity and Seizures in Mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "EEG analyses indicate that Atp6v1b2emR506* mutant mice have interictal epileptic activity and that both heterozygous (like patients) and homozygous mice have reduced seizure thresholds to pentylenetetrazol."
    explanation: Establishes the knock-in as a model of the seizure-susceptibility arm of the p.Arg506* spectrum.
- name: Cochlea-specific Atp6v1b2 morpholino knockdown mouse
  species: Mouse
  genotype: Wild-type mouse with intracochlear Atp6v1b2 splice-blocking morpholino
  publication: PMID:24913193
  description: >
    Acute knockdown of Atp6v1b2 in the cochlea by microinjection of a
    splice-blocking morpholino into the scala media before postnatal day 3. This
    was the original demonstration that Atp6v1b2 deficiency alone is sufficient
    to cause sensorineural hearing loss, and the same approach was later used to
    profile the lysosomal and autophagic changes in cochlear tissue.
  modeled_mechanisms:
  - target: Impaired Endolysosomal Acidification
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Cochlear knockdown reproduces the reduction in V-ATPase activity and
      lysosomal acidification that underlies the human disease, measured in
      cochlear tissue rather than in a heterologous cell line.
    limitations: >-
      Morpholino knockdown reduces wild-type transcript rather than expressing
      the truncated p.Arg506* subunit, so it models a pure dose reduction and
      cannot distinguish haploinsufficiency from a dominant-negative effect of
      the truncated protein. The effect is also acute and postnatal rather than
      developmental.
    readouts:
    - name: Cochlear V-ATPase and cathepsin-D activity
      target: Impaired Endolysosomal Acidification
      direction: DECREASED
      interpretation: Biochemical correlate of the acidification node in cochlear tissue.
      evidence:
      - reference: PMID:41995948
        reference_title: ATP6V1B2 Regulating Autophagy Flux To Affect Abnormal Auditory Development.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Mechanistically, cochlear V-ATPase and Cath-D activities were significantly reduced, while lysosomal membrane proteins (LAMP1, LAMP2) and ion channel proteins (TPC1, TPC2) were upregulated, suggesting lysosomal acidification dysfunction."
        explanation: Reports the enzyme-activity measurements behind this readout.
    evidence:
    - reference: PMID:41995948
      reference_title: ATP6V1B2 Regulating Autophagy Flux To Affect Abnormal Auditory Development.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "A DDOD syndrome mouse model was established via cochlear microinjection of ATP6V1B2-specific morpholino, while control mice injected with a scramble morpholino."
      explanation: Establishes the model and its use for the cochlear acidification question.
  evidence:
  - reference: PMID:24913193
    reference_title: De novo mutation in ATP6V1B2 impairs lysosome acidification and causes dominant deafness-onychodystrophy syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We generated a cochlea-specific Atp6v1b2-knockdown mouse model and found that Atp6v1b2 deficiency leads to severe sensorineural hearing loss."
    explanation: Establishes that cochlear Atp6v1b2 deficiency is sufficient for sensorineural hearing loss.
- name: Hair-cell-specific Atp6v1b2 conditional knockout mouse
  species: Mouse
  genotype: "Atp6v1b2 fl/fl; Atoh1-Cre/+ conditional knockout"
  publication: PMID:40068100
  description: >
    Conditional deletion of Atp6v1b2 in cochlear hair cells, generated to
    provide a tractable platform for inner-ear gene therapy. It reproduces hair
    cell loss and abnormal lysosomal morphology, and a single intracochlear dose
    of an AAV vector carrying wild-type Atp6v1b2 rescued both.
  modeled_mechanisms:
  - target: Apoptotic Degeneration of Spiral Ganglion Neurons and Hair Cells
    relationship: RESCUES
    fidelity: MODERATE
    description: >-
      A single postnatal administration of AAV-ie-Eh3-mAtp6v1b2 into the scala
      media prevented hair cell degeneration and restored lysosome morphology
      and auditory and vestibular function, providing the strongest available
      causal test that the cochlear degeneration node is Atp6v1b2-dependent and
      in principle reversible.
    limitations: >-
      The model is a hair-cell-restricted complete knockout, not the
      heterozygous truncating genotype of human DDOD, and it does not address
      the spiral ganglion neuron compartment. Rescue was delivered at postnatal
      days 0 to 2, a developmental window with no direct human equivalent given
      that DDOD deafness is already present at birth. This is a preclinical
      result, not an available therapy.
    readouts:
    - name: Auditory and vestibular function after AAV gene transfer
      target: Apoptotic Degeneration of Spiral Ganglion Neurons and Hair Cells
      direction: RESTORED
      interpretation: Functional rescue confirming the node is Atp6v1b2-dependent.
      evidence:
      - reference: PMID:40068100
        reference_title: Single Administration of AAV-mAtp6v1b2 Gene Therapy Rescues Hearing and Vestibular Disorders Caused by Atp6v1b2-Induced Lysosomal Dysfunction in Hair Cells.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "A single administration of AAV-ie-Eh3-mAtp6v1b2 into the scala media at postnatal days 0-2, prevented hair cell degeneration, restored lysosome morphology, and robustly rescued auditory and vestibular function for at least 24 weeks."
        explanation: Reports the functional and histological rescue measured in this model.
    evidence:
    - reference: PMID:40068100
      reference_title: Single Administration of AAV-mAtp6v1b2 Gene Therapy Rescues Hearing and Vestibular Disorders Caused by Atp6v1b2-Induced Lysosomal Dysfunction in Hair Cells.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The study generates a hair cell-specific knockout mouse (Atp6v1b2fl/fl;Atoh1Cre/+) recapitulating the human phenotypes, with pathological features including hair cell loss and abnormal lysosomal morphology and function."
      explanation: Establishes the model as informative for the cochlear degeneration node.
experimental_models:
- name: DDOD patient-derived iPSC line CPGHi002-A
  experimental_model_type: IPSC_DERIVED_MODEL
  description: >
    Induced pluripotent stem cell line reprogrammed from a 10-month-old female
    DDOD patient heterozygous for the recurrent ATP6V1B2 c.1516C>T variant, with
    an isogenic gene-corrected counterpart, CPGHi002-A-1, generated from it.
    Together they provide a patient-genotype, isogenic-control platform for
    studying the DDOD allele in human cells, which is the gap the mouse models
    leave open.
  evidence:
  - reference: PMID:32961450
    reference_title: "Establishment of human induced pluripotent stem cell line (CPGHi002-A) from a 10-month-old female patient with DDOD syndrome carrying a heterozygous c.1516 C > T mutation in ATP6V1B2."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The induced pluripotent stem cell (iPSC) line was generated using the non-integrating episomal vector method from peripheral blood mononuclear cells (PBMCs) of a 10-month-old female DDOD patient with heterozygous ATP6V1B2 c.1516 C > T variant."
    explanation: Establishes the provenance and genotype of the patient-derived iPSC line.
  - reference: PMID:33714068
    reference_title: "Generation of a gene corrected human isogenic iPSC line (CPGHi002-A-1) from a DDOD patient with heterozygous c.1516 C>T mutation in the ATP6V1B2 gene."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here we genetically corrected the c.1516 C>T mutation in the ATP6V1B2 gene using CRISPR/Cas9 technology to generate an isogenic control, CPGHi002-A-1."
    explanation: Establishes the availability of an isogenic gene-corrected control line, which is what makes the pair usable for the proposed experiments.
discussions:
- discussion_id: ddod_haploinsufficiency_vs_dominant_negative
  kind: KNOWLEDGE_GAP
  attaches_to:
  - "pathophysiology#ATP6V1B2 C-Terminal Truncation and Weakened V-ATPase Subunit Interaction"
  prompt: >-
    Does the DDOD p.Arg506* allele act by haploinsufficiency or by a
    dominant-negative effect of the expressed truncated B2 subunit?
  rationale: >-
    The distinction is not cosmetic. The mutant transcript escapes
    nonsense-mediated decay, so a truncated subunit is expressed and can be
    incorporated into V-ATPase complexes; the observed weakening of the V1B2 to
    V1E interaction is consistent with a poisoned complex rather than with
    simple dosage reduction. Yuan et al. concluded haploinsufficiency from a
    transfection dose-response, but a later review of the same allele stated
    only that it causes loss of function and left the route open. The answer
    determines whether allele-specific knockdown would be therapeutic, or
    whether gene augmentation of the kind demonstrated in the hair-cell knockout
    mouse is the right strategy for patients. It is also why this entry records
    `functional_impact_category: LOSS_OF_FUNCTION` rather than the more specific
    DOMINANT_NEGATIVE.
  proposed_experiments:
  - experiment_id: ddod_exp_allele_dosage_vs_poisoning
    name: Allele-specific dosage versus poisoning test in patient iPSC-derived cells
    description: >-
      Compare endolysosomal pH, V-ATPase assembly and autophagic flux across the
      patient iPSC line, its isogenic corrected control, and a heterozygous null
      created in the corrected background. If the patient line is worse than the
      heterozygous null, the truncated subunit is dominant negative; if the two
      are equivalent, the mechanism is haploinsufficiency.
  evidence:
  - reference: PMID:37628590
    reference_title: The ATP6V1B2 DDOD/DOORS-Associated p.Arg506* Variant Causes Hyperactivity and Seizures in Mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Altogether, these results indicates that the p.R506* variant causes a loss of function either as a result of a dominant negative effect or haploinsufficiency."
    explanation: States the unresolved alternative directly.
  - reference: PMID:24913193
    reference_title: De novo mutation in ATP6V1B2 impairs lysosome acidification and causes dominant deafness-onychodystrophy syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Taken together, these results suggest that ATP6V1B2 c.1516 C>T mutation is a haploinsufficient mutation."
    explanation: The competing haploinsufficiency reading, offered as a suggestion from transfection data rather than as a settled result.
- discussion_id: ddod_bidirectional_lysosomal_ph
  kind: KNOWLEDGE_GAP
  attaches_to:
  - "pathophysiology#Impaired Endolysosomal Acidification"
  prompt: >-
    Why do the DDOD truncating allele and the ZLS2 missense alleles move
    lysosomal pH in opposite directions while producing an overlapping clinical
    continuum?
  rationale: >-
    This is the central unresolved problem of the dominant ATP6V1B2 spectrum,
    and it is easy to curate away by mistake. For the DDOD p.Arg506* allele,
    lysosomal acidification is reduced, with transfected cells showing raised
    lysosomal pH and cochlear tissue showing reduced V-ATPase and cathepsin-D
    activity. For the ZLS2-associated missense alleles, patient fibroblasts show
    the reverse, a hyperactive pump and significantly more acidic lysosomes, and
    the authors proposed increased acidification as the driver of the whole
    spectrum. Critically, p.Arg506* was not among the alleles tested in that
    hyperactivity series, so the two results do not directly contradict each
    other; they were simply never measured side by side. The DDOD side has since
    been replicated in isogenic CRISPR-engineered p.Arg506* cells, which removes
    the overexpression caveat attaching to the original transfection result and
    makes the divergence harder to explain away as an artefact of method. Until
    the alleles are compared directly, a
    unifying claim that the spectrum is driven by V-ATPase upregulation should
    not be imported into this entry, and conformance to
    `lysosomal_substrate_accumulation` is deliberately not declared here because
    the cholesterol and ceramide storage data come from the missense lines, not
    from DDOD cells.
  proposed_experiments:
  - experiment_id: ddod_exp_allelic_series_ph_panel
    name: Side-by-side lysosomal pH panel across the ATP6V1B2 allelic series
    description: >-
      Measure intraorganellar pH, substrate storage and autophagic flux in one
      laboratory, using one protocol, across patient-derived fibroblasts or
      isogenic iPSC lines carrying p.Arg506*, p.Arg485Pro and the ADP/ATP-site
      missense cluster, with shared controls. This is the experiment that would
      establish whether the continuum is one mechanism with a bidirectional
      readout or two distinct mechanisms converging on overlapping phenotypes.
  evidence:
  - reference: PMID:24913193
    reference_title: De novo mutation in ATP6V1B2 impairs lysosome acidification and causes dominant deafness-onychodystrophy syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "A statistically significant difference in lysosomal pH was detected between ATP6V1B2 WT- and c.1516 C>T mutant-transfected cells (LSD test, p = 0.02, Supplementary information, Figure S1E), indicating the reduced acidification caused by c.1516 C>T mutation."
    explanation: The DDOD-allele result showing reduced acidification.
  - reference: PMID:39210597
    reference_title: Dominantly acting variants in ATP6V1C1 and ATP6V1B2 cause a multisystem phenotypic spectrum by altering lysosomal and/or autophagosome function.
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "We observed a significant higher acidity of lysosomes in all patients’ cell lines compared with control cells, indicating a hyperactive behavior of the proton pumps assembling the mutant B2/C1 subunits."
    explanation: The opposing result from the missense alleles of the same gene; REFUTE because it contradicts the reduced-acidification direction, though it was measured on different alleles.
  - reference: PMID:41896517
    reference_title: Therapeutic potential of cAMP-mediated lysosomal pH modulation in ATP6V1B2-related neuropathology.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Isogenic HEK293T models (ATP6V1B2R506X/+ and ATP6V1B2R506X/R506X) were generated using CRISPR/Cas9 for dynamic lysosomal pH monitoring via ratiometric RpH-LAMP1-3×flag imaging to evaluate pathophysiological mechanisms."
    explanation: Independent isogenic replication of the DDOD-allele direction without transient overexpression. Note that these heterozygous and homozygous lines are close to the design proposed under the haploinsufficiency-versus-dominant-negative discussion, so that gap may now be partly addressable from published data.
- discussion_id: ddod_nail_matrix_mechanism_unmeasured
  kind: KNOWLEDGE_GAP
  attaches_to:
  - "pathophysiology#Impaired Nail Matrix and Distal Digit Development"
  prompt: >-
    By what route does impaired V-ATPase function in nail-matrix keratinocytes
    and developing digits produce onychodystrophy and terminal phalangeal
    hypoplasia?
  rationale: >-
    Onychodystrophy is one of the two obligate features of DDOD, yet every
    mechanistic study of the gene to date has been done in the cochlea or in
    fibroblasts. There is no published measurement of lysosomal pH, autophagic
    flux or apoptosis in nail matrix or in the developing autopod for any
    ATP6V1B2 allele, so the nail arm of this entry rests on clinical observation
    alone. The digit-selective pattern, with the thumb and fifth finger most
    affected and the second to fourth digits relatively spared, is itself
    unexplained and suggests an interaction with limb patterning rather than a
    uniform keratinocyte defect.
  proposed_experiments:
  - experiment_id: ddod_exp_nail_autopod_endolysosomal_profiling
    name: Endolysosomal profiling of DDOD nail-matrix and autopod tissue
    description: >-
      Differentiate the patient iPSC line and its isogenic control towards
      keratinocyte and limb-bud mesenchymal fates, and assay lysosomal pH,
      cathepsin activity and autophagic flux. Complement with conditional
      Atp6v1b2 deletion in nail-matrix and autopod lineages in mouse to test
      whether the digit-selective pattern is reproduced.
  evidence:
  - reference: PMID:39210597
    reference_title: Dominantly acting variants in ATP6V1C1 and ATP6V1B2 cause a multisystem phenotypic spectrum by altering lysosomal and/or autophagosome function.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Specifically, individuals with DDOD syndrome primarily share sensorineural deafness and onychodystrophy with digital anomalies characterized by bulbous fingertips of digits, and finger-like thumbs/triphalangeal thumb."
    explanation: Establishes the nail and digit phenotype whose mechanism is unmeasured.
- discussion_id: ddod_subtle_cns_involvement
  kind: KNOWLEDGE_GAP
  attaches_to:
  - "pathophysiology#Impaired Endolysosomal Acidification"
  prompt: >-
    Is cognition genuinely spared in DDOD, or is there subtle learning and
    memory involvement that routine assessment of a congenitally deaf child
    cannot detect?
  rationale: >-
    "Normal development and cognition" is the axis this entry uses to separate
    DDOD from the DOORS and ZLS2 poles, so any softness in it matters. The claim
    is well supported at the level of frank intellectual disability, and the
    original probands achieved oral-language rehabilitation after implantation.
    But follow-up of implanted DDOD patients found language rehabilitation
    unsatisfactory despite a well-functioning device on standard mapping
    indicators, which the reporting group attributed to learning and memory
    problems, and the same group described a DDOD pedigree with mild
    intellectual impairment. The p.Arg506* knock-in mouse independently shows
    cognitive deficits with an impaired hippocampal CA1 region. The honest
    reading is that DDOD lacks the frank intellectual disability of DOORS and
    ZLS2, not that the CNS is demonstrably uninvolved. The gap is partly
    methodological: systematic CNS evaluation in these patients is unavailable,
    because mild deficits are hard to assess in early childhood against severe
    congenital deafness, and resting-state fMRI cannot be performed once a
    cochlear implant is in place.
  proposed_experiments:
  - experiment_id: ddod_exp_systematic_cognitive_phenotyping
    name: Deafness-matched cognitive phenotyping of molecularly confirmed DDOD patients
    description: >-
      Assess learning and memory in p.Arg506* carriers using instruments
      validated for congenitally deaf children, against deaf controls with
      non-syndromic hearing loss matched for implantation age and device
      performance. A deafness-matched control arm is what separates a real
      DDOD-specific cognitive effect from the general effect of congenital
      deafness on these measures.
  evidence:
  - reference: PMID:31257146
    reference_title: A subunit of V-ATPases, ATP6V1B2, underlies the pathology of intellectual disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical follow-up of DDOD syndrome patients with cochlear implantation revealed the language rehabilitation was unsatisfactory although the implanted cochlea worked well, which indicates there might be learning and memory problems in DDOD syndrome patients."
    explanation: The clinical observation that raises the question, and the reason this entry does not state cognitive sparing more strongly than it does.
  - reference: PMID:31257146
    reference_title: A subunit of V-ATPases, ATP6V1B2, underlies the pathology of intellectual disability.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Additionally, the impaired hippocampal CA1 region may be the pathological basis of the behavioral defects seen in Atp6v1b2Arg506X/Arg506X mice."
    explanation: Independent model-organism support for a CNS arm of the same allele, from the same study.
  - reference: PMID:39210597
    reference_title: Dominantly acting variants in ATP6V1C1 and ATP6V1B2 cause a multisystem phenotypic spectrum by altering lysosomal and/or autophagosome function.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals with DDOD syndrome usually show normal development and cognitive function, while those with DOORS syndrome and ZLS present with intellectual disability (ID), with or without seizures."
    explanation: The competing reading. Note the hedge "usually", which is what leaves room for the subtler involvement above; PARTIAL because it supports cognitive sparing as the norm without excluding subclinical involvement.
- discussion_id: ddod_mouse_hearing_onset_mismatch
  kind: HUMAN_MODEL_MISMATCH
  attaches_to:
  - "pathophysiology#Apoptotic Degeneration of Spiral Ganglion Neurons and Hair Cells"
  prompt: >-
    Do the Atp6v1b2 p.Arg506* knock-in mice model human DDOD deafness, given
    that their hearing loss is late-onset while the human phenotype is
    congenital and profound?
  rationale: >-
    Both published knock-in lines have essentially normal early hearing.
    Auditory brainstem responses were normal at 14 weeks in the IMPC-phenotyped
    line, and the cochlear-pathology line showed only hidden hearing loss early
    with late-onset threshold shifts. The proposed explanation is compensatory
    upregulation of the paralogue Atp6v1b1 in hair cells, a species-level rescue
    with no evidence of a human counterpart. The mismatch matters for
    interpretation in both directions. Mechanistic findings about spiral
    ganglion apoptosis are drawn from a system where the insult is milder than
    in patients, and any therapeutic rescue demonstrated in these mice starts
    from a less severe baseline and within a postnatal window that has no human
    equivalent, because human DDOD deafness is already established at birth.
  proposed_experiments:
  - experiment_id: ddod_exp_human_atp6v1b1_compensation
    name: Test whether ATP6V1B1 compensation occurs in human cochlear cells
    description: >-
      Quantify ATP6V1B1 transcript and protein in human iPSC-derived otic and
      hair-cell-like cells carrying p.Arg506* against the isogenic corrected
      control. Absence of compensation would confirm the paralogue rescue as the
      species difference and would explain the severity gap directly.
  - experiment_id: ddod_exp_adult_onset_rescue_window
    name: Adult-onset rescue window test
    description: >-
      Deliver AAV-mediated Atp6v1b2 augmentation to knock-in mice after hearing
      loss is established, rather than at postnatal days 0 to 2, to determine
      whether rescue is possible outside a developmental window that human
      patients have already passed at diagnosis.
  evidence:
  - reference: PMID:37628590
    reference_title: The ATP6V1B2 DDOD/DOORS-Associated p.Arg506* Variant Causes Hyperactivity and Seizures in Mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The auditory brainstem response (ABR) confirmed proper auditory function at 14 weeks of age"
    explanation: Documents preserved hearing in the knock-in mouse, the core of the mismatch.
  - reference: PMID:34746137
    reference_title: Syndromic Deafness Gene ATP6V1B2 Controls Degeneration of Spiral Ganglion Neurons Through Modulating Proton Flux.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We observed increased transcription of Atp6v1b1 in hair cells of Atp6v1b2Arg506*/Arg506* mice and inferred that Atp6v1b1 compensated for the Atp6v1b2 dysfunction by increasing its own transcription level. Genetic compensation in hair cells explains the milder hearing impairment in Atp6v1b2Arg506*/Arg506* mice."
    explanation: Gives the proposed species-specific compensation mechanism behind the mismatch.
references:
- reference: PMID:24913193
  title: De novo mutation in ATP6V1B2 impairs lysosome acidification and causes dominant deafness-onychodystrophy syndrome.
- reference: PMID:39210597
  title: Dominantly acting variants in ATP6V1C1 and ATP6V1B2 cause a multisystem phenotypic spectrum by altering lysosomal and/or autophagosome function.
- reference: PMID:34232384
  title: Genetic architecture and phenotypic landscape of deafness and onychodystrophy syndromes.

📚

References & Deep Research

References

3

PMID:24913193

De novo mutation in ATP6V1B2 impairs lysosome acidification and causes dominant deafness-onychodystrophy syndrome.

No top-level findings curated for this source.

PMID:39210597

Dominantly acting variants in ATP6V1C1 and ATP6V1B2 cause a multisystem phenotypic spectrum by altering lysosomal and/or autophagosome function.

No top-level findings curated for this source.

PMID:34232384

Genetic architecture and phenotypic landscape of deafness and onychodystrophy syndromes.

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

Dominant Deafness–Onychodystrophy Syndrome (DDOD): Disease-Characteristics Research Report

Edison Scientific Literature 17 citations 2026-08-21T21:23:38.962371

Dominant Deafness–Onychodystrophy Syndrome (DDOD): Disease-Characteristics Research Report

Scope. This report summarizes evidence available through 2024, prioritizing primary human studies and recent mechanistic work. DDOD is exceptionally rare; consequently, many requested fields have no population-level data, standardized criteria, or disease-specific clinical trials. Frequencies from broader ATP6V1B2-related cohorts should not be interpreted as frequencies in narrowly defined classic DDOD.

Domain	Best-supported finding	Suggested ontology terms	Evidence type/strength
Disease identity	Dominant Deafness-Onychodystrophy syndrome (DDOD) is a rare ATP6V1B2-related Mendelian syndrome defined classically by congenital sensorineural deafness with nail and distal digital anomalies; OMIM 124480.	OMIM 124480; dominant deafness-onychodystrophy syndrome	Human primary reports + review-level synthesis; strong for core identity (yuan2014denovomutation pages 1-3, beauregardlacroix2021doorssyndromeand pages 1-2, shaw2020exomereportnovel pages 7-9)
Causal gene/variant	The best-supported recurrent pathogenic variant for classic DDOD is heterozygous ATP6V1B2 c.1516C>T, p.Arg506 (also written p.R506 or p.Arg506X).	ATP6V1B2; nonsense variant; germline heterozygous	Human discovery and segregation evidence; strong (yuan2014denovomutation pages 1-3, li2021casereportexome pages 1-2)
Inheritance	Inheritance is autosomal dominant; early reports emphasized de novo occurrence, while later pedigrees established vertical transmission in affected parent-child pairs/families.	autosomal dominant inheritance; de novo mutation	Human genetic evidence; strong (yuan2014denovomutation pages 1-3, li2021casereportexome pages 1-2, beauregardlacroix2021doorssyndromeand pages 1-2)
Hearing phenotype	Hearing loss is typically congenital, bilateral, sensorineural, and severe/profound in reported classic DDOD cases.	HP:0000407 sensorineural hearing impairment; congenital hearing impairment; bilateral hearing impairment	Human clinical evidence; strong for core phenotype (yuan2014denovomutation pages 1-3, beauregardlacroix2021doorssyndromeand pages 1-2)
Nail phenotype	Onychodystrophy is a hallmark, ranging from dystrophic/hypoplastic nails to complete or partial anonychia of fingers and toes.	HP:0001597 abnormality of the nail; HP:0001798 anonychia	Human clinical evidence; strong (yuan2014denovomutation pages 1-3, li2021casereportexome pages 1-2)
Skeletal/digital phenotype	Distal digital anomalies commonly include brachydactyly, shortened fifth fingers, and distal/middle phalangeal hypoplasia or aplasia.	HP:0001156 brachydactyly; distal phalangeal aplasia/hypoplasia	Human clinical/radiographic evidence; strong (yuan2014denovomutation pages 1-3, li2021casereportexome pages 1-2)
Neurodevelopmental spectrum	Intellectual disability and seizures were initially considered absent from classic DDOD, but newer ATP6V1B2 cohort data support a broader phenotypic spectrum in which some carriers have developmental delay/intellectual disability and/or seizures.	HP:0001249 intellectual disability; HP:0001250 seizures	Human cohort and family evidence; moderate, with spectrum/ascertainment uncertainty (carpentieri2024dominantlyactingvariants pages 6-9, shaw2020exomereportnovel pages 7-9)
Differential diagnosis	Major differentials are TBC1D24-related DOORS syndrome and ATP6V1B2-related Zimmermann-Laband spectrum; presence of intellectual disability/seizures or gingival hyperplasia can shift classification away from classic DDOD.	DOORS syndrome; Zimmermann-Laband syndrome	Human comparative clinical genetics; moderate-strong (beauregardlacroix2021doorssyndromeand pages 1-2)
Molecular function	ATP6V1B2 encodes a V-ATPase V1 subunit involved in organelle proton transport and lysosomal/endolysosomal acidification.	vacuolar ATPase complex; lysosome acidification; autophagy; protein catabolic process in lysosome	Human/mammalian functional evidence; strong (yuan2014denovomutation pages 1-3, qiu2021syndromicdeafnessgene pages 7-9, shaw2020exomereportnovel pages 7-9)
Mechanism/pathophysiology	Mechanistic evidence converges on lysosomal/autophagic dysfunction, but directionality remains unsettled across studies: older work linked p.Arg506* to impaired lysosome acidification/hypoacidification, whereas 2024 data on additional dominant ATP6V1B2 variants found increased lysosomal acidity/hyperactive pump behavior with lysosomal storage/autophagy defects.	lysosomal dysfunction; autophagic flux defect; lysosomal storage; apoptosis	Human cells + animal models; moderate, with explicit mechanistic conflict/uncertainty (yuan2014denovomutation pages 1-3, qiu2021syndromicdeafnessgene pages 7-9, carpentieri2024dominantlyactingvariants pages 1-2, carpentieri2024dominantlyactingvariants pages 6-9, carpentieri2024dominantlyactingvariants pages 5-6)
Cellular/anatomical involvement	Disease-relevant structures include cochlear/spiral ganglion neurons, auditory nerve, hair cells, nails, and distal phalanges; some studies also implicate hippocampal circuitry in cognitive features.	spiral ganglion neuron; cochlea; nail; phalanx; hippocampus	Human phenotype plus animal mechanistic evidence; moderate (qiu2021syndromicdeafnessgene pages 7-9, zhao2019asubunitof pages 1-2)
Diagnostics	Diagnosis is supported by the combination of congenital bilateral SNHL plus nail/digital anomalies, with confirmation by exome or targeted ATP6V1B2 sequencing and segregation testing. Radiographs can document phalangeal defects; audiologic testing is central.	HP:0000407 sensorineural hearing impairment; HP:0001597 abnormality of the nail; molecular genetic testing	Human case-based evidence; moderate-strong (yuan2014denovomutation pages 1-3, beauregardlacroix2021doorssyndromeand pages 1-2, li2021casereportexome pages 1-2)
Treatment/management	Management is supportive. Published DDOD cases underwent cochlear implantation; hearing intervention is the main real-world treatment, with additional developmental/neurologic follow-up as needed. No disease-specific approved pharmacotherapy was identified.	cochlear implantation; supportive care; audiologic rehabilitation	Human case reports + animal preclinical suggestion only; moderate for supportive care, weak for disease-modifying therapy (yuan2014denovomutation pages 1-3, qiu2021syndromicdeafnessgene pages 7-9)
Epidemiology	Epidemiology is poorly defined; DDOD is ultra-rare and no reliable prevalence or incidence estimates were identified in the retrieved evidence.	rare disease	Evidence gap / disease-level inference; weak-direct (yuan2014denovomutation pages 1-3, beauregardlacroix2021doorssyndromeand pages 1-2)
Population genetics	Newly described dominant missense ATP6V1B2 variants in 2024 were reported absent from gnomAD in the cited study; classic p.Arg506* is recurrent but still rare.	absent from gnomAD; rare pathogenic variant	Human genetics evidence; moderate (carpentieri2024dominantlyactingvariants pages 5-6)
Model systems	Available models include Atp6v1b2 p.Arg506* mice, cochlear conditional mouse models, zebrafish knockdown, and patient/cell-based assays. Models recapitulate selected auditory, seizure, cognitive, lysosomal, and autophagy phenotypes, but not the full human syndrome consistently.	mouse model; zebrafish model; cellular model	Animal/in vitro evidence; strong for existence of models, moderate for fidelity (rousseau2023theatp6v1b2ddoddoorsassociated pages 1-2, zhao2019asubunitof pages 1-2, rousseau2023theatp6v1b2ddoddoorsassociated pages 10-12)

Table: This table condenses the best-supported findings for Dominant Deafness-Onychodystrophy syndrome across human, cellular, and animal evidence. It is useful as a quick reference for core phenotype, causative genetics, mechanism, diagnostics, and current evidence gaps.

1. Disease information

Definition

Dominant deafness–onychodystrophy syndrome is a rare autosomal-dominant syndromic hearing-loss disorder classically characterized by congenital severe/profound sensorineural hearing loss, onychodystrophy or anonychia, and distal digital abnormalities such as brachydactyly or phalangeal hypoplasia/aplasia. The molecularly defined disorder is caused most consistently by heterozygous ATP6V1B2 c.1516C>T (p.Arg506Ter/p.Arg506*). The original molecular study described three unrelated Chinese patients with severe congenital sensorineural hearing loss, absent or dystrophic nails, and fifth-finger middle-phalangeal aplasia, without inner-ear malformation or intellectual disability. (yuan2014denovomutation pages 1-3)

Identifiers and synonyms

OMIM/MIM: 124480, “Deafness, congenital, and onychodystrophy, autosomal dominant.”
Causal-gene OMIM: ATP6V1B2, MIM 606939. (beauregardlacroix2021doorssyndromeand pages 1-2)
Common synonyms: dominant deafness–onychodystrophy syndrome; DDOD; autosomal dominant deafness and onychodystrophy; congenital deafness with onychodystrophy.
MONDO: a stable disease-specific MONDO identifier was not established from the retrieved primary literature; this should be verified directly against the current MONDO release before database ingestion.
Orphanet, MeSH, ICD-10/ICD-11: no disease-specific identifiers were established from the retrieved evidence. Clinically, hearing loss and congenital nail malformations may require component-level coding rather than a dedicated DDOD code.

This synthesis is derived from aggregated disease-level resources and published case/family reports, not individual EHR records.

Important nosologic distinction

Classic DDOD was initially separated from DOORS syndrome because affected individuals lacked intellectual disability and seizures. DOORS—deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures—is commonly caused by biallelic TBC1D24 variants. Later reports show that ATP6V1B2 p.Arg506* can produce overlapping DDOD/DOORS phenotypes, making the boundary a spectrum rather than an absolute molecular division. (yuan2014denovomutation pages 1-3, beauregardlacroix2021doorssyndromeand pages 1-2)

2. Etiology

Causal factor

The primary cause is a germline heterozygous pathogenic ATP6V1B2 variant. The recurrent classic allele is NM_001693.4:c.1516C>T, p.Arg506*, a nonsense variant truncating the final six amino acids of the B2 subunit of vacuolar H+-ATPase. Early cases arose de novo; subsequent mother–son and father–daughter segregation established genuine autosomal-dominant transmission. (yuan2014denovomutation pages 1-3, li2021casereportexome pages 1-2)

The 2021 WES study analyzed 542 individuals in 166 congenital-hearing-loss families and identified p.Arg506* in two independent multigenerational DDOD families. This was the first direct demonstration of vertical transmission of classic ATP6V1B2-related DDOD. The same study noted high ATP6V1B2 loss-of-function constraint, reported as pLI 0.99. (li2021casereportexome pages 1-2)

Genetic risk factors

A heterozygous pathogenic allele confers high disease risk under an autosomal-dominant model.
Family history is relevant, although de novo occurrence means a negative history does not exclude DDOD.
Broader ATP6V1B2-related disease also results from dominant missense variants, often producing Zimmermann–Laband-like or neurodevelopmental phenotypes rather than classic DDOD. Six de novo variants reported in 2024—p.Tyr328His, p.Tyr328Cys, p.Ala332Val, p.Glu374Gln, p.Gln376Lys, and p.Gln376Arg—were absent from gnomAD. (carpentieri2024dominantlyactingvariants pages 6-9, carpentieri2024dominantlyactingvariants pages 5-6)

Environmental, infectious, and lifestyle risk factors

No environmental toxin, infection, diet, occupation, smoking behavior, sex-specific exposure, or lifestyle factor has been shown to cause DDOD. Ordinary acquired causes of hearing loss may add to disability but are not established etiologic components.

Protective factors and gene–environment interaction

No protective ATP6V1B2 allele, modifier gene, lifestyle factor, or validated gene–environment interaction has been reported. Avoiding preventable ototoxic/noise injury is prudent hearing conservation, but it does not prevent the congenital syndrome.

3. Phenotypes

Core phenotype

Manifestation	Type and characteristics	Suggested HPO annotation
Sensorineural hearing loss	Clinical sign; typically congenital, bilateral, severe/profound; deafness was present in all 20 evaluable ATP6V1B2 subjects in a broader 2024 cohort, although that cohort was not limited to classic DDOD.	HP:0000407 Sensorineural hearing impairment; congenital/bilateral/severe qualifiers
Onychodystrophy/nail hypoplasia	Physical manifestation; congenital and generally stable; ranges from small/dystrophic nails to absent fingernails or toenails.	HP:0001597 Abnormality of the nail; nail hypoplasia
Anonychia	Physical manifestation; complete or digit-specific nail absence. In one family, first- and fifth-fingernails were absent; toenails 1–2 were absent and 3–5 hypoplastic.	HP:0001798 Anonychia
Brachydactyly/short fifth finger	Physical sign; congenital and nonprogressive.	HP:0001156 Brachydactyly; short fifth finger
Phalangeal hypoplasia/aplasia	Radiographic/physical finding, commonly distal or middle phalanges.	Hypoplasia/aplasia of phalanges; absent distal phalanx
Intellectual disability/developmental delay	Historically absent in classic DDOD, but variably present across the ATP6V1B2 p.Arg506*/broader disease spectrum.	HP:0001249 Intellectual disability; global developmental delay
Seizures/epilepsy	Not part of the narrow historical definition, but reported in ATP6V1B2-associated overlapping phenotypes.	HP:0001250 Seizure
Gingival enlargement	More characteristic of Zimmermann–Laband-spectrum ATP6V1B2 disease than classic DDOD.	Gingival overgrowth

The 2024 ATP6V1B2 cohort found nail/skeletal hypoplasia or aplasia in 20/20, facial features in 18/20 (90%), developmental delay/intellectual disability in 8/20 (40%), and seizures in 7/20 (35%). These statistics demonstrate the expanding ATP6V1B2 spectrum, not necessarily classic-DDOD penetrance. (carpentieri2024dominantlyactingvariants pages 6-9, carpentieri2024dominantlyactingvariants pages 5-6)

A separate seven-member family carrying a non-p.Arg506 ATP6V1B2 missense allele had epilepsy in 7/7, intellectual disability in 4/7, mild nail findings in 4/7, postural tremor in 4/7, and mild gingival enlargement in 3/7*; seizure onset ranged from early childhood to 16 years. This family is better classified as broader ATP6V1B2-related neurodevelopmental disease than archetypal DDOD. (shaw2020exomereportnovel pages 7-9)

Onset, severity, progression, and quality of life

Onset: hearing and nail/digital abnormalities are congenital; neurologic features, when present, may emerge in childhood.
Course: nail and skeletal malformations are structurally stable. Human evidence is insufficient to decide whether DDOD hearing loss is universally stable or progressive. Mouse models show early hidden hearing loss followed by later threshold loss, but extrapolation to humans is uncertain. (qiu2021syndromicdeafnessgene pages 7-9)
Quality of life: no DDOD-specific EQ-5D, SF-36, PROMIS, language, or participation cohort was identified. Severe congenital deafness can impair language acquisition, education, communication, and social participation. Hand/nail abnormalities are usually less functionally limiting but may affect fine-motor tasks, protection of fingertips, and appearance.

4. Genetic and molecular information

Causal gene

Gene: ATP6V1B2, encoding V-type proton ATPase subunit B2.
Variant most specific to classic DDOD: c.1516C>T, p.Arg506Ter.
Origin: germline heterozygous; either de novo or inherited.
Class: nonsense/truncating.
Population frequency: no reliable allele frequency was supplied for p.Arg506* in the retrieved evidence; the allele is exceptionally rare. Several newer dominant missense variants were absent from gnomAD. (carpentieri2024dominantlyactingvariants pages 5-6)

The original paper found the same de novo variant in three unrelated patients and showed conservation of residues 506–511. Structural modeling predicted loss of a Tyr504–Asp507 hydrogen bond. (yuan2014denovomutation pages 1-3)

Pathogenic classification and mechanism

Published reports describe p.Arg506 as pathogenic. The mechanism should not* be reduced uncritically to simple haploinsufficiency:

ATP6V1B2 is loss-of-function constrained.
The truncated protein can be expressed and incorporated sufficiently to perturb complex behavior.
Earlier studies showed weakened B2–V1E interaction and impaired lysosome acidification despite retained V-ATPase assembly. (zhao2019asubunitof pages 1-2, yuan2014denovomutation pages 1-3)
The 2024 study instead concluded that dominant ATP6V1B2/ATP6V1C1 alleles can produce gain-of-function/hyperactive proton-pump behavior, increased lysosomal acidity, abnormal lysosomal morphology, defective autophagic flux, and cholesterol/ceramide storage. (carpentieri2024dominantlyactingvariants pages 1-2, carpentieri2024dominantlyactingvariants pages 6-9, carpentieri2024dominantlyactingvariants pages 5-6)

Thus, the current expert interpretation is dominant dysregulation of V-ATPase and endolysosomal homeostasis, with allele- and assay-dependent directionality, rather than a settled universal loss-of-function model.

Modifier, epigenetic, and chromosomal evidence

No validated modifier genes, methylation signature, histone alteration, recurrent copy-number variant, translocation, inversion, or aneuploidy specific to DDOD has been reported. Additional TJP2 and KIF11 variants occurred in the 2021 families, but causative modification of DDOD severity was not established. (li2021casereportexome pages 1-2)

5. Environmental information

DDOD is not infectious and has no demonstrated toxicologic, occupational, dietary, alcohol, smoking, radiation, or pollution cause. No pathogen or zoonotic transmission applies. Environmental hearing hazards can worsen residual auditory function but are nonspecific secondary exposures.

6. Mechanism and pathophysiology

Normal molecular role

V-ATPase is a multisubunit ATP-driven proton pump that acidifies lysosomes, endosomes, and synaptic vesicles. Acidic luminal pH is required for endocytic degradation, lysosomal hydrolase activity, vesicle trafficking, and autophagic turnover. ATP6V1B2 encodes the B2 subunit of the peripheral V1 ATP-hydrolytic sector. (shaw2020exomereportnovel pages 7-9, rousseau2023theatp6v1b2ddoddoorsassociated pages 1-2)

Proposed causal chain

Germline dominant ATP6V1B2 variant → altered B2 structure/subunit interaction and V-ATPase proton transport → abnormal endolysosomal pH and lysosomal organization → impaired autophagic flux and substrate clearance → abnormal mitochondria, apoptosis, and/or altered developmental signaling → injury to auditory neurons/hair-cell circuitry and developmental defects of nails/phalanges → congenital deafness, onychodystrophy, and digital anomalies. In susceptible alleles/individuals, neuronal and synaptic dysfunction may additionally produce intellectual disability, behavioral abnormalities, and seizures. (zhao2019asubunitof pages 1-2, qiu2021syndromicdeafnessgene pages 7-9, carpentieri2024dominantlyactingvariants pages 1-2)

Auditory mechanism

In p.Arg506 mice, auditory-pathway abnormalities included auditory-nerve demyelination, subsequent fiber and spiral-ganglion-neuron loss, increased cleaved caspase-3, reduced Bcl-2, accumulated autolysosomes, and abnormal mitochondria. Hair cells upregulated Atp6v1b1*, suggesting partial genetic compensation. This may explain why some mouse models have milder auditory disease than humans. (qiu2021syndromicdeafnessgene pages 7-9)

Neurologic mechanism

Mouse studies implicate hippocampal CA1 dysfunction and altered brain connectivity in cognitive/behavioral findings. The 2023 heterozygous p.Arg506* model showed interictal epileptic activity and increased seizure susceptibility, supporting a direct neuronal consequence of the allele. (zhao2019asubunitof pages 1-2, rousseau2023theatp6v1b2ddoddoorsassociated pages 10-12)

Suggested ontology annotations

GO biological processes: lysosomal acidification; proton transmembrane transport; autophagy; autophagosome–lysosome fusion; lysosomal substrate catabolism; regulation of neuron apoptotic process; auditory receptor-cell development.
GO cellular components: V-type ATPase complex; lysosomal membrane; endosome; synaptic vesicle; autophagosome; mitochondrion.
Cell Ontology terms: cochlear inner/outer hair cell; spiral ganglion neuron; auditory neuron; Schwann cell; nail matrix keratinocyte; osteoblast/chondrocyte. The latter nail/skeletal cell assignments are biologically plausible but not directly demonstrated in DDOD-specific single-cell experiments.

Metabolism, immunity, and molecular profiling

Cholesterol and ceramide accumulation in patient-derived cells provides limited lipid-storage evidence. No disease-specific systemic metabolomic signature, immune mechanism, chronic inflammation, autoimmunity, transcriptomic atlas, proteomic biomarker, single-cell dataset, spatial transcriptomic study, or integrated multi-omics analysis was identified through 2024. (carpentieri2024dominantlyactingvariants pages 6-9, carpentieri2024dominantlyactingvariants pages 5-6)

7. Anatomical structures affected

Primary structures

Inner ear/auditory system: cochlea, organ of Corti/hair-cell circuitry, spiral ganglion, auditory nerve; hearing loss is typically bilateral.
Nail apparatus: fingernails and toenails, including nail plate/matrix.
Appendicular skeleton: distal and sometimes middle phalanges, especially fifth fingers.

Secondary/variable structures

The central nervous system, particularly hippocampal and seizure-generating networks, may be involved in the broader ATP6V1B2 spectrum. Gingiva and craniofacial structures are more prominent in Zimmermann–Laband-like phenotypes. (carpentieri2024dominantlyactingvariants pages 6-9, shaw2020exomereportnovel pages 7-9, zhao2019asubunitof pages 1-2)

Suggested anatomical ontology terms

UBERON: cochlea; organ of Corti; spiral ganglion; auditory nerve; nail; distal phalanx; middle phalanx; hippocampus.
GO cellular components: lysosome, endosome, autophagosome, synaptic vesicle, V-type ATPase complex.
Lateralization: hearing loss is generally bilateral; nail/digital involvement may be symmetric but varies by digit.

8. Temporal development

DDOD begins during embryonic/fetal development. Hearing impairment and nail/digital abnormalities are apparent at birth or recognized in infancy. It is a lifelong chronic disorder rather than an episodic disease. There is no validated staging system.

The critical clinical period is early infancy and childhood, when delayed identification of profound hearing loss can compromise language development. Newborn hearing detection, rapid diagnostic audiology, and early auditory rehabilitation therefore represent the major actionable window. Neurologic surveillance should continue through childhood because seizures or developmental problems may emerge beyond the neonatal period in broader ATP6V1B2 disease. Human longitudinal natural-history data remain insufficient to quantify progression.

9. Inheritance and population

Inheritance

Mode: autosomal dominant.
Recurrence: an affected heterozygous individual theoretically has a 50% probability of transmitting the variant in each pregnancy.
De novo disease: common in initial reports; parental testing is important.
Penetrance: apparently high for hearing/nail manifestations in classic reported families, but exact penetrance is unknown.
Expressivity: variable, especially for intellectual disability, epilepsy, gingival abnormalities, and skeletal severity. p.Arg506* can produce DDOD or overlapping DOORS-like disease. (beauregardlacroix2021doorssyndromeand pages 1-2, rousseau2023theatp6v1b2ddoddoorsassociated pages 10-12)
Anticipation: not reported.
Founder effect: not demonstrated.
Consanguinity: not relevant to the dominant mechanism, although relevant to recessive TBC1D24-DOORS differential diagnosis.
Germline mosaicism: not documented, but a low residual recurrence risk after an apparently de novo variant is standard counseling practice.

Epidemiology

No reliable prevalence, incidence, carrier frequency, sex ratio, ethnic enrichment, or geographic distribution estimate exists. Published patients include Chinese, European, and other ancestries; this supports worldwide potential rather than a defined endemic population. The small number of reports is consistent with ultra-rarity, but publication counts cannot be converted into prevalence.

10. Diagnostics

Clinical assessment

Audiology: newborn hearing screening followed by diagnostic auditory brainstem response, otoacoustic emissions, tympanometry, and age-appropriate pure-tone/speech audiometry.
Physical examination: document each nail, digit length, distal phalanges, gingiva, craniofacial features, growth, and neurologic development.
Radiography: hand/foot radiographs can establish distal or middle phalangeal hypoplasia/aplasia.
Neurologic evaluation: developmental testing and EEG when seizures, regression, or suspicious episodes occur.
Imaging: temporal-bone CT/MRI is useful for cochlear-implant planning and excluding structural causes; the original DDOD cases had no inner-ear malformation. (yuan2014denovomutation pages 1-3)

Molecular testing

A practical strategy is:

A comprehensive syndromic hearing-loss panel including ATP6V1B2 and TBC1D24, with copy-number analysis where validated.
Targeted ATP6V1B2 sequencing when the phenotype is highly characteristic.
Trio WES/WGS when panel testing is negative or the phenotype includes epilepsy, intellectual disability, gingival enlargement, or atypical skeletal findings.
Confirm candidate variants and familial segregation by Sanger sequencing or equivalent orthogonal testing.

WES successfully identified p.Arg506* and segregating alleles in two families. WGS may detect noncoding or structural causes but has no demonstrated DDOD-specific incremental yield. CMA, karyotyping, FISH, mitochondrial testing, and repeat-expansion testing are not first-line for a classic phenotype unless additional findings suggest another disorder. (li2021casereportexome pages 1-2, beauregardlacroix2021doorssyndromeand pages 1-2)

Differential diagnosis

TBC1D24-related DOORS: usually autosomal recessive; profound deafness, nail/phalangeal abnormalities, osteodystrophy, intellectual disability, and seizures.
ATP6V1B2-related Zimmermann–Laband syndrome: gingival enlargement, bulbous/soft distal digits, hypoplastic nails/distal phalanges, characteristic face, and variable intellectual disability/epilepsy.
ATP6V1B2-associated DDOD/DOORS overlap: molecularly and clinically continuous with classic DDOD.
Coffin–Siris syndrome: hypoplastic/absent fifth fingernails/distal phalanges plus developmental disability, but a different chromatin-remodeling etiology.
Other syndromic deafness/nail disorders and acquired congenital hearing-loss causes should be considered according to examination and family history.

No consensus society diagnostic criteria, biochemical enzyme assay, circulating biomarker, biopsy signature, or validated omics diagnostic exists.

11. Outcome and prognosis

There are no 5- or 10-year survival estimates, disease-specific mortality rates, or formal prognostic models. Classic DDOD is not known to shorten life expectancy. A reported ATP6V1B2 p.Arg506* patient with a broader DOORS-like presentation lived to 72 years, showing that long survival is possible, although a single case cannot define prognosis. (beauregardlacroix2021doorssyndromeand pages 1-2)

The principal morbidity is lifelong auditory disability and its effect on spoken-language development. Nail and phalangeal abnormalities are permanent. Prognosis for communication depends on severity, age at intervention, auditory-nerve integrity, developmental status, rehabilitation, and access to sign/spoken-language support. Neurologic prognosis is more variable in individuals with epilepsy or intellectual disability. No validated prognostic biomarker is available.

12. Treatment

Current real-world management

There is no approved disease-modifying therapy. Care is multidisciplinary and supportive:

Hearing aids where usable residual hearing exists.
Cochlear implantation for severe/profound bilateral sensorineural loss after standard candidacy evaluation. The original three probands underwent unilateral implantation between ages 2 and 18 years. (yuan2014denovomutation pages 1-3)
Auditory-verbal, speech-language, educational, and sign-language support, individualized to family goals and developmental profile.
Nail/hand care: protection from trauma, dermatology/podiatry management, occupational therapy if fine-motor limitations occur.
Seizure treatment: standard antiseizure therapy based on seizure type; no ATP6V1B2-specific pharmacogenomic recommendation exists.
Developmental services: early intervention, neuropsychological assessment, and school accommodations.

Suggested NCIT concepts include Cochlear Implantation, Hearing Aid, Speech and Language Therapy, Occupational Therapy, Genetic Counseling, and Supportive Care.

Treatment outcomes and limitations

Cochlear implants are functional in reported DDOD patients, but one study noted unsatisfactory language rehabilitation despite functioning devices, raising concern for unrecognized cognitive or central auditory involvement. This is case-based evidence, not a response-rate estimate. (zhao2019asubunitof pages 1-2)

Experimental treatments

In mice, the apoptosis inhibitor BIP-V5 improved auditory phenotypic/pathologic outcomes in only two treated mutant animals; this is exploratory preclinical evidence and not a clinical recommendation. (qiu2021syndromicdeafnessgene pages 7-9)

The 2023 p.Arg506* mouse is proposed for drug screening, but no DDOD-specific human interventional trial was identified. No validated gene therapy, CRISPR therapy, antisense oligonucleotide, RNA therapy, cell therapy, or immune therapy had entered clinical use through 2024. (rousseau2023theatp6v1b2ddoddoorsassociated pages 1-2, rousseau2023theatp6v1b2ddoddoorsassociated pages 10-12)

13. Prevention

Primary prevention

The phenotype cannot be prevented through vaccination, diet, or lifestyle modification. Reproductive options after molecular diagnosis include genetic counseling, prenatal diagnosis, and preimplantation genetic testing where legally and ethically available.

Secondary prevention/early detection

Universal newborn hearing screening.
Prompt diagnostic audiology after failed screening.
Cascade testing of first-degree relatives once a familial ATP6V1B2 variant is known.
Developmental and seizure surveillance in variant-positive children.

Tertiary prevention

Early hearing intervention, communication access, educational support, hearing conservation, avoidance of unnecessary ototoxic exposure, and prompt epilepsy treatment can reduce secondary disability. There is no vaccine, chemoprophylaxis, or population carrier-screening recommendation specific to DDOD.

14. Other species and natural disease

No naturally occurring veterinary DDOD equivalent was identified in companion animals, livestock, or wildlife, and there is no zoonotic potential. ATP6V1B2 function is evolutionarily conserved, as illustrated by conservation of the human protein’s terminal residues and phenotypes after experimental perturbation in mouse and zebrafish. (yuan2014denovomutation pages 1-3, zhao2019asubunitof pages 1-2)

Relevant experimental taxa are Mus musculus (NCBI Taxonomy 10090) and Danio rerio (7955). Breed-specific VBO annotations are not applicable to the reported engineered models.

15. Model organisms and research systems

Mouse

Atp6v1b2 p.Arg506* knock-in/transgenic models: reproduce selected cognitive, auditory, behavioral, and seizure phenotypes.
The 2023 heterozygous model—genetically analogous to patients—showed locomotor hyperactivity, reduced anxiety-associated behavior, interictal epileptic activity, and reduced pentylenetetrazol seizure threshold. Homozygotes were also viable in this engineered context and showed stronger abnormalities. (rousseau2023theatp6v1b2ddoddoorsassociated pages 10-12, rousseau2023theatp6v1b2ddoddoorsassociated pages 1-2)
An auditory model showed hidden hearing loss early and later-onset threshold loss, with spiral-ganglion degeneration and autophagy/apoptosis abnormalities. (qiu2021syndromicdeafnessgene pages 7-9)
A prior knock-in study found cognitive abnormalities but normal hearing/cochlear morphology, illustrating model- and protocol-dependent phenotypic fidelity. (zhao2019asubunitof pages 1-2)
Complete loss of Atp6v1b2 is embryonically lethal, emphasizing that null models and human terminal truncation are not equivalent. (rousseau2023theatp6v1b2ddoddoorsassociated pages 1-2)

Zebrafish

Atp6v1b2 knockdown produced multisystem developmental abnormalities and has been used to investigate developmental and neurologic consequences. Its limitations include transient knockdown, species differences in auditory anatomy, and imperfect modeling of heterozygous p.Arg506*. (zhao2019asubunitof pages 1-2)

Cellular systems

Patient fibroblasts and transfected mammalian cells have been used to measure lysosomal pH, V-ATPase-subunit interaction, lysosomal morphology/localization, autophagic flux, and cholesterol/ceramide storage. These systems are mechanistically informative but do not reproduce cochlear architecture, nail development, or organism-level neurodevelopment. (carpentieri2024dominantlyactingvariants pages 1-2, carpentieri2024dominantlyactingvariants pages 6-9, carpentieri2024dominantlyactingvariants pages 5-6)

Advanced-technology gap

No DDOD-specific organoid, iPSC-derived cochlear model, single-cell or spatial transcriptomic atlas, CRISPR screen, comprehensive proteome/metabolome/lipidome, or integrated multi-omics study was identified through 2024. The principal current platforms remain engineered mice, zebrafish perturbation, and patient-derived fibroblasts.

Key recent developments and expert interpretation

2023: heterozygous p.Arg506* mice established that one mutant allele is sufficient to increase seizure susceptibility, strengthening the biological basis for epilepsy within the ATP6V1B2 spectrum. The abstract states that “both heterozygous (like patients) and homozygous mice have reduced seizure thresholds to pentylenetetrazol.” (rousseau2023theatp6v1b2ddoddoorsassociated pages 10-12, rousseau2023theatp6v1b2ddoddoorsassociated pages 1-2)
2024: a 20-person ATP6V1B2 series quantified broad phenotypic variability and connected dominant ATP6V1B2/ATP6V1C1 variants to altered lysosome morphology, increased acidity, defective autophagic flux, and lipid storage. This supports classifying these conditions as disorders of lysosomal homeostasis. (carpentieri2024dominantlyactingvariants pages 1-2, carpentieri2024dominantlyactingvariants pages 6-9, carpentieri2024dominantlyactingvariants pages 5-6)
Current expert synthesis: p.Arg506 remains the allele most strongly linked to classic DDOD, but DDOD, ATP6V1B2-related DOORS, and Zimmermann–Laband presentations overlap. Classification should therefore record both the named phenotype and the broader ATP6V1B2-related disorder* umbrella, with patient-level annotations for hearing, nails/phalanges, neurodevelopment, seizures, and gingiva. (beauregardlacroix2021doorssyndromeand pages 1-2)

Principal evidence gaps

Reliable prevalence, penetrance, longitudinal hearing trajectories, cochlear-implant response rates, quality-of-life measurements, genotype-specific prognosis, modifier genes, epigenetic signatures, validated biomarkers, treatment guidelines, and disease-modifying clinical trials are unavailable. The most important research needs are a multinational natural-history registry, standardized audiologic/developmental outcomes, allele-resolved functional studies, cochlear/nail-relevant human cell models, and prospective evaluation of auditory intervention.

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(carpentieri2024dominantlyactingvariants pages 5-6): Giovanna Carpentieri, Serena Cecchetti, Gianfranco Bocchinfuso, Francesca Clementina Radio, Chiara Leoni, Roberta Onesimo, Paolo Calligari, Agostina Pietrantoni, Andrea Ciolfi, Marco Ferilli, Cristina Calderan, Gerarda Cappuccio, Simone Martinelli, Elena Messina, Viviana Caputo, Ulrike Hüffmeier, Cyril Mignot, Stéphane Auvin, Yline Capri, Charles Marques Lourenco, Bianca E. Russell, Ahna Neustad, Nicola Brunetti Pierri, Boris Keren, André Reis, Julie S. Cohen, Alexis Heidlebaugh, Clay Smith, Christian T. Thiel, Leonardo Salviati, Giuseppe Zampino, Philippe M. Campeau, Lorenzo Stella, Marco Tartaglia, and Elisabetta Flex. Dominantly acting variants in atp6v1c1 and atp6v1b2 cause a multisystem phenotypic spectrum by altering lysosomal and/or autophagosome function. Oct 2024. URL: https://doi.org/10.1016/j.xhgg.2024.100349, doi:10.1016/j.xhgg.2024.100349. This article has 14 citations and is from a peer-reviewed journal.
(zhao2019asubunitof pages 1-2): Weihao Zhao, Xue Gao, Shiwei Qiu, Bo Gao, Song Gao, Xin Zhang, Dongyang Kang, Weiju Han, Pu Dai, and Yongyi Yuan. A subunit of v-atpases, atp6v1b2, underlies the pathology of intellectual disability. EBioMedicine, 45:408-421, Jul 2019. URL: https://doi.org/10.1016/j.ebiom.2019.06.035, doi:10.1016/j.ebiom.2019.06.035. This article has 44 citations and is from a peer-reviewed journal.
(rousseau2023theatp6v1b2ddoddoorsassociated pages 1-2): Justine Rousseau, Samuel Boris Tene Tadoum, Marisol Lavertu Jolin, Thi Tuyet Mai Nguyen, Norbert Fonya Ajeawung, Ann M. Flenniken, Lauryl M. J. Nutter, Igor Vukobradovic, Elsa Rossignol, and Philippe M. Campeau. The atp6v1b2 ddod/doors-associated p.arg506* variant causes hyperactivity and seizures in mice. Genes, 14:1538, Jul 2023. URL: https://doi.org/10.3390/genes14081538, doi:10.3390/genes14081538. This article has 7 citations.
(rousseau2023theatp6v1b2ddoddoorsassociated pages 10-12): Justine Rousseau, Samuel Boris Tene Tadoum, Marisol Lavertu Jolin, Thi Tuyet Mai Nguyen, Norbert Fonya Ajeawung, Ann M. Flenniken, Lauryl M. J. Nutter, Igor Vukobradovic, Elsa Rossignol, and Philippe M. Campeau. The atp6v1b2 ddod/doors-associated p.arg506* variant causes hyperactivity and seizures in mice. Genes, 14:1538, Jul 2023. URL: https://doi.org/10.3390/genes14081538, doi:10.3390/genes14081538. This article has 7 citations.

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Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	8
Resolved	8
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	8
On topic	3
Off topic	0

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Classifications

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Differential Diagnoses

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Dominant Deafness–Onychodystrophy Syndrome (DDOD): Disease-Characteristics Research Report

1. Disease information

Definition

Identifiers and synonyms

Important nosologic distinction

2. Etiology

Causal factor

Genetic risk factors

Environmental, infectious, and lifestyle risk factors

Protective factors and gene–environment interaction

3. Phenotypes

Core phenotype

Onset, severity, progression, and quality of life

4. Genetic and molecular information

Causal gene

Pathogenic classification and mechanism

Modifier, epigenetic, and chromosomal evidence

5. Environmental information

6. Mechanism and pathophysiology

Normal molecular role

Proposed causal chain

Auditory mechanism

Neurologic mechanism

Suggested ontology annotations

Metabolism, immunity, and molecular profiling

7. Anatomical structures affected

Primary structures

Secondary/variable structures

Suggested anatomical ontology terms

8. Temporal development

9. Inheritance and population

Inheritance

Epidemiology

10. Diagnostics

Clinical assessment

Molecular testing

Differential diagnosis

11. Outcome and prognosis

12. Treatment

Current real-world management

Treatment outcomes and limitations

Experimental treatments

13. Prevention

Primary prevention

Secondary prevention/early detection

Tertiary prevention

14. Other species and natural disease

15. Model organisms and research systems

Mouse

Zebrafish

Cellular systems

Advanced-technology gap

Key recent developments and expert interpretation

Principal evidence gaps

Artifacts

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