Brown syndrome

Summary

Brown syndrome (MONDO:0014624) is a disease with 3 cohort genes and 1 clinical trial.

At a glance

• Cohort genes: 3
• ClinVar variants: 4
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Brown syndrome
Mondo ID	MONDO:0014624
OMIM	616407
DOID	DOID:10235
ICD-10-CM	H50.61
SNOMED CT	35929003
UMLS	C0155339
MedGen	102332
Is cancer (heuristic)	no

Also known as: Brown syndrome · Brown tendon sheath syndrome · Brown’s (tendon) sheath syndrome · Brown’s sheath syndrome · Brown’s tendon sheath syndrome · BRWNS · superior oblique tendon sheath syndrome · tendon sheath adherence, Superior oblique

Data availability: 4 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › cranial nerve neuropathy › ocular motility disease › strabismus › mechanical strabismus › Brown 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

4 retrieved; paginated sample, class counts are floors:

4 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
3061824	NM_005461.5(MAFB):c.821T>C (p.Ile274Thr)	MAFB	Uncertain significance	criteria provided, single submitter
3061826	NM_001308120.2(TOGARAM1):c.3932G>A (p.Arg1311His)	TOGARAM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3061827	NM_001308120.2(TOGARAM1):c.3361A>G (p.Thr1121Ala)	TOGARAM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3061830	NM_006087.4(TUBB4A):c.800T>C (p.Met267Thr)	TUBB4A	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 6 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TOGARAM1	Orphanet:475	Isolated Joubert syndrome
TUBB4A	Orphanet:139441	Hypomyelination with atrophy of basal ganglia and cerebellum
TUBB4A	Orphanet:98805	Primary dystonia, DYT4 type
MAFB	Orphanet:233	Duane retraction syndrome
MAFB	Orphanet:2774	Multicentric carpo-tarsal osteolysis with or without nephropathy
MAFB	Orphanet:529574	Duane retraction syndrome with congenital deafness

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TOGARAM1	HGNC:19959	ENSG00000198718	Q9Y4F4	TOG array regulator of axonemal microtubules protein 1	clinvar
TUBB4A	HGNC:20774	ENSG00000104833	P04350	Tubulin beta-4A chain	clinvar
MAFB	HGNC:6408	ENSG00000204103	Q9Y5Q3	Transcription factor MafB	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TOGARAM1	TOG array regulator of axonemal microtubules protein 1	Involved in ciliogenesis.
TUBB4A	Tubulin beta-4A chain	Tubulin is the major constituent of microtubules, a cylinder consisting of laterally associated linear protofilaments composed of alpha- and beta-tubulin heterodimers.
MAFB	Transcription factor MafB	Acts as a transcriptional activator or repressor.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · 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
Transcription factor	1	2.8×	0.587
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TOGARAM1	Other/Unknown	no		ARM-like, ARM-type_fold, TOG
TUBB4A	Other/Unknown	no		Tubulin, Beta_tubulin, Tubulin_FtsZ_GTPase
MAFB	Transcription factor	no		bZIP_Maf, bZIP, TF_DNA-bd_sf

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bronchial epithelial cell	1
epithelium of bronchus	1
tibia	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
gingiva	1
renal glomerulus	1
skin of hip	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TOGARAM1	288	ubiquitous	marker	bronchial epithelial cell, tibia, epithelium of bronchus
TUBB4A	201	broad	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
MAFB	277	ubiquitous	marker	renal glomerulus, skin of hip, gingiva

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TUBB4A	5,138
MAFB	2,671
TOGARAM1	731

Structural data

PDB: 0 · AlphaFold-only: 3 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TUBB4A	P04350	92.25
MAFB	Q9Y5Q3	63.87
TOGARAM1	Q9Y4F4	62.26

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 95. Enrichment computed across 3 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
Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane	1	271.9×	0.031	TUBB4A
Transport of connexons to the plasma membrane	1	271.9×	0.031	TUBB4A
Gap junction trafficking and regulation	1	237.9×	0.031	TUBB4A
Gap junction trafficking	1	237.9×	0.031	TUBB4A
Post-chaperonin tubulin folding pathway	1	237.9×	0.031	TUBB4A
Activation of HOX genes during differentiation	1	219.6×	0.031	MAFB
Formation of tubulin folding intermediates by CCT/TriC	1	211.5×	0.031	TUBB4A
Cooperation of Prefoldin and TriC/CCT in actin and tubulin folding	1	203.9×	0.031	TUBB4A
Prefoldin mediated transfer of substrate to CCT/TriC	1	196.9×	0.031	TUBB4A
Activation of AMPK downstream of NMDARs	1	190.3×	0.031	TUBB4A
RHO GTPases activate IQGAPs	1	173.0×	0.031	TUBB4A
Sealing of the nuclear envelope (NE) by ESCRT-III	1	173.0×	0.031	TUBB4A
HCMV Infection	1	163.1×	0.031	TUBB4A
Chaperonin-mediated protein folding	1	150.3×	0.031	TUBB4A
Gap junction assembly	1	146.4×	0.031	TUBB4A
Nuclear Envelope (NE) Reassembly	1	146.4×	0.031	TUBB4A
Selective autophagy	1	139.3×	0.031	TUBB4A
Protein folding	1	129.8×	0.031	TUBB4A
Centrosome maturation	1	126.9×	0.031	TUBB4A
Assembly and cell surface presentation of NMDA receptors	1	126.9×	0.031	TUBB4A
Cargo trafficking to the periciliary membrane	1	124.1×	0.031	TUBB4A
Aggrephagy	1	124.1×	0.031	TUBB4A
Carboxyterminal post-translational modifications of tubulin	1	119.0×	0.031	TUBB4A
Recycling pathway of L1	1	112.0×	0.031	TUBB4A
COPI-independent Golgi-to-ER retrograde traffic	1	103.8×	0.031	TUBB4A
Post NMDA receptor activation events	1	102.0×	0.031	TUBB4A
Intraflagellar transport	1	100.2×	0.031	TUBB4A
Antimicrobial mechanism of IFN-stimulated genes	1	98.5×	0.031	TUBB4A
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	1	96.8×	0.031	TUBB4A
Activation of NMDA receptors and postsynaptic events	1	92.1×	0.031	TUBB4A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
rhombomere 6 development	1	5617.3×	0.003	MAFB
rhombomere 5 development	1	2808.7×	0.003	MAFB
abducens nerve formation	1	2808.7×	0.003	MAFB
microtubule cytoskeleton organization	2	80.8×	0.003	TOGARAM1, TUBB4A
brain segmentation	1	1872.4×	0.003	MAFB
regulation of myeloid cell differentiation	1	1123.5×	0.005	MAFB
cornified envelope assembly	1	936.2×	0.005	MAFB
segment specification	1	702.2×	0.006	MAFB
negative regulation of erythrocyte differentiation	1	510.7×	0.007	MAFB
negative regulation of microtubule polymerization	1	432.1×	0.007	TUBB4A
integrated stress response signaling	1	234.1×	0.011	MAFB
sensory organ development	1	224.7×	0.011	MAFB
positive regulation of microtubule polymerization	1	224.7×	0.011	TOGARAM1
respiratory gaseous exchange by respiratory system	1	208.1×	0.011	MAFB
axoneme assembly	1	181.2×	0.011	TOGARAM1
negative regulation of osteoclast differentiation	1	181.2×	0.011	MAFB
T cell differentiation in thymus	1	137.0×	0.013	MAFB
thymus development	1	112.3×	0.015	MAFB
inner ear morphogenesis	1	100.3×	0.015	MAFB
response to nutrient	1	98.5×	0.015	MAFB
non-motile cilium assembly	1	96.8×	0.015	TOGARAM1
keratinocyte differentiation	1	82.6×	0.017	MAFB
fat cell differentiation	1	60.4×	0.022	MAFB
protein processing	1	56.7×	0.023	MAFB
mitotic cell cycle	1	44.6×	0.028	TUBB4A
cilium assembly	1	24.5×	0.047	TOGARAM1
in utero embryonic development	1	24.0×	0.047	MAFB
regulation of DNA-templated transcription	1	10.5×	0.102	MAFB
positive regulation of DNA-templated transcription	1	9.3×	0.111	MAFB
negative regulation of transcription by RNA polymerase II	1	5.9×	0.165	MAFB

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) 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
TUBB4A	COLCHICINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TUBB4A	21	4
TOGARAM1	0	0
MAFB	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
COLCHICINE	4	TUBB4A
VINBLASTINE	4	TUBB4A
LEVOFLOXACIN ANHYDROUS	4	TUBB4A
DOCETAXEL	4	TUBB4A
NOSCAPINE	4	TUBB4A
VINBLASTINE SULFATE	4	TUBB4A
PACLITAXEL	4	TUBB4A
LEVOFLOXACIN	4	TUBB4A
VINORELBINE	4	TUBB4A
TIRBANIBULIN	4	TUBB4A
PODOFILOX	4	TUBB4A
VINCRISTINE	4	TUBB4A
DOCETAXEL ANHYDROUS	4	TUBB4A
PATUPILONE	3	TUBB4A
ABT-751	2	TUBB4A
MAYTANSINE	2	TUBB4A
DOLASTATIN-10	2	TUBB4A
INDIBULIN	2	TUBB4A
PARBENDAZOLE	2	TUBB4A
NOCODAZOLE	2	TUBB4A
COMBRETASTATIN	1	TUBB4A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TUBB4A	1,758	Binding:1718, Functional:34, ADMET:6

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TUBB4A	1,758

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

21 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)
COLCHICINE	4	TUBB4A
VINBLASTINE	4	TUBB4A
LEVOFLOXACIN ANHYDROUS	4	TUBB4A
DOCETAXEL	4	TUBB4A
NOSCAPINE	4	TUBB4A
VINBLASTINE SULFATE	4	TUBB4A
PACLITAXEL	4	TUBB4A
LEVOFLOXACIN	4	TUBB4A
VINORELBINE	4	TUBB4A
TIRBANIBULIN	4	TUBB4A
PODOFILOX	4	TUBB4A
VINCRISTINE	4	TUBB4A
DOCETAXEL ANHYDROUS	4	TUBB4A
PATUPILONE	3	TUBB4A
ABT-751	2	TUBB4A
MAYTANSINE	2	TUBB4A
DOLASTATIN-10	2	TUBB4A
INDIBULIN	2	TUBB4A
PARBENDAZOLE	2	TUBB4A
NOCODAZOLE	2	TUBB4A
COMBRETASTATIN	1	TUBB4A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TUBB4A
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	TOGARAM1, MAFB

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)
TOGARAM1	0	—
MAFB	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03059420	Not specified	RECRUITING	Genetic Studies of Strabismus, Congenital Cranial Dysinnervation Disorders (CCDDs), and Their Associated Anomalies