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.

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

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:

1. ATP6V1B2 is loss-of-function constrained.
2. The truncated protein can be expressed and incorporated sufficiently to perturb complex behavior.
3. Earlier studies showed weakened B2–V1E interaction and impaired lysosome acidification despite retained V-ATPase assembly. (zhao2019asubunitof pages 1-2, yuan2014denovomutation pages 1-3)
4. 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

1. Audiology: newborn hearing screening followed by diagnostic auditory brainstem response, otoacoustic emissions, tympanometry, and age-appropriate pure-tone/speech audiometry.
2. Physical examination: document each nail, digit length, distal phalanges, gingiva, craniofacial features, growth, and neurologic development.
3. Radiography: hand/foot radiographs can establish distal or middle phalangeal hypoplasia/aplasia.
4. Neurologic evaluation: developmental testing and EEG when seizures, regression, or suspicious episodes occur.
5. 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

1. 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)
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)
3. 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.

References

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10. (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.

11. (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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