Autosomal dominant nonsyndromic hearing loss 22

Summary

Autosomal dominant nonsyndromic hearing loss 22 (MONDO:0011660) is a disease caused by MYO6 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: MYO6 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 219

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant nonsyndromic hearing loss 22
Mondo ID	MONDO:0011660
MeSH	C538197
OMIM	606346
DOID	DOID:0110552
UMLS	C2931767
MedGen	419894
GARD	0009167
Is cancer (heuristic)	no

Also known as: autosomal dominant deafness 22 · autosomal dominant nonsyndromic deafness 22 · autosomal dominant nonsyndromic deafness caused by mutation in MYO6 · autosomal dominant nonsyndromic deafness type 22 · deafness, autosomal dominant 22 · deafness, autosomal dominant 22, with hypertrophic cardiomyopathy · deafness, autosomal dominant nonsyndromic sensorineural 22 · deafness, autosomal dominant type 22 · DFNA 22 · DFNA22 · MYO6 autosomal dominant nonsyndromic deafness

Data availability: 219 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › autosomal dominant nonsyndromic hearing loss › autosomal dominant nonsyndromic hearing loss 22

Related subtypes (75): autosomal dominant nonsyndromic hearing loss 1, autosomal dominant nonsyndromic hearing loss 2A, autosomal dominant nonsyndromic hearing loss 4A, autosomal dominant nonsyndromic hearing loss 6, autosomal dominant nonsyndromic hearing loss 5, autosomal dominant nonsyndromic hearing loss 10, autosomal dominant nonsyndromic hearing loss 11, autosomal dominant nonsyndromic hearing loss 9, autosomal dominant nonsyndromic hearing loss 7, autosomal dominant nonsyndromic hearing loss 12, autosomal dominant nonsyndromic hearing loss 3A, autosomal dominant nonsyndromic hearing loss 13, autosomal dominant nonsyndromic hearing loss 15, autosomal dominant nonsyndromic hearing loss 17, autosomal dominant nonsyndromic hearing loss 16, autosomal dominant nonsyndromic hearing loss 20, autosomal dominant nonsyndromic hearing loss 23, autosomal dominant nonsyndromic hearing loss 25, autosomal dominant nonsyndromic hearing loss 18, autosomal dominant nonsyndromic hearing loss 24, autosomal dominant nonsyndromic hearing loss 30, autosomal dominant nonsyndromic hearing loss 36, autosomal dominant nonsyndromic hearing loss 21, autosomal dominant nonsyndromic hearing loss 44, autosomal dominant nonsyndromic hearing loss 48, autosomal dominant nonsyndromic hearing loss 41, autosomal dominant nonsyndromic hearing loss 49, autosomal dominant nonsyndromic hearing loss 43, autosomal dominant nonsyndromic hearing loss 28, autosomal dominant nonsyndromic hearing loss 31, autosomal dominant nonsyndromic hearing loss 47, autosomal dominant auditory neuropathy 1, autosomal dominant nonsyndromic hearing loss 53, autosomal dominant nonsyndromic hearing loss 27, autosomal dominant nonsyndromic hearing loss 59, autosomal dominant nonsyndromic hearing loss 3B, autosomal dominant nonsyndromic hearing loss 2B, autosomal dominant nonsyndromic hearing loss 50, autosomal dominant nonsyndromic hearing loss 51, autosomal dominant nonsyndromic hearing loss 64, autosomal dominant nonsyndromic hearing loss 33, autosomal dominant nonsyndromic hearing loss 4B, autosomal dominant nonsyndromic hearing loss 56, autosomal dominant nonsyndromic hearing loss 54, autosomal dominant nonsyndromic hearing loss 58, autosomal dominant nonsyndromic hearing loss 65, autosomal dominant nonsyndromic hearing loss 67, autosomal dominant nonsyndromic hearing loss 40, autosomal dominant nonsyndromic hearing loss 69, autosomal dominant nonsyndromic hearing loss 68, autosomal dominant nonsyndromic hearing loss 70, autosomal dominant nonsyndromic hearing loss 66, hearing loss, autosomal dominant 74, hearing loss, autosomal dominant 77, hearing loss, autosomal dominant 81, hearing loss, autosomal dominant 82, hearing loss, autosomal dominant 83, hearing loss, autosomal dominant 84, hearing loss, autosomal dominant 80, hearing loss, autosomal dominant 37, hearing loss, autosomal dominant 75, hearing loss, autosomal dominant 76, hearing loss, autosomal dominant 71, hearing loss, autosomal dominant 72, hearing loss, autosomal dominant 73, hearing loss, autosomal dominant 34, with or without inflammation, hearing loss, autosomal dominant 78, hearing loss, autosomal dominant 79, hearing loss, autosomal dominant 85, hearing loss, autosomal dominant 86, hearing loss, autosomal dominant 87, hearing loss, autosomal dominant 88, hearing loss, autosomal dominant 89, hearing loss, autosomal dominant 90, autosomal dominant nonsyndromic hearing loss 91

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

219 retrieved; paginated sample, class counts are floors:

101 uncertain significance, 64 conflicting classifications of pathogenicity, 18 benign, 12 likely pathogenic, 10 benign/likely benign, 9 pathogenic, 4 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1064988	NM_004999.4(MYO6):c.866_869del (p.Lys289fs)	MYO6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
164634	NM_004999.4(MYO6):c.826C>T (p.Arg276Ter)	MYO6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
178957	NM_004999.4(MYO6):c.238C>T (p.Arg80Ter)	MYO6	Pathogenic	reviewed by expert panel
228278	NM_004999.4(MYO6):c.2839C>T (p.Arg947Ter)	MYO6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
236034	NM_004999.4(MYO6):c.1473_1473+2delinsC	MYO6	Pathogenic	no assertion criteria provided
3377135	NM_004999.4(MYO6):c.406C>T (p.Arg136Ter)	MYO6	Pathogenic	criteria provided, single submitter
544693	NM_004999.4(MYO6):c.2717C>A (p.Ser906Ter)	MYO6	Pathogenic	criteria provided, single submitter
620495	NM_004999.4(MYO6):c.1159C>T (p.Arg387Ter)	MYO6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
813826	NM_004999.4(MYO6):c.3765del (p.Cys1256fs)	MYO6	Pathogenic	criteria provided, single submitter
8577	NM_004999.4(MYO6):c.1325G>A (p.Cys442Tyr)	MYO6	Pathogenic	no assertion criteria provided
8582	NM_004999.4(MYO6):c.2545C>T (p.Arg849Ter)	MYO6	Pathogenic	criteria provided, multiple submitters, no conflicts
8583	NM_004999.4(MYO6):c.2417-1758T>G	MYO6	Pathogenic	no assertion criteria provided
917516	NM_004999.4(MYO6):c.1452dup (p.Asn485Ter)	MYO6	Pathogenic	criteria provided, single submitter
1707543	NM_004999.4(MYO6):c.2639_2649delinsGAAATTAAGGTATGTAATTAAGGTATGT (p.Thr880_Ala883delinsArgAsnTer)	MYO6	Likely pathogenic	criteria provided, single submitter
1709519	NM_004999.4(MYO6):c.2442_2445dup (p.Ala816Ter)	MYO6	Likely pathogenic	criteria provided, single submitter
2445628	NM_004999.4(MYO6):c.188-1G>T	MYO6	Likely pathogenic	criteria provided, single submitter
2775439	NM_004999.4(MYO6):c.2437C>T (p.Arg813Ter)	MYO6	Likely pathogenic	criteria provided, single submitter
3066288	NM_004999.4(MYO6):c.1381+1G>T	MYO6	Likely pathogenic	criteria provided, single submitter
3382328	NM_004999.4(MYO6):c.3216_3219dup (p.Lys1074Ter)	MYO6	Likely pathogenic	criteria provided, single submitter
3601437	NM_004999.4(MYO6):c.2677G>T (p.Glu893Ter)	MYO6	Likely pathogenic	criteria provided, single submitter
402263	NM_004999.4(MYO6):c.897G>T (p.Glu299Asp)	MYO6	Likely pathogenic	criteria provided, single submitter
4540417	NM_004999.4(MYO6):c.2480G>A (p.Trp827Ter)	MYO6	Likely pathogenic	criteria provided, single submitter
4755431	NM_004999.4(MYO6):c.2186T>A (p.Leu729Ter)	MYO6	Likely pathogenic	criteria provided, single submitter
523937	NM_004999.4(MYO6):c.2751dup (p.Gln918fs)	MYO6	Likely pathogenic	reviewed by expert panel
978024	NM_004999.4(MYO6):c.2078-2A>G	MYO6	Likely pathogenic	criteria provided, single submitter
420403	NM_139343.3(BIN1):c.1264-11_1270del	BIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
164644	NM_004999.4(MYO6):c.3246T>C (p.Tyr1082=)	MYO6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
178474	NM_004999.4(MYO6):c.2595C>T (p.Pro865=)	MYO6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
178623	NM_004999.4(MYO6):c.1674+13A>G	MYO6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
180087	NM_004999.4(MYO6):c.441C>T (p.Ile147=)	MYO6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 5 · 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
MYO6	Definitive	Autosomal dominant	autosomal dominant nonsyndromic hearing loss 22	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MYO6	Orphanet:228012	Progressive sensorineural hearing loss-hypertrophic cardiomyopathy syndrome
MYO6	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
MYO6	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
BIN1	Orphanet:169186	Autosomal recessive centronuclear myopathy
BIN1	Orphanet:169189	Autosomal dominant centronuclear myopathy

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MYO6	HGNC:7605	ENSG00000196586	Q9UM54	Unconventional myosin-VI	gencc,clinvar
BIN1	HGNC:1052	ENSG00000136717	O00499	Myc box-dependent-interacting protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MYO6	Unconventional myosin-VI	Myosins are actin-based motor molecules with ATPase activity.
BIN1	Myc box-dependent-interacting protein 1	Is a key player in the control of plasma membrane curvature, membrane shaping and membrane remodeling.

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 0 · 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
Scaffold/PPI	2	17.3×	0.003

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MYO6	Scaffold/PPI	no		Myosin_head_motor_dom-like, SH3_Myosin, Myosin_S1_N
BIN1	Scaffold/PPI	no		SH3_domain, Amphiphysin, Amphiphysin_2

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
amniotic fluid	1
corpus callosum	1
medial globus pallidus	1
gastrocnemius	1
hindlimb stylopod muscle	1
skeletal muscle tissue of rectus abdominis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MYO6	278	ubiquitous	marker	amniotic fluid, medial globus pallidus, corpus callosum
BIN1	287	ubiquitous	marker	gastrocnemius, hindlimb stylopod muscle, skeletal muscle tissue of rectus abdominis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BIN1	3,571
MYO6	2,972

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MYO6	Q9UM54	8
BIN1	O00499	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 19. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Membrane Trafficking	2	37.1×	0.008	MYO6, BIN1
Vesicle-mediated transport	2	34.8×	0.008	MYO6, BIN1
Gap junction degradation	1	475.8×	0.008	MYO6
RHOBTB GTPase Cycle	1	407.9×	0.008	MYO6
Glutamate binding, activation of AMPA receptors and synaptic plasticity	1	380.7×	0.008	MYO6
Trafficking of AMPA receptors	1	271.9×	0.008	MYO6
Gap junction trafficking and regulation	1	237.9×	0.008	MYO6
Gap junction trafficking	1	237.9×	0.008	MYO6
RHOBTB2 GTPase cycle	1	237.9×	0.008	MYO6
RHOBTB1 GTPase cycle	1	237.9×	0.008	MYO6
RHOU GTPase cycle	1	139.3×	0.012	MYO6
Neurotransmitter receptors and postsynaptic signal transmission	1	50.1×	0.031	MYO6
Clathrin-mediated endocytosis	1	42.6×	0.034	BIN1
Transmission across Chemical Synapses	1	38.1×	0.035	MYO6
RHO GTPase cycle	1	30.1×	0.042	MYO6
Neuronal System	1	22.1×	0.053	MYO6
Signaling by Rho GTPases	1	17.1×	0.062	MYO6
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	16.7×	0.062	MYO6
Signal Transduction	1	5.1×	0.187	MYO6

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of ventricular cardiac muscle cell action potential	1	8426.0×	0.002	BIN1
endocytosis	2	95.2×	0.002	MYO6, BIN1
lipid tube assembly	1	4213.0×	0.002	BIN1
negative regulation of calcium ion transmembrane transport via high voltage-gated calcium channel	1	2106.5×	0.004	BIN1
T-tubule organization	1	1404.3×	0.004	BIN1
regulation of secretion	1	1404.3×	0.004	MYO6
quinolinate biosynthetic process	1	766.0×	0.005	BIN1
positive regulation of astrocyte differentiation	1	702.2×	0.005	BIN1
negative regulation of potassium ion transmembrane transport	1	702.2×	0.005	BIN1
inner ear auditory receptor cell differentiation	1	601.9×	0.005	MYO6
regulation of cell cycle process	1	495.6×	0.006	BIN1
negative regulation of amyloid-beta formation	1	443.5×	0.006	BIN1
actin filament-based movement	1	401.2×	0.006	MYO6
positive regulation of endocytosis	1	401.2×	0.006	BIN1
regulation of neuron differentiation	1	366.4×	0.006	BIN1
nucleus organization	1	280.9×	0.007	BIN1
synaptic vesicle endocytosis	1	216.1×	0.008	BIN1
regulation of heart rate by cardiac conduction	1	187.2×	0.009	BIN1
DNA damage response, signal transduction by p53 class mediator	1	179.3×	0.009	MYO6
endosome to lysosome transport	1	168.5×	0.009	BIN1
positive regulation of actin filament polymerization	1	165.2×	0.009	BIN1
inner ear morphogenesis	1	150.5×	0.009	MYO6
cytoskeleton organization	1	66.3×	0.020	BIN1
response to lipopolysaccharide	1	62.4×	0.021	BIN1
actin filament organization	1	59.3×	0.021	MYO6
intracellular protein localization	1	52.3×	0.023	MYO6
sensory perception of sound	1	50.5×	0.023	MYO6
response to xenobiotic stimulus	1	34.5×	0.032	MYO6
intracellular protein transport	1	32.4×	0.033	MYO6
positive regulation of apoptotic process	1	28.4×	0.036	BIN1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MYO6	0	0
BIN1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
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	2	MYO6, BIN1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MYO6	0	—
BIN1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.