Deafness dystonia syndrome

Summary

Deafness dystonia syndrome (MONDO:0010578) is a disease caused by TIMM8A (GenCC Definitive), with 2 cohort genes and 3 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TIMM8A (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 28
• Phenotypes (HPO): 41
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		91	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

41 HPO clinical features (Orphanet curated; top 41 by frequency):

HPO ID	Term	Frequency
HP:0000375	Abnormal cochlea morphology	Frequent (30-79%)
HP:0000399	Prelingual sensorineural hearing impairment	Frequent (30-79%)
HP:0000407	Sensorineural hearing impairment	Frequent (30-79%)
HP:0000505	Visual impairment	Frequent (30-79%)
HP:0000648	Optic atrophy	Frequent (30-79%)
HP:0000649	Abnormality of visual evoked potentials	Frequent (30-79%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0001268	Mental deterioration	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0001751	Abnormal vestibular function	Frequent (30-79%)
HP:0002283	Global brain atrophy	Frequent (30-79%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0004463	Absent brainstem auditory responses	Frequent (30-79%)
HP:0006801	Hyperactive deep tendon reflexes	Frequent (30-79%)
HP:0007256	Abnormal pyramidal sign	Frequent (30-79%)
HP:0007325	Generalized dystonia	Frequent (30-79%)
HP:0007377	Abnormality of somatosensory evoked potentials	Frequent (30-79%)
HP:0008596	Postlingual sensorineural hearing impairment	Frequent (30-79%)
HP:0011448	Ankle clonus	Frequent (30-79%)
HP:0012048	Oromandibular dystonia	Frequent (30-79%)
HP:0000551	Color vision defect	Occasional (5-29%)
HP:0000572	Visual loss	Occasional (5-29%)
HP:0000603	Central scotoma	Occasional (5-29%)
HP:0000613	Photophobia	Occasional (5-29%)
HP:0000726	Dementia	Occasional (5-29%)
HP:0000751	Personality changes	Occasional (5-29%)
HP:0000763	Sensory neuropathy	Occasional (5-29%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0002015	Dysphagia	Occasional (5-29%)
HP:0002172	Postural instability	Occasional (5-29%)
HP:0002186	Apraxia	Occasional (5-29%)
HP:0002340	Caudate atrophy	Occasional (5-29%)
HP:0002362	Shuffling gait	Occasional (5-29%)
HP:0002540	Inability to walk	Occasional (5-29%)
HP:0004373	Focal dystonia	Occasional (5-29%)
HP:0004432	Agammaglobulinemia	Occasional (5-29%)
HP:0009830	Peripheral neuropathy	Occasional (5-29%)
HP:0011951	Aspiration pneumonia	Occasional (5-29%)
HP:0011999	Paranoia	Occasional (5-29%)
HP:0100704	Cerebral visual impairment	Occasional (5-29%)
HP:0007018	Attention deficit hyperactivity disorder	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	deafness dystonia syndrome
Mondo ID	MONDO:0010578
MeSH	C535808
OMIM	304700
Orphanet	52368
DOID	DOID:0050757
SNOMED CT	702423009
UMLS	C0796074
MedGen	162903
GARD	0008331
NORD	280622
Is cancer (heuristic)	no

Also known as: DDON syndrome · DDP · deafness - dystonia - optic neuronopathy syndrome · deafness dystonia optic neuronopathy syndrome (DDON) · deafness dystonia syndrome · deafness-dystonia-optic neuronopathy (DDON) syndrome · Deafness-Dystonia-Optic Neuronopathy Syndrome · deafness-dystonia-optic neuronopathy syndrome · MOHR-Tranebjaerg syndrome · Mohr-Tranebjaerg syndrome · Mohr-Tranebjaerg syndrome, X-linked recessive · MTS

Data availability: 28 ClinVar variants · 7 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › neurodegenerative disease › inherited neurodegenerative disorder › deafness dystonia syndrome

Related subtypes (81): Huntington disease and related disorders, agenesis of the corpus callosum with peripheral neuropathy, striatonigral degeneration, angioid streaks of choroid, amyotrophic lateral sclerosis-parkinsonism-dementia complex, inherited Creutzfeldt-Jakob disease, mitochondrial DNA depletion syndrome 4a, cerebellar ataxia-hypogonadism syndrome, myoclonic cerebellar dyssynergia, cerebral sclerosis similar to Pelizaeus-Merzbacher disease, Chediak-Higashi syndrome, encephalopathy due to beta-mercaptolactate-cysteine disulfiduria, PEHO syndrome, Kennedy disease, fatal familial insomnia, Huntington disease-like 1, neuronal intranuclear inclusion disease, ataxia-telangiectasia-like disorder, radiation sensitivity/chromosome instability syndrome, autosomal dominant, Huntington disease-like 2, microphthalmia-brain atrophy syndrome, neurodegenerative syndrome due to cerebral folate transport deficiency, hereditary sensory neuropathy-deafness-dementia syndrome, infantile cerebellar-retinal degeneration, Alzheimer disease 17, hypotonia, infantile, with psychomotor retardation and characteristic facies, Alzheimer disease 18, diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome, severe neurodegenerative syndrome with lipodystrophy, developmental and epileptic encephalopathy, 35, combined oxidative phosphorylation deficiency 29, neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities, neuronal ceroid lipofuscinosis, frontotemporal dementia with motor neuron disease, frontotemporal dementia, GM2 gangliosidosis, attenuated Chédiak-Higashi syndrome, autosomal recessive cerebral atrophy, neurodegeneration with brain iron accumulation, fatal post-viral neurodegenerative disorder, ferro-cerebro-cutaneous syndrome, PRKAR1B-related neurodegenerative dementia with intermediate filaments, ITM2B amyloidosis, corticobasal syndrome, infantile-onset axonal motor and sensory neuropathy-optic atrophy-neurodegenerative syndrome, recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome, posterior cortical atrophy, progressive supranuclear palsy, leukodystrophy, hereditary spastic paraplegia, facial onset sensory and motor neuronopathy, X-linked neurodegenerative syndrome, Bertini type, X-linked neurodegenerative syndrome, Hamel type, boylan dew greco syndrome, hereditary motor neuron disease, neurodegeneration, childhood-onset, with ataxia, tremor, optic atrophy, and cognitive decline, frontotemporal dementia and/or amyotrophic lateral sclerosis, neurodegeneration, childhood-onset, with hypotonia, respiratory insufficiency, and brain imaging abnormalities, neurodegeneration with ataxia and late-onset optic atrophy, neurodegeneration, childhood-onset, with cerebellar atrophy, neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia, neurodegeneration, infantile-onset, biotin-responsive, hereditary optic atrophy, early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, psychomotor regression-oculomotor apraxia-movement disorder-nephropathy syndrome, familial Alzheimer disease, neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, hereditary cerebellar ataxia, DCTN1-related neurodegeneration, early-childhood-onset neurodegeneration with retinitis pigmentosa, sensorineural hearing loss, and demyelinating peripheral neuropathy, TUBB4A-related neurologic disorder, neurodegeneration, childhood-onset, with progressive microcephaly, neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, neurodegeneration and seizures due to copper transport defect, neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities, neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, neurodegenerative disorder, X-linked, female-restricted, with parkinsonism and cognitive impairment, neurodegenerative disorder with cerebellar and caudate atrophy, APP-related brain and vascular amyloidosis

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

28 retrieved; paginated sample, class counts are floors:

23 pathogenic, 3 likely pathogenic, 1 benign, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1312516	NC_000023.10:g.100564340_100627836del	BTK	Pathogenic	no assertion criteria provided
1312517	NC_000023.10:g.100580141_100619992del	BTK	Pathogenic	no assertion criteria provided
1312518	NC_000023.10:g.100582860_100610076del	BTK	Pathogenic	no assertion criteria provided
11323	NC_000023.11:g.(?101345661)(101348742_?)del	LOC130068494	Pathogenic	no assertion criteria provided
11318	NM_004085.4(TIMM8A):c.116del (p.Met39fs)	TIMM8A	Pathogenic	no assertion criteria provided
11319	NM_004085.4(TIMM8A):c.148_157del (p.Lys50fs)	TIMM8A	Pathogenic	criteria provided, single submitter
11320	NM_004085.4(TIMM8A):c.70G>T (p.Glu24Ter)	TIMM8A	Pathogenic	no assertion criteria provided
11322	NM_004085.4(TIMM8A):c.73del (p.Glu24_Val25insTer)	TIMM8A	Pathogenic	criteria provided, single submitter
11324	NM_004085.4(TIMM8A):c.238C>T (p.Arg80Ter)	TIMM8A	Pathogenic	no assertion criteria provided
11325	NM_004085.4(TIMM8A):c.133-23A>C	TIMM8A	Pathogenic	no assertion criteria provided
11326	NM_004085.4(TIMM8A):c.127del (p.Cys43fs)	TIMM8A	Pathogenic	no assertion criteria provided
1185085	NM_004085.4(TIMM8A):c.66_67del (p.Ile23fs)	TIMM8A	Pathogenic	no assertion criteria provided
1312519	NC_000023.11:g.101345283_101347393del	TIMM8A	Pathogenic	no assertion criteria provided
1686260	NM_004085.4(TIMM8A):c.181del (p.Ala61fs)	TIMM8A	Pathogenic	criteria provided, single submitter
1703041	NM_004085.4(TIMM8A):c.223C>T (p.Gln75Ter)	TIMM8A	Pathogenic	no assertion criteria provided
21393	NM_004085.4(TIMM8A):c.112C>T (p.Gln38Ter)	TIMM8A	Pathogenic	criteria provided, single submitter
3601877	NM_004085.4(TIMM8A):c.132G>A (p.Trp44Ter)	TIMM8A	Pathogenic	criteria provided, single submitter
3601878	NM_004085.4(TIMM8A):c.133-1G>A	TIMM8A	Pathogenic	criteria provided, single submitter
3601880	NM_004085.4(TIMM8A):c.153_223dup (p.Gln75delinsLeuGlyGlnSerTrpThrValGlyLeuArgProValLeuTer)	TIMM8A	Pathogenic	criteria provided, single submitter
3601881	NM_004085.4(TIMM8A):c.217dup (p.Thr73fs)	TIMM8A	Pathogenic	criteria provided, single submitter
3601882	NM_004085.4(TIMM8A):c.28del (p.Ala10fs)	TIMM8A	Pathogenic	criteria provided, single submitter
4686644	NM_004085.4(TIMM8A):c.58C>T (p.Gln20Ter)	TIMM8A	Pathogenic	criteria provided, single submitter
929951	NC_000023.11:g.(?101346475)(101348757_?)del	TIMM8A	Pathogenic	criteria provided, single submitter
11321	NM_004085.4(TIMM8A):c.198C>G (p.Cys66Trp)	TIMM8A	Likely pathogenic	criteria provided, single submitter
1185678	NM_004085.4(TIMM8A):c.232_233insCAAT (p.Leu78fs)	TIMM8A	Likely pathogenic	no assertion criteria provided
804062	NM_004085.4(TIMM8A):c.127T>C (p.Cys43Arg)	TIMM8A	Likely pathogenic	criteria provided, multiple submitters, no conflicts
940697	NM_004085.4(TIMM8A):c.133-2A>G	TIMM8A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
21394	NM_004085.4(TIMM8A):c.*503_*505dup	TIMM8A	Benign	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
TIMM8A	Definitive	X-linked	deafness dystonia syndrome	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TIMM8A	Orphanet:52368	Mohr-Tranebjaerg syndrome
BTK	Orphanet:47	X-linked agammaglobulinemia
BTK	Orphanet:632	Short stature due to isolated growth hormone deficiency with X-linked hypogammaglobulinemia

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
TIMM8A	HGNC:11817	ENSG00000126953	O60220	Mitochondrial import inner membrane translocase subunit Tim8 A	gencc,clinvar
BTK	HGNC:1133	ENSG00000010671	Q06187	Tyrosine-protein kinase BTK	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TIMM8A	Mitochondrial import inner membrane translocase subunit Tim8 A	Mitochondrial intermembrane chaperone that participates in the import and insertion of some multi-pass transmembrane proteins into the mitochondrial inner membrane.
BTK	Tyrosine-protein kinase BTK	Non-receptor tyrosine kinase indispensable for B lymphocyte development, differentiation and signaling.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Kinase	1	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TIMM8A	Other/Unknown	no		Tim10-like, Tim10-like_dom_sf
BTK	Kinase	yes	2.7.10.2	Prot_kinase_dom, SH2, Ser-Thr/Tyr_kinase_cat_dom

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
endothelial cell	1
mucosa of transverse colon	1
primordial germ cell in gonad	1
leukocyte	1
monocyte	1
mononuclear cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TIMM8A	204	ubiquitous	marker	endothelial cell, primordial germ cell in gonad, mucosa of transverse colon
BTK	206	broad	marker	monocyte, mononuclear cell, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BTK	4,467
TIMM8A	1,927

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BTK	Q06187	156

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TIMM8A	O60220	87.07

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 46. 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
G-protein beta:gamma signalling	1	951.7×	0.019	BTK
Diseases of Immune System	1	439.2×	0.019	BTK
Diseases associated with the TLR signaling cascade	1	439.2×	0.019	BTK
G beta:gamma signalling through BTK	1	317.2×	0.019	BTK
MyD88 deficiency (TLR2/4)	1	300.5×	0.019	BTK
IRAK4 deficiency (TLR2/4)	1	285.5×	0.019	BTK
DAP12 interactions	1	237.9×	0.019	BTK
DAP12 signaling	1	184.2×	0.019	BTK
FCERI mediated Ca+2 mobilization	1	178.4×	0.019	BTK
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers	1	178.4×	0.019	BTK
Parasite infection	1	173.0×	0.019	BTK
Leishmania phagocytosis	1	173.0×	0.019	BTK
Signaling by the B Cell Receptor (BCR)	1	173.0×	0.019	BTK
Antigen processing-Cross presentation	1	158.6×	0.019	BTK
RHO GTPases Activate WASPs and WAVEs	1	158.6×	0.019	BTK
Fcgamma receptor (FCGR) dependent phagocytosis	1	139.3×	0.020	BTK
Fc epsilon receptor (FCERI) signaling	1	135.9×	0.020	BTK
FCGR3A-mediated phagocytosis	1	93.6×	0.022	BTK
Regulation of actin dynamics for phagocytic cup formation	1	92.1×	0.022	BTK
Toll Like Receptor TLR6:TLR2 Cascade	1	87.8×	0.022	BTK
Toll Like Receptor 2 (TLR2) Cascade	1	86.5×	0.022	BTK
Mitochondrial protein import	1	84.0×	0.022	TIMM8A
Toll Like Receptor TLR1:TLR2 Cascade	1	84.0×	0.022	BTK
Leishmania infection	1	81.6×	0.022	BTK
Parasitic Infection Pathways	1	81.6×	0.022	BTK
MyD88:MAL(TIRAP) cascade initiated on plasma membrane	1	76.1×	0.023	BTK
G alpha (12/13) signalling events	1	68.8×	0.024	BTK
Toll Like Receptor 4 (TLR4) Cascade	1	65.6×	0.024	BTK
ER-Phagosome pathway	1	64.9×	0.024	BTK
Toll-like Receptor Cascades	1	62.1×	0.025	BTK

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
regulation of B cell cytokine production	1	8426.0×	0.002	BTK
monocyte proliferation	1	8426.0×	0.002	BTK
positive regulation of interleukin-17A production	1	8426.0×	0.002	BTK
positive regulation of type I hypersensitivity	1	4213.0×	0.002	BTK
B cell affinity maturation	1	4213.0×	0.002	BTK
regulation of B cell apoptotic process	1	4213.0×	0.002	BTK
positive regulation of type III hypersensitivity	1	2808.7×	0.002	BTK
proteoglycan catabolic process	1	2808.7×	0.002	BTK
positive regulation of synoviocyte proliferation	1	2808.7×	0.002	BTK
eosinophil homeostasis	1	2808.7×	0.002	BTK
cellular response to molecule of fungal origin	1	2106.5×	0.002	BTK
histamine secretion by mast cell	1	1685.2×	0.002	BTK
positive regulation of cGAS/STING signaling pathway	1	1053.2×	0.003	BTK
neutrophil homeostasis	1	766.0×	0.004	BTK
protein insertion into mitochondrial inner membrane	1	648.1×	0.004	TIMM8A
cellular response to interleukin-7	1	648.1×	0.004	BTK
positive regulation of B cell differentiation	1	561.7×	0.005	BTK
MyD88-dependent toll-like receptor signaling pathway	1	468.1×	0.005	BTK
negative regulation of B cell proliferation	1	468.1×	0.005	BTK
negative regulation of interleukin-10 production	1	366.4×	0.006	BTK
Fc-epsilon receptor signaling pathway	1	366.4×	0.006	BTK
positive regulation of NLRP3 inflammasome complex assembly	1	290.6×	0.007	BTK
mesoderm development	1	263.3×	0.007	BTK
positive regulation of immunoglobulin production	1	240.7×	0.008	BTK
B cell activation	1	227.7×	0.008	BTK
cell maturation	1	221.7×	0.008	BTK
peptidyl-tyrosine phosphorylation	1	210.7×	0.008	BTK
cellular response to reactive oxygen species	1	205.5×	0.008	BTK
B cell receptor signaling pathway	1	200.6×	0.008	BTK
positive regulation of B cell proliferation	1	172.0×	0.009	BTK

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
BTK	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BTK	84	4
TIMM8A	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	BTK
FEDRATINIB	4	BTK
NERATINIB	4	BTK
IBRUTINIB	4	BTK
ENTRECTINIB	4	BTK
CERITINIB	4	BTK
VANDETANIB	4	BTK
BOSUTINIB	4	BTK
OSIMERTINIB	4	BTK
BRIGATINIB	4	BTK
FUTIBATINIB	4	BTK
ACALABRUTINIB	4	BTK
OLMUTINIB	4	BTK
ZANUBRUTINIB	4	BTK
TIRABRUTINIB	4	BTK
RITLECITINIB	4	BTK
PIRTOBRUTINIB	4	BTK
NINTEDANIB	4	BTK
SUNITINIB	4	BTK
DASATINIB	4	BTK
MITOXANTRONE	4	BTK
CRIZOTINIB	4	BTK
SARACATINIB	3	BTK
CANERTINIB	3	BTK
ENTOSPLETINIB	3	BTK
TESEVATINIB	3	BTK
POZIOTINIB	3	BTK
ROCILETINIB	3	BTK
PYROTINIB	3	BTK
RILZABRUTINIB	3	BTK

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
BTK	1,836	Binding:1810, Functional:23, ADMET:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BTK	2.7.10.2	non-specific protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
BTK	1,836

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

30 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)
PONATINIB	4	BTK
FEDRATINIB	4	BTK
NERATINIB	4	BTK
IBRUTINIB	4	BTK
ENTRECTINIB	4	BTK
CERITINIB	4	BTK
VANDETANIB	4	BTK
BOSUTINIB	4	BTK
OSIMERTINIB	4	BTK
BRIGATINIB	4	BTK
FUTIBATINIB	4	BTK
ACALABRUTINIB	4	BTK
OLMUTINIB	4	BTK
ZANUBRUTINIB	4	BTK
TIRABRUTINIB	4	BTK
RITLECITINIB	4	BTK
PIRTOBRUTINIB	4	BTK
NINTEDANIB	4	BTK
SUNITINIB	4	BTK
DASATINIB	4	BTK
MITOXANTRONE	4	BTK
CRIZOTINIB	4	BTK
SARACATINIB	3	BTK
CANERTINIB	3	BTK
ENTOSPLETINIB	3	BTK
TESEVATINIB	3	BTK
POZIOTINIB	3	BTK
ROCILETINIB	3	BTK
PYROTINIB	3	BTK
RILZABRUTINIB	3	BTK

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	BTK
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	1	TIMM8A

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TIMM8A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02281006	PHASE2	TERMINATED	Efficacy of Trans-tympanic Injections of a Sodium Thiosulfate Gel to Prevent Cisplatin-induced Ototoxicity
NCT04187911	Not specified	RECRUITING	Relationships in Good Hands - Clinical and Cost-effectiveness of Dyadic Developmental Psychotherapy
NCT04763720	Not specified	ENROLLING_BY_INVITATION	Implementing Dyadic Developmental Psychotherapy (DDP) - Evaluation Research