Congenital fibrosis of extraocular muscles

Summary

Congenital fibrosis of extraocular muscles (MONDO:0007614) is a disease (an umbrella term covering 8 Mondo subtypes) caused by variants in KIF21A and TUBA1A, with 15 cohort genes and 1 clinical trial. The dominant Reactome pathway is RHO GTPases activate IQGAPs (5 cohort genes).

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Causal genes: KIF21A (GenCC Definitive), TUBA1A (GenCC Strong)
• Umbrella term: 8 Mondo subtypes
• Cohort genes: 15
• ClinVar variants: 16
• Phenotypes (HPO): 36
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000		Europe	Validated
Point prevalence	1-9 / 1 000 000	0.43	United Kingdom	Validated

Signs & symptoms

Clinical features (HPO)

36 HPO clinical features (Orphanet curated; top 36 by frequency):

HPO ID	Term	Frequency
HP:0000486	Strabismus	Very frequent (80-99%)
HP:0000508	Ptosis	Very frequent (80-99%)
HP:0000542	Impaired ocular adduction	Very frequent (80-99%)
HP:0000577	Exotropia	Very frequent (80-99%)
HP:0001491	Congenital fibrosis of extraocular muscles	Very frequent (80-99%)
HP:0011347	Abnormality of ocular abduction	Very frequent (80-99%)
HP:0012241	Levator palpebrae superioris atrophy	Very frequent (80-99%)
HP:0025721	Limited vertical extraocular movement	Very frequent (80-99%)
HP:0030211	Slow pupillary light response	Very frequent (80-99%)
HP:0030534	Abnormal best corrected visual acuity test	Very frequent (80-99%)
HP:6000709	Absent Bell phenomenon	Very frequent (80-99%)
HP:0000512	Abnormal electroretinogram	Frequent (30-79%)
HP:0000539	Abnormality of refraction	Frequent (30-79%)
HP:0000616	Miosis	Frequent (30-79%)
HP:0000646	Amblyopia	Frequent (30-79%)
HP:0001477	Compensatory chin elevation	Frequent (30-79%)
HP:0007831	Nonprogressive restrictive external ophthalmoplegia	Frequent (30-79%)
HP:0012547	Abnormal involuntary eye movements	Frequent (30-79%)
HP:0025309	Abnormal pupil shape	Frequent (30-79%)
HP:0030588	Abnormal visual field test	Frequent (30-79%)
HP:0009380	Finger aplasia	Occasional (5-29%)
HP:0000044	Hypogonadotropic hypogonadism	Occasional (5-29%)
HP:0000473	Torticollis	Occasional (5-29%)
HP:0000518	Cataract	Occasional (5-29%)
HP:0000565	Esotropia	Occasional (5-29%)
HP:0000609	Optic nerve hypoplasia	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001357	Plagiocephaly	Occasional (5-29%)
HP:0002013	Vomiting	Occasional (5-29%)
HP:0002126	Polymicrogyria	Occasional (5-29%)
HP:0002194	Delayed gross motor development	Occasional (5-29%)
HP:0008527	Congenital sensorineural hearing impairment	Occasional (5-29%)
HP:0009916	Anisocoria	Occasional (5-29%)
HP:0025186	Marcus Gunn jaw winking synkinesis	Occasional (5-29%)
HP:0032466	Aplasia of the olfactory bulb	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital fibrosis of extraocular muscles
Mondo ID	MONDO:0007614
MeSH	C580012
OMIM	135700
Orphanet	45358
DOID	DOID:0080143
ICD-11	887449084
SNOMED CT	400946004
UMLS	C1302995
MedGen	724506
GARD	0012590
NORD	997
Is cancer (heuristic)	no

Also known as: CFEOM1 · Congenital Fibrosis of the Extraocular Muscles · congenital fibrosis of the extraocular muscles · FEOM · fibrosis of extraocular muscles, congenital · fibrosis of extraocular muscles, congenital, 1 · fibrosis of extraocular muscles, congenital, type 1 · Tukel syndrome

Data availability: 16 ClinVar variants · 8 GenCC gene-disease records.

Disease family

An umbrella term covering 8 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › cranial nerve neuropathy › ocular motility disease › congenital fibrosis of extraocular muscles

Related subtypes (5): ophthalmoplegia, strabismus, pathologic nystagmus, Tolosa-Hunt syndrome, Weber syndrome

Subtypes (8): fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvement, fibrosis of extraocular muscles, congenital, 2, fibrosis of extraocular muscles, congenital, 3c, Tukel syndrome, fibrosis of extraocular muscles, congenital, with synergistic divergence, fibrosis of extraocular muscles, congenital, 5, congenital fibrosis of extraocular muscles type 1, fibrosis of extraocular muscles, congenital, 3b

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

16 retrieved; paginated sample, class counts are floors:

10 uncertain significance, 4 conflicting classifications of pathogenicity, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
988579	NM_006009.4(TUBA1A):c.467G>A (p.Arg156His)	TUBA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
430312	NM_006086.4(TUBB3):c.424G>A (p.Gly142Ser)	TUBB3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
522672	NM_176795.5(HRAS):c.500dup (p.Pro169fs)	HRAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
308574	NM_001173464.2(KIF21A):c.2305A>G (p.Thr769Ala)	KIF21A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
988578	NM_006009.4(TUBA1A):c.1216C>G (p.His406Asp)	TUBA1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
988580	NM_006009.4(TUBA1A):c.1193T>G (p.Met398Arg)	TUBA1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3024413	NM_001903.5(CTNNA1):c.2438A>C (p.Asp813Ala)	CTNNA1	Uncertain significance	criteria provided, single submitter
3024396	NM_019113.4(FGF21):c.133C>T (p.Arg45Trp)	FGF21	Uncertain significance	criteria provided, single submitter
3061831	NM_003906.5(MCM3AP):c.5116C>T (p.Leu1706Phe)	MCM3AP	Uncertain significance	criteria provided, single submitter
3024408	NM_001256012.3(MYH10):c.938G>T (p.Gly313Val)	MYH10	Uncertain significance	criteria provided, multiple submitters, no conflicts
3024412	NM_001256012.3(MYH10):c.965A>G (p.Asn322Ser)	MYH10	Uncertain significance	criteria provided, multiple submitters, no conflicts
2301221	NM_006617.2(NES):c.23A>T (p.Glu8Val)	NES	Uncertain significance	criteria provided, multiple submitters, no conflicts
4819071	NM_006009.4(TUBA1A):c.2T>C (p.Met1Thr)	TUBA1A	Uncertain significance	criteria provided, single submitter
3061815	NM_006082.3(TUBA1B):c.554A>G (p.Tyr185Cys)	TUBA1B	Uncertain significance	criteria provided, single submitter
3061829	NM_178014.4(TUBB):c.1198G>C (p.Gly400Arg)	TUBB	Uncertain significance	criteria provided, single submitter
4070912	NM_001300939.2(WNT8A):c.634T>G (p.Cys212Gly)	WNT8A	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 55 · Orphanet: 25 · 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
KIF21A	Definitive	Autosomal dominant	congenital fibrosis of extraocular muscles	9
PHOX2A	Strong	Autosomal recessive	fibrosis of extraocular muscles, congenital, 2	5
TUBA1A	Strong	Autosomal dominant	congenital fibrosis of extraocular muscles	7
TUBB3	Strong	Autosomal dominant	fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvement	11
TUBB2B	Supportive	Autosomal dominant	congenital fibrosis of extraocular muscles	9
GRHL2	Limited	Unknown	congenital fibrosis of extraocular muscles	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KIF21A	Orphanet:45358	Congenital fibrosis of extraocular muscles
KIF21A	Orphanet:994	Fetal akinesia deformation sequence
TUBA1A	Orphanet:171680	Lissencephaly due to TUBA1A mutation
TUBA1A	Orphanet:45358	Congenital fibrosis of extraocular muscles
TUBA1A	Orphanet:467166	Tubulinopathy-associated dysgyria
TUBA1A	Orphanet:994	Fetal akinesia deformation sequence
TUBB3	Orphanet:300570	Cortical dysgenesis with pontocerebellar hypoplasia due to TUBB3 mutation
TUBB3	Orphanet:45358	Congenital fibrosis of extraocular muscles
TUBB3	Orphanet:467166	Tubulinopathy-associated dysgyria
GRHL2	Orphanet:423454	Nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome
GRHL2	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
GRHL2	Orphanet:98973	Posterior polymorphous corneal dystrophy
TUBB2B	Orphanet:1766	Dysequilibrium syndrome
TUBB2B	Orphanet:300573	Polymicrogyria due to TUBB2B mutation
TUBB2B	Orphanet:45358	Congenital fibrosis of extraocular muscles
TUBB2B	Orphanet:467166	Tubulinopathy-associated dysgyria
PHOX2A	Orphanet:45358	Congenital fibrosis of extraocular muscles
TUBB	Orphanet:2505	Multiple benign circumferential skin creases on limbs
CTNNA1	Orphanet:26106	Hereditary diffuse gastric cancer
CTNNA1	Orphanet:99001	Butterfly-shaped pigment dystrophy
HRAS	Orphanet:146	Differentiated thyroid carcinoma
HRAS	Orphanet:2612	Linear nevus sebaceus syndrome
HRAS	Orphanet:2874	Phakomatosis pigmentokeratotica
HRAS	Orphanet:3071	Costello syndrome
HRAS	Orphanet:79414	Woolly hair nevus

Cohort genes → proteins

15 cohort genes, 15 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	15

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KIF21A	HGNC:19349	ENSG00000139116	Q7Z4S6	Kinesin-like protein KIF21A	gencc,clinvar
TUBA1A	HGNC:20766	ENSG00000167552	Q71U36	Tubulin alpha-1A chain	gencc,clinvar
TUBB3	HGNC:20772	ENSG00000258947	Q13509	Tubulin beta-3 chain	gencc,clinvar
GRHL2	HGNC:2799	ENSG00000083307	Q6ISB3	Grainyhead-like protein 2 homolog	gencc
TUBB2B	HGNC:30829	ENSG00000137285	Q9BVA1	Tubulin beta-2B chain	gencc
PHOX2A	HGNC:691	ENSG00000165462	O14813	Paired mesoderm homeobox protein 2A	gencc
WNT8A	HGNC:12788	ENSG00000061492	Q9H1J5	Protein Wnt-8a	clinvar
TUBA1B	HGNC:18809	ENSG00000123416	P68363	Tubulin alpha-1B chain	clinvar
TUBB	HGNC:20778	ENSG00000196230	P07437	Tubulin beta chain	clinvar
CTNNA1	HGNC:2509	ENSG00000044115	P35221	Catenin alpha-1	clinvar
FGF21	HGNC:3678	ENSG00000105550	Q9NSA1	Fibroblast growth factor 21	clinvar
HRAS	HGNC:5173	ENSG00000174775	P01112	GTPase HRas	clinvar
MCM3AP	HGNC:6946	ENSG00000160294	O60318	Germinal-center associated nuclear protein	clinvar
MYH10	HGNC:7568	ENSG00000133026	P35580	Myosin-10	clinvar
NES	HGNC:7756	ENSG00000132688	P48681	Nestin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KIF21A	Kinesin-like protein KIF21A	Processive microtubule plus-end directed motor protein involved in neuronal axon guidance.
TUBA1A	Tubulin alpha-1A chain	Tubulin is the major constituent of microtubules, a cylinder consisting of laterally associated linear protofilaments composed of alpha- and beta-tubulin heterodimers.
TUBB3	Tubulin beta-3 chain	Tubulin is the major constituent of microtubules, protein filaments consisting of alpha- and beta-tubulin heterodimers.
GRHL2	Grainyhead-like protein 2 homolog	Transcription factor playing an important role in primary neurulation and in epithelial development.
TUBB2B	Tubulin beta-2B chain	Tubulin is the major constituent of microtubules, a cylinder consisting of laterally associated linear protofilaments composed of alpha- and beta-tubulin heterodimers.
PHOX2A	Paired mesoderm homeobox protein 2A	May be involved in regulating the specificity of expression of the catecholamine biosynthetic genes.
WNT8A	Protein Wnt-8a	Ligand for members of the frizzled family of seven transmembrane receptors.
TUBA1B	Tubulin alpha-1B chain	Tubulin is the major constituent of microtubules, protein filaments consisting of alpha- and beta-tubulin heterodimers.
TUBB	Tubulin beta chain	Tubulin is the major constituent of microtubules, a cylinder consisting of laterally associated linear protofilaments composed of alpha- and beta-tubulin heterodimers.
CTNNA1	Catenin alpha-1	Associates with the cytoplasmic domain of a variety of cadherins.
FGF21	Fibroblast growth factor 21	Stimulates glucose uptake in differentiated adipocytes via the induction of glucose transporter SLC2A1/GLUT1 expression (but not SLC2A4/GLUT4 expression).
HRAS	GTPase HRas	Involved in the activation of Ras protein signal transduction.
MCM3AP	Germinal-center associated nuclear protein	As a component of the TREX-2 complex, involved in the export of mRNAs to the cytoplasm through the nuclear pores.
MYH10	Myosin-10	Cellular myosin that appears to play a role in cytokinesis, cell shape, and specialized functions such as secretion and capping.
NES	Nestin	Required for brain and eye development.

Protein-family classification

Druggable: 1 · Difficult: 4 · Unknown: 10 · Druggable fraction: 0.07

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	2.3×	0.564
Other/Unknown	10	1.2×	0.564
Transcription factor	2	1.1×	0.729
Enzyme (other)	1	0.8×	0.729

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KIF21A	Scaffold/PPI	no		WD40_rpt, Kinesin_motor_dom, WD40/YVTN_repeat-like_dom_sf
TUBA1A	Other/Unknown	no		Tubulin, Alpha_tubulin, Tubulin_FtsZ_GTPase
TUBB3	Other/Unknown	no		Tubulin, Beta_tubulin, Tubulin_FtsZ_GTPase
GRHL2	Transcription factor	no		CP2, TF_CP2-like, GRHL1/CP2_C
TUBB2B	Other/Unknown	no		Tubulin, Beta_tubulin, Tubulin_FtsZ_GTPase
PHOX2A	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
WNT8A	Other/Unknown	no		Wnt, Wnt8, Wnt_CS
TUBA1B	Other/Unknown	no		Tubulin, Alpha_tubulin, Tubulin_FtsZ_GTPase
TUBB	Other/Unknown	no		Tubulin, Beta_tubulin, Tubulin_FtsZ_GTPase
CTNNA1	Other/Unknown	no		Vinculin_CS, Alpha_catenin, Vinculin/catenin
FGF21	Other/Unknown	no		Fibroblast_GF_fam, IL1/FGF, FGF15/19/21
HRAS	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
MCM3AP	Other/Unknown	no		PCI_dom, SAC3/GANP/THP3_conserved, MCM3AP_GANP
MYH10	Scaffold/PPI	no		IQ_motif_EF-hand-BS, Myosin_head_motor_dom-like, Myosin_tail
NES	Other/Unknown	no		IF_conserved, Nestin, IF_rod_dom

Expression context

Cohort genes with no expression data: 0.

14 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)	15
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	4
ganglionic eminence	4
ventricular zone	4
primordial germ cell in gonad	2
dorsal root ganglion	1
pons	1
substantia nigra pars compacta	1
endothelial cell	1
embryo	1
buccal mucosa cell	1
cervix squamous epithelium	1
oviduct epithelium	1
male germ line stem cell (sensu Vertebrata) in testis	1
parotid gland	1
pancreatic ductal cell	1
tibialis anterior	1
frontal pole	1
superior frontal gyrus	1
amniotic fluid	1
calcaneal tendon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KIF21A	253	ubiquitous	marker	dorsal root ganglion, substantia nigra pars compacta, pons
TUBA1A	288	ubiquitous	marker	endothelial cell, cortical plate, ganglionic eminence
TUBB3	144	ubiquitous	marker	cortical plate, ganglionic eminence, embryo
GRHL2	200	broad	marker	buccal mucosa cell, oviduct epithelium, cervix squamous epithelium
TUBB2B	265	ubiquitous	marker	cortical plate, ganglionic eminence, ventricular zone
PHOX2A	68	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, parotid gland
WNT8A	33	tissue_specific	marker	primordial germ cell in gonad, pancreatic ductal cell, tibialis anterior
TUBA1B	153	ubiquitous	marker	ventricular zone, superior frontal gyrus, frontal pole
TUBB	133	ubiquitous	marker	cortical plate, ganglionic eminence, ventricular zone
CTNNA1	305	ubiquitous	marker	colonic epithelium, calcaneal tendon, amniotic fluid
FGF21	37	tissue_specific	yes	right lobe of liver, liver, type B pancreatic cell
HRAS	139	ubiquitous	marker	skin of abdomen, skin of leg, zone of skin
MCM3AP	287	ubiquitous	marker	tendon of biceps brachii, tibial nerve, right uterine tube
MYH10	300	ubiquitous	marker	blood vessel layer, saphenous vein, right coronary artery
NES	247	ubiquitous	marker	ventricular zone, gluteal muscle, apex of heart

Protein interactions among cohort

Intra-cohort edges: 12.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HRAS	8,064
TUBB3	6,797
TUBB2B	4,736
NES	4,700
MYH10	3,368
CTNNA1	3,128
MCM3AP	2,386
FGF21	2,164
KIF21A	1,564
TUBB	1,512

Intra-cohort edges

A	B	Sources
KIF21A	PHOX2A	string_interaction
KIF21A	TUBB2B	string_interaction
KIF21A	TUBB3	string_interaction
NES	TUBB3	string_interaction
PHOX2A	TUBB3	string_interaction
TUBA1A	TUBA1B	intact
TUBA1A	TUBB	intact
TUBA1A	TUBB2B	intact
TUBA1A	TUBB3	intact
TUBA1B	TUBB3	intact
TUBB	TUBB3	intact
TUBB2B	TUBB3	biogrid_interaction

Structural data

PDB: 13 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HRAS	P01112	246
TUBA1B	P68363	39
TUBB3	Q13509	28
TUBB	P07437	21
TUBA1A	Q71U36	15
CTNNA1	P35221	10
MCM3AP	O60318	7
KIF21A	Q7Z4S6	5
TUBB2B	Q9BVA1	3
FGF21	Q9NSA1	3
GRHL2	Q6ISB3	1
WNT8A	Q9H1J5	1
MYH10	P35580	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PHOX2A	O14813	64.49
NES	P48681	49.18

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 192. Enrichment computed across 15 evidence-associated genes (11 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 11 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RHO GTPases activate IQGAPs	5	157.3×	1e-08	TUBA1A, TUBB3, TUBA1B, CTNNA1, TUBB2B
Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane	4	197.8×	1e-07	TUBA1A, TUBB3, TUBA1B, TUBB2B
Transport of connexons to the plasma membrane	4	197.8×	1e-07	TUBA1A, TUBB3, TUBA1B, TUBB2B
Kinesins	5	81.1×	1e-07	KIF21A, TUBA1A, TUBB3, TUBA1B, TUBB2B
Gap junction trafficking and regulation	4	173.0×	1e-07	TUBA1A, TUBB3, TUBA1B, TUBB2B
Gap junction trafficking	4	173.0×	1e-07	TUBA1A, TUBB3, TUBA1B, TUBB2B
Post-chaperonin tubulin folding pathway	4	173.0×	1e-07	TUBA1A, TUBB3, TUBA1B, TUBB2B
Formation of tubulin folding intermediates by CCT/TriC	4	153.8×	2e-07	TUBA1A, TUBB3, TUBA1B, TUBB2B
Cooperation of Prefoldin and TriC/CCT in actin and tubulin folding	4	148.3×	2e-07	TUBA1A, TUBB3, TUBA1B, TUBB2B
Golgi-to-ER retrograde transport	5	60.4×	2e-07	KIF21A, TUBA1A, TUBB3, TUBA1B, TUBB2B
Activation of AMPK downstream of NMDARs	4	138.4×	2e-07	TUBA1A, TUBB3, TUBA1B, TUBB2B
Mitotic G2-G2/M phases	5	57.7×	2e-07	TUBA1A, TUBB3, TUBA1B, TUBB, TUBB2B
G2/M Transition	5	57.7×	2e-07	TUBA1A, TUBB3, TUBA1B, TUBB, TUBB2B
Sealing of the nuclear envelope (NE) by ESCRT-III	4	125.8×	2e-07	TUBA1A, TUBB3, TUBA1B, TUBB2B
Recruitment of NuMA to mitotic centrosomes	5	53.0×	2e-07	TUBA1A, TUBB3, TUBA1B, TUBB, TUBB2B
HCMV Infection	4	118.7×	3e-07	TUBA1A, TUBB3, TUBA1B, TUBB2B
COPI-dependent Golgi-to-ER retrograde traffic	5	50.4×	3e-07	KIF21A, TUBA1A, TUBB3, TUBA1B, TUBB2B
Cilium Assembly	5	49.4×	3e-07	TUBA1A, TUBB3, TUBA1B, TUBB, TUBB2B
Intra-Golgi and retrograde Golgi-to-ER traffic	5	47.6×	3e-07	KIF21A, TUBA1A, TUBB3, TUBA1B, TUBB2B
Chaperonin-mediated protein folding	4	109.3×	3e-07	TUBA1A, TUBB3, TUBA1B, TUBB2B
Gap junction assembly	4	106.5×	3e-07	TUBA1A, TUBB3, TUBA1B, TUBB2B
Nuclear Envelope (NE) Reassembly	4	106.5×	3e-07	TUBA1A, TUBB3, TUBA1B, TUBB2B
Selective autophagy	4	101.3×	4e-07	TUBA1A, TUBB3, TUBA1B, TUBB2B
Protein folding	4	94.4×	5e-07	TUBA1A, TUBB3, TUBA1B, TUBB2B
Assembly and cell surface presentation of NMDA receptors	4	92.3×	5e-07	TUBA1A, TUBB3, TUBA1B, TUBB2B
Cargo trafficking to the periciliary membrane	4	90.3×	5e-07	TUBA1A, TUBB3, TUBA1B, TUBB2B
Aggrephagy	4	90.3×	5e-07	TUBA1A, TUBB3, TUBA1B, TUBB2B
Carboxyterminal post-translational modifications of tubulin	4	86.5×	6e-07	TUBA1A, TUBB3, TUBA1B, TUBB2B
Recycling pathway of L1	4	81.4×	8e-07	TUBA1A, TUBB3, TUBA1B, TUBB2B
COPI-independent Golgi-to-ER retrograde traffic	4	75.5×	1e-06	TUBA1A, TUBB3, TUBA1B, TUBB2B

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 15 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
microtubule-based process	4	264.4×	2e-07	TUBA1A, TUBA1B, TUBB, TUBB2B
mitotic cell cycle	5	44.6×	6e-06	TUBA1A, TUBB3, TUBA1B, TUBB, TUBB2B
microtubule cytoskeleton organization	5	40.4×	7e-06	TUBA1A, TUBB3, TUBA1B, TUBB, TUBB2B
cytoskeleton-dependent intracellular transport	3	187.2×	2e-05	TUBA1A, TUBA1B, TUBB
neuron apoptotic process	3	37.0×	0.003	TUBA1A, HRAS, NES
neuron migration	3	26.8×	0.006	TUBA1A, TUBB2B, MYH10
regulation of synapse organization	2	86.4×	0.007	TUBA1A, TUBB
trochlear nerve formation	1	1123.5×	0.016	PHOX2A
locus ceruleus development	1	1123.5×	0.016	PHOX2A
positive regulation of intermediate filament depolymerization	1	1123.5×	0.016	NES
epithelium migration	1	1123.5×	0.016	GRHL2
fourth ventricle development	1	561.7×	0.025	MYH10
oculomotor nerve formation	1	561.7×	0.025	PHOX2A
positive regulation of axon guidance	1	561.7×	0.025	TUBB2B
regulation of low-density lipoprotein particle clearance	1	374.5×	0.028	FGF21
somatic motor neuron differentiation	1	374.5×	0.028	PHOX2A
epithelial cell morphogenesis involved in placental branching	1	374.5×	0.028	GRHL2
positive regulation of miRNA metabolic process	1	374.5×	0.028	HRAS
cerebral cortex development	2	27.4×	0.028	TUBA1A, TUBB2B
neural crest cell fate commitment	1	280.9×	0.028	WNT8A
regulation of microtubule depolymerization	1	280.9×	0.028	KIF21A
regulation of respiratory gaseous exchange	1	280.9×	0.028	PHOX2A
anterior neural tube closure	1	280.9×	0.028	GRHL2
negative regulation of integrin-mediated signaling pathway	1	280.9×	0.028	CTNNA1
smoothened signaling pathway	2	24.2×	0.028	TUBA1A, CTNNA1
cell division	3	9.2×	0.029	TUBA1A, TUBA1B, TUBB
third ventricle development	1	224.7×	0.029	MYH10
pyramidal neuron differentiation	1	224.7×	0.029	TUBA1A
cellular response to indole-3-methanol	1	224.7×	0.029	CTNNA1
dorsal root ganglion development	1	224.7×	0.029	TUBB3

Therapeutics

Drug target analysis

Approved (phase 4): 7 · Phase ≥3: 7 · Phased (≥1): 7 · Undrugged: 8

Druggability breadth: 10 of 15 evidence-associated genes (67%) 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
TUBA1A	COLCHICINE
TUBB3	COLCHICINE
TUBB2B	COLCHICINE
TUBA1B	COLCHICINE
TUBB	COLCHICINE
HRAS	LONAFARNIB
MYH10	QUIZARTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TUBA1A	22	4
TUBB	22	4
TUBB3	21	4
TUBB2B	21	4
TUBA1B	21	4
HRAS	4	4
MYH10	2	4
KIF21A	0	0
GRHL2	0	0
PHOX2A	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
COLCHICINE	4	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
VINBLASTINE	4	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
LEVOFLOXACIN ANHYDROUS	4	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
DOCETAXEL	4	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
NOSCAPINE	4	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
VINBLASTINE SULFATE	4	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
PACLITAXEL	4	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
LEVOFLOXACIN	4	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
VINORELBINE	4	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
TIRBANIBULIN	4	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
PODOFILOX	4	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
VINCRISTINE	4	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
DOCETAXEL ANHYDROUS	4	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
LONAFARNIB	4	HRAS
QUIZARTINIB	4	MYH10
PATUPILONE	3	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
ABT-751	2	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
MAYTANSINE	2	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
DOLASTATIN-10	2	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
INDIBULIN	2	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
PARBENDAZOLE	2	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
NOCODAZOLE	2	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
MOLIBRESIB	2	TUBA1A, TUBB
STALLIMYCIN	2	HRAS
R-406	2	MYH10
COMBRETASTATIN	1	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
L-778123 FREE BASE	1	HRAS
BMS-214662	1	HRAS

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
TUBB3	1,781	Binding:1741, Functional:34, ADMET:6
TUBB	1,780	Binding:1740, Functional:34, ADMET:6
TUBB2B	1,757	Binding:1717, Functional:34, ADMET:6
TUBA1A	1,696	Binding:1655, Functional:35, ADMET:6
TUBA1B	1,689	Binding:1648, Functional:35, ADMET:6
HRAS	48	Binding:45, Functional:3
KIF21A	4	Binding:3, Toxicity:1
MYH10	3	Binding:3
CTNNA1	2	Binding:2
NES	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HRAS	3.6.5.2	small monomeric GTPase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TUBA1A	1,696
TUBB3	1,781
TUBB2B	1,757
TUBA1B	1,689
TUBB	1,780

Pharmacogenomics

Cohort genes with a PharmGKB record: 15; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

28 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	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
VINBLASTINE	4	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
LEVOFLOXACIN ANHYDROUS	4	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
DOCETAXEL	4	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
NOSCAPINE	4	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
VINBLASTINE SULFATE	4	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
PACLITAXEL	4	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
LEVOFLOXACIN	4	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
VINORELBINE	4	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
TIRBANIBULIN	4	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
PODOFILOX	4	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
VINCRISTINE	4	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
DOCETAXEL ANHYDROUS	4	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
LONAFARNIB	4	HRAS
QUIZARTINIB	4	MYH10
PATUPILONE	3	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
ABT-751	2	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
MAYTANSINE	2	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
DOLASTATIN-10	2	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
INDIBULIN	2	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
PARBENDAZOLE	2	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
NOCODAZOLE	2	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
MOLIBRESIB	2	TUBA1A, TUBB
STALLIMYCIN	2	HRAS
R-406	2	MYH10
COMBRETASTATIN	1	TUBA1A, TUBA1B, TUBB, TUBB2B, TUBB3
L-778123 FREE BASE	1	HRAS
BMS-214662	1	HRAS

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	7	TUBA1A, TUBB3, TUBB2B, TUBA1B, TUBB, HRAS, MYH10
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	8	KIF21A, GRHL2, PHOX2A, WNT8A, CTNNA1, FGF21, MCM3AP, NES

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
KIF21A	4	TUBB3
PHOX2A	0	TUBB3
GRHL2	0	—
WNT8A	0	—
CTNNA1	2	—
FGF21	0	—
MCM3AP	0	—
NES	1	—

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