| 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 (pqac-00000001, pqac-00000004, pqac-00000006) |
| 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 (pqac-00000001, pqac-00000002, pqac-00000011) |
| 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 (pqac-00000001, pqac-00000002, pqac-00000004) |
| 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 (pqac-00000001, pqac-00000004) |
| 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 (pqac-00000001, pqac-00000011) |
| 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 (pqac-00000001, pqac-00000011, pqac-00000016) |
| 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 (pqac-00000008, pqac-00000010) |
| 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 (pqac-00000004, pqac-00000015) |
| 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 (pqac-00000001, pqac-00000003, pqac-00000006) |
| 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 (pqac-00000001, pqac-00000003, pqac-00000007, pqac-00000008, pqac-00000009) |
| 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 (pqac-00000003, pqac-00000018) |
| 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 (pqac-00000001, pqac-00000015, pqac-00000016) |
| 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 (pqac-00000001, pqac-00000003) |
| 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 (pqac-00000001, pqac-00000004) |
| 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 (pqac-00000009) |
| 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 (pqac-00000017, pqac-00000018, pqac-00000019) |


*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.*