Autosomal dominant deafness - onychodystrophy syndrome

Summary

Autosomal dominant deafness - onychodystrophy syndrome (MONDO:0007420) is a disease caused by ATP6V1B2 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ATP6V1B2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 12
• Phenotypes (HPO): 20

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		22	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

20 HPO clinical features (Orphanet curated; top 20 by frequency):

HPO ID	Term	Frequency
HP:0001817	Absent fingernail	Very frequent (80-99%)
HP:0008625	Severe sensorineural hearing impairment	Very frequent (80-99%)
HP:0000164	Abnormality of the dentition	Frequent (30-79%)
HP:0000677	Oligodontia	Frequent (30-79%)
HP:0001199	Triphalangeal thumb	Frequent (30-79%)
HP:0001802	Absent toenail	Frequent (30-79%)
HP:0008386	Aplasia/Hypoplasia of the nails	Frequent (30-79%)
HP:0000268	Dolichocephaly	Occasional (5-29%)
HP:0000348	High forehead	Occasional (5-29%)
HP:0001057	Aplasia cutis congenita	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001763	Pes planus	Occasional (5-29%)
HP:0001800	Hypoplastic toenails	Occasional (5-29%)
HP:0001999	Abnormal facial shape	Occasional (5-29%)
HP:0002465	Poor speech	Occasional (5-29%)
HP:0009778	Short thumb	Occasional (5-29%)
HP:0012554	Absent thumbnail	Occasional (5-29%)
HP:0200104	Absent fifth fingernail	Occasional (5-29%)
HP:0200141	Small, conical teeth	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant deafness - onychodystrophy syndrome
Mondo ID	MONDO:0007420
OMIM	124480
Orphanet	79499
DOID	DOID:0080720
UMLS	C2675730
MedGen	382676
GARD	0004732
Is cancer (heuristic)	no

Also known as: autosomal dominant deafness-onychodystrophy syndrome · DDOD · DDOD syndrome · deafness and onychodystrophy, dominant form · deafness, congenital, and onychodystrophy, autosomal dominant · deafness-onychodystrophy syndrome, autosomal dominant · familial ectodermal dysplasia with sensori-neural deafness and other anomalies · Robinson Miller Bensimon syndrome · Robinson-Miller-Bensimon syndrome

Data availability: 12 ClinVar variants · 2 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › autosomal dominant deafness - onychodystrophy syndrome

Related subtypes (35): Neu-Laxova syndrome, cutaneous mycosis, integumentary system benign neoplasm, integumentary system cancer, nipple neoplasm, nail disorder, disorder of pilosebaceous unit, Bartholin duct cyst, benign mammary dysplasia, skin disorder, breast fibrosis, breast mucosa-associated lymphoid tissue lymphoma, panniculitis, alopecia-epilepsy-pyorrhea-intellectual disability syndrome, keratoderma hereditarium mutilans, Rombo syndrome, Sjogren-Larsson syndrome, mucosulfatidosis, ichthyosis prematurity syndrome, ANE syndrome, frontonasal dysplasia with alopecia and genital anomaly, peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome, mandibulofacial dysostosis with alopecia, cutis laxa, X-linked ichthyosis syndrome, demodicidosis, Proteus-like syndrome, familial atypical multiple mole melanoma syndrome, familial tumoral calcinosis, subcutaneous tissue disorder, Bartholin gland neoplasm, pseudoxanthoma elasticum (inherited or acquired), skin appendage disorder, keratinization disease, paraneoplastic cutaneous syndrome

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

12 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 2 conflicting classifications of pathogenicity, 1 benign, 1 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
203442	NM_001693.4(ATP6V1B2):c.1516C>T (p.Arg506Ter)	ATP6V1B2	Pathogenic	criteria provided, multiple submitters, no conflicts
3342486	NM_001693.4(ATP6V1B2):c.1517G>A (p.Arg506Gln)	ATP6V1B2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1803330	NM_001693.4(ATP6V1B2):c.1516C>G (p.Arg506Gly)	ATP6V1B2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3393387	NM_001693.4(ATP6V1B2):c.1322A>C (p.Glu441Ala)	ATP6V1B2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029522	NM_001693.4(ATP6V1B2):c.1315G>A (p.Val439Ile)	ATP6V1B2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2672118	NM_001693.4(ATP6V1B2):c.472A>G (p.Ile158Val)	ATP6V1B2	Uncertain significance	criteria provided, single submitter
3131899	NM_001693.4(ATP6V1B2):c.14C>A (p.Ala5Glu)	ATP6V1B2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3233384	NM_001693.4(ATP6V1B2):c.1001T>C (p.Ile334Thr)	ATP6V1B2	Uncertain significance	criteria provided, single submitter
3382980	NM_001693.4(ATP6V1B2):c.1018C>T (p.Arg340Ter)	ATP6V1B2	Uncertain significance	criteria provided, single submitter
3595460	NM_001693.4(ATP6V1B2):c.631G>C (p.Gly211Arg)	ATP6V1B2	Uncertain significance	criteria provided, single submitter
3780594	NM_001693.4(ATP6V1B2):c.545G>C (p.Ser182Thr)	ATP6V1B2	Uncertain significance	criteria provided, single submitter
1192466	NM_001693.4(ATP6V1B2):c.463+6T>G	ATP6V1B2	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ATP6V1B2	Strong	Autosomal dominant	autosomal dominant deafness - onychodystrophy syndrome	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATP6V1B2	Orphanet:3473	Zimmermann-Laband syndrome
ATP6V1B2	Orphanet:79499	Autosomal dominant deafness-onychodystrophy syndrome
ATP6V1B2	Orphanet:79500	DOORS syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ATP6V1B2	HGNC:854	ENSG00000147416	P21281	V-type proton ATPase subunit B, brain isoform	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATP6V1B2	V-type proton ATPase subunit B, brain isoform	Non-catalytic subunit of the V1 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ATP6V1B2	Other/Unknown	no		ATPase_F1/V1/A1_a/bsu_nucl-bd, ATPase_F1/V1/A1_a/bsu_N, ATPase_V1-cplx_bsu

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
lateral nuclear group of thalamus	1
monocyte	1
pons	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATP6V1B2	300	ubiquitous	marker	pons, monocyte, lateral nuclear group of thalamus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATP6V1B2	2,898

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATP6V1B2	P21281	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Regulation of MITF-M-dependent genes involved in lysosome biogenesis and autophagy	1	671.8×	0.004	ATP6V1B2
Insulin receptor recycling	1	380.7×	0.004	ATP6V1B2
Transferrin endocytosis and recycling	1	368.4×	0.004	ATP6V1B2
ROS and RNS production in phagocytes	1	335.9×	0.004	ATP6V1B2
Amino acids regulate mTORC1	1	200.3×	0.006	ATP6V1B2
Ion channel transport	1	96.0×	0.010	ATP6V1B2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
synaptic vesicle lumen acidification	1	936.2×	0.003	ATP6V1B2
vacuolar acidification	1	732.7×	0.003	ATP6V1B2
ATP metabolic process	1	468.1×	0.003	ATP6V1B2
proton transmembrane transport	1	312.1×	0.003	ATP6V1B2
regulation of macroautophagy	1	295.6×	0.003	ATP6V1B2

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
ATP6V1B2	ENOXACIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATP6V1B2	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ENOXACIN	4	ATP6V1B2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ATP6V1B2	3	Binding:3

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
ENOXACIN	4	ATP6V1B2

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ATP6V1B2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.