Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome

Summary

Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome (MONDO:0044646) is a disease caused by variants in TBCD and TBCE, with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal genes: TBCD (GenCC Definitive), TBCE (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 120
• Phenotypes (HPO): 56

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		39	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

56 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0001257	Spasticity	Very frequent (80-99%)
HP:0001324	Muscle weakness	Very frequent (80-99%)
HP:0001510	Growth delay	Very frequent (80-99%)
HP:0002079	Hypoplasia of the corpus callosum	Very frequent (80-99%)
HP:0002120	Cerebral cortical atrophy	Very frequent (80-99%)
HP:0003202	Skeletal muscle atrophy	Very frequent (80-99%)
HP:0000648	Optic atrophy	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001272	Cerebellar atrophy	Frequent (30-79%)
HP:0001344	Absent speech	Frequent (30-79%)
HP:0002069	Bilateral tonic-clonic seizure	Frequent (30-79%)
HP:0002187	Intellectual disability, profound	Frequent (30-79%)
HP:0002191	Progressive spasticity	Frequent (30-79%)
HP:0002445	Tetraplegia	Frequent (30-79%)
HP:0002465	Poor speech	Frequent (30-79%)
HP:0002878	Respiratory failure	Frequent (30-79%)
HP:0005484	Secondary microcephaly	Frequent (30-79%)
HP:0006808	Cerebral hypomyelination	Frequent (30-79%)
HP:0007179	Absent smooth pursuit	Frequent (30-79%)
HP:0008947	Floppy infant	Frequent (30-79%)
HP:0010818	Generalized tonic seizure	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0000020	Urinary incontinence	Occasional (5-29%)
HP:0000316	Hypertelorism	Occasional (5-29%)
HP:0000347	Micrognathia	Occasional (5-29%)
HP:0000582	Upslanted palpebral fissure	Occasional (5-29%)
HP:0000687	Widely spaced teeth	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001284	Areflexia	Occasional (5-29%)
HP:0001357	Plagiocephaly	Occasional (5-29%)
HP:0001561	Polyhydramnios	Occasional (5-29%)
HP:0002015	Dysphagia	Occasional (5-29%)
HP:0002342	Intellectual disability, moderate	Occasional (5-29%)
HP:0002376	Developmental regression	Occasional (5-29%)
HP:0002380	Fasciculations	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002804	Arthrogryposis multiplex congenita	Occasional (5-29%)
HP:0003084	Fractures of the long bones	Occasional (5-29%)
HP:0003236	Elevated circulating creatine kinase concentration	Occasional (5-29%)
HP:0004887	Respiratory failure requiring assisted ventilation	Occasional (5-29%)
HP:0011451	Congenital microcephaly	Occasional (5-29%)
HP:0012450	Chronic constipation	Occasional (5-29%)
HP:0045075	Sparse eyebrow	Occasional (5-29%)
HP:0000011	Neurogenic bladder	Very rare (<1-4%)
HP:0000400	Macrotia	Very rare (<1-4%)
HP:0000733	Abnormal repetitive mannerisms	Very rare (<1-4%)
HP:0000767	Pectus excavatum	Very rare (<1-4%)
HP:0000768	Pectus carinatum	Very rare (<1-4%)
HP:0001007	Hirsutism	Very rare (<1-4%)
HP:0001332	Dystonia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome
Mondo ID	MONDO:0044646
OMIM	617193
Orphanet	496641
DOID	DOID:0070423
UMLS	C5567454
MedGen	1798877
GARD	0017911
Is cancer (heuristic)	no

Also known as: encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum · encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum; PEBAT · PEBAT

Data availability: 120 ClinVar variants · 6 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome

Related subtypes (216): polymicrogyria, congenital myasthenic syndrome with tubular aggregates, prenatal-onset spinal muscular atrophy with congenital bone fractures, anencephaly, cerebral cavernous malformation, meningocele, progressive external ophthalmoplegia, congenital nystagmus, congenital toxoplasmosis, congenital contractural arachnodactyly, congenital trigeminal anesthesia, familial congenital palsy of trochlear nerve, Myhre syndrome, Aase-Smith syndrome, KBG syndrome, autosomal dominant primary microcephaly, Mobius syndrome, MYH7-related skeletal myopathy, congenital stationary night blindness autosomal dominant 2, Prader-Willi syndrome, congenital myopathy 7A, myosin storage, autosomal dominant, Smith-Magenis syndrome, spina bifida, Freeman-Sheldon syndrome, isolated cerebellar hypoplasia/agenesis, Chediak-Higashi syndrome, Cohen syndrome, multiple pterygium-malignant hyperthermia syndrome, corpus callosum, agenesis of, congenital lactic acidosis, Saguenay-Lac-Saint-Jean type, facial dysmorphism-macrocephaly-myopia-Dandy-Walker malformation syndrome, diastematomyelia, EEM syndrome, Mowat-Wilson syndrome, Johanson-Blizzard syndrome, intellectual disability, Buenos-Aires type, myasthenia, congenital, refractory to acetylcholinesterase inhibitors, congenital myasthenic syndrome 6, Bailey-Bloch congenital myopathy, congenital stationary night blindness 1B, radioulnar synostosis-developmental delay-hypotonia syndrome, Schinzel-Giedion syndrome, schizencephaly, intellectual disability, Wolff type, X-linked intellectual disability-plagiocephaly syndrome, X-linked adrenal hypoplasia congenita, syndromic X-linked intellectual disability 7, syndromic X-linked intellectual disability Shashi type, syndromic X-linked intellectual disability Lubs type, syndromic X-linked intellectual disability Abidi type, syndromic X-linked intellectual disability Siderius type, X-linked intellectual disability, Cabezas type, X-linked intellectual disability-cubitus valgus-dysmorphism syndrome, syndromic X-linked intellectual disability Claes-Jensen type, moyamoya angiopathy-short stature-facial dysmorphism-hypergonadotropic hypogonadism syndrome, multiple congenital anomalies-hypotonia-seizures syndrome 2, developmental and epileptic encephalopathy, 36, blepharophimosis - intellectual disability syndrome, MKB type, X-linked intellectual disability-short stature-overweight syndrome, intellectual disability, X-linked, syndromic 33, syndromic X-linked intellectual disability 34, infantile-onset X-linked spinal muscular atrophy, syndromic X-linked intellectual disability 5, holoprosencephaly-hypokinesia-congenital contractures syndrome, X-linked intellectual disability with marfanoid habitus, Wieacker-Wolff syndrome, MERRF syndrome, macrocephaly-spastic paraplegia-dysmorphism syndrome, intellectual disability-sparse hair-brachydactyly syndrome, myofibrillar myopathy 1, isolated hereditary congenital facial paralysis, fibrosis of extraocular muscles, congenital, 2, Pierpont syndrome, congenital cataracts-facial dysmorphism-neuropathy syndrome, Bohring-Opitz syndrome, PHACE syndrome, B4GALT1-congenital disorder of glycosylation, developmental malformations-deafness-dystonia syndrome, sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, AICA-ribosiduria, myofibrillar myopathy 3, fibrosis of extraocular muscles, congenital, 3c, myofibrillar myopathy 4, myofibrillar myopathy 5, cone-rod synaptic disorder, congenital nonprogressive, congenital stationary night blindness autosomal dominant 3, congenital stationary night blindness autosomal dominant 1, intellectual disability, autosomal recessive 12, progressive myoclonic epilepsy type 3, chromosome 15q13.3 microdeletion syndrome, combined pituitary hormone deficiencies, genetic form, congenital stationary night blindness 1D, DYRK1A-related intellectual disability syndrome, Pitt-Hopkins-like syndrome 2, developmental and epileptic encephalopathy, 15, Schuurs-Hoeijmakers syndrome, severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome, severe intellectual disability-progressive spastic diplegia syndrome, hypotonia, infantile, with psychomotor retardation and characteristic facies, developmental and epileptic encephalopathy, 18, CTCF-related neurodevelopmental disorder, autism spectrum disorder due to AUTS2 deficiency, developmental and epileptic encephalopathy, 23, ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder, Bardet-Biedl syndrome 11, cerebellar-facial-dental syndrome, fibrosis of extraocular muscles, congenital, 5, congenital myasthenic syndrome 15, lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome, congenital myasthenic syndrome 18, autosomal recessive spinocerebellar ataxia 20, Houge-Janssens syndrome 1, intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome, congenital stationary night blindness 1G, hypomyelinating leukodystrophy 10, developmental and epileptic encephalopathy, 50, congenital insensitivity to pain-hypohidrosis syndrome, macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, SLC39A8-CDG, spastic paraplegia-severe developmental delay-epilepsy syndrome, cardiac anomalies - developmental delay - facial dysmorphism syndrome, severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome, intellectual disability, autosomal recessive 53, TELO2-related intellectual disability-neurodevelopmental disorder, micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome, autosomal recessive limb-girdle muscular dystrophy type 2Y, myofibrillar myopathy 7, short stature-brachydactyly-obesity-global developmental delay syndrome, autosomal recessive limb-girdle muscular dystrophy type 2R1, severe microbrachycephaly-intellectual disability-athetoid cerebral palsy syndrome, congenital laryngeal palsy, congenital or early infantile CACH syndrome, congenital epulis, severe congenital nemaline myopathy, intermediate nemaline myopathy, typical nemaline myopathy, childhood-onset nemaline myopathy, adult-onset nemaline myopathy, qualitative or quantitative defects of protein involved in O-glycosylation of alpha-dystroglycan, holoprosencephaly, congenital insensitivity to pain with hyperhidrosis, congenital hydrocephalus, familial congenital mirror movements, macrocephaly-short stature-paraplegia syndrome, cephalocele, mitochondrial neurogastrointestinal encephalomyopathy, X-linked intellectual disability-hypogonadism-ichthyosis-obesity-short stature syndrome, 7p22.1 microduplication syndrome, congenital achiasma, congenital retinal arteriovenous communication, 3q27.3 microdeletion syndrome, Prader-Willi-like syndrome, 9q31.1q31.3 microdeletion syndrome, congenital oculomotor nerve palsy, congenital abducens nerve palsy, neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome, congenital insensitivity to pain with severe intellectual disability, X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, lissencephaly spectrum disorders, hyaline body myopathy, 22q11.2 deletion syndrome, craniorachischisis, Leber congenital amaurosis, Ritscher-Schinzel syndrome, Rubinstein-Taybi syndrome, X-linked intellectual disability-hypogammaglobulinemia-progressive neurological deterioration syndrome, X-linked intellectual disability-epilepsy-progressive joint contractures-dysmorphism syndrome, X-linked intellectual disability, Pai type, X-linked intellectual disability, Stevenson type, X-linked intellectual disability, Stoll type, congenital muscular dystrophy, congenital vitreoretinal dysplasia, periventricular nodular heterotopia, postsynaptic congenital myasthenic syndrome, subcortical band heterotopia, congenital fibrosis of extraocular muscles type 1, Al Gazali Khidr Prem Chandran syndrome, distal arthrogryposis Moore weaver type, congenital myotonic dystrophy, myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive, intellectual disability, autosomal dominant 47, intellectual disability, autosomal dominant 48, spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosis, myasthenic syndrome, congenital, 23, presynaptic, myasthenic syndrome, congenital, 24, presynaptic, myasthenic syndrome, congenital, 25, presynaptic, developmental and epileptic encephalopathy, 77, night blindness, congenital stationary, type1i, neuropathy, congenital hypomelinating, congenital axonal neuropathy with encephalopathy, developmental and epileptic encephalopathy, 73, PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome, isolated exencephaly, myasthenic syndrome, congenital, 22, intellectual developmental disorder with gastrointestinal difficulties and high pain threshold, intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, 9q33.3q34.11 microdeletion syndrome, congenital labioscrotal agenesis-cerebellar malformation-corneal dystrophy-facial dysmorphism syndrome, SIN3A-related intellectual disability syndrome, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, X-linked congenital stationary night blindness, neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, FOXG1 disorder, alpha-actinopathy, TPM3-related myopathy, X-linked recessive mitochondrial myopathy, RYR1-related myopathy, TTN-related myopathy, TPM2-related myopathy, myopathy caused by variation in POMGNT1, central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, segmental spinal dysgenesis, myopathy, myofibrillar, 13, with rimmed vacuoles, congenital neuronal ceroid lipofuscinosis 10

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

120 retrieved; paginated sample, class counts are floors:

54 uncertain significance, 22 conflicting classifications of pathogenicity, 13 benign, 13 likely pathogenic, 10 pathogenic, 8 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1030991	NM_005993.5(TBCD):c.1957C>T (p.Gln653Ter)	TBCD	Pathogenic	criteria provided, single submitter
1342503	NM_005993.5(TBCD):c.907C>T (p.Arg303Ter)	TBCD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1683318	NM_005993.5(TBCD):c.1224-2A>G	TBCD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1686668	NM_005993.4(TBCD):c.1150_1171del	TBCD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1700434	NM_005993.5(TBCD):c.1306C>T (p.Arg436Ter)	TBCD	Pathogenic	criteria provided, multiple submitters, no conflicts
1707501	NM_005993.5(TBCD):c.1006C>T (p.Gln336Ter)	TBCD	Pathogenic	criteria provided, single submitter
268166	NM_005993.5(TBCD):c.1564-12C>G	TBCD	Pathogenic	no assertion criteria provided
268167	NM_005993.5(TBCD):c.2314C>T (p.Arg772Cys)	TBCD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
268168	NM_005993.5(TBCD):c.2761G>A (p.Ala921Thr)	TBCD	Pathogenic	no assertion criteria provided
268169	NM_005993.5(TBCD):c.1160T>G (p.Met387Arg)	TBCD	Pathogenic	no assertion criteria provided
268170	NM_005993.5(TBCD):c.2280C>A (p.Tyr760Ter)	TBCD	Pathogenic	criteria provided, multiple submitters, no conflicts
268172	NM_005993.5(TBCD):c.2810C>G (p.Pro937Arg)	TBCD	Pathogenic	no assertion criteria provided
268175	NM_005993.5(TBCD):c.1130G>A (p.Arg377Gln)	TBCD	Pathogenic	no assertion criteria provided
279953	NM_005993.5(TBCD):c.1423G>A (p.Ala475Thr)	TBCD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3764606	NM_005993.5(TBCD):c.2792_2793insG (p.Phe931fs)	TBCD	Pathogenic	criteria provided, single submitter
452575	NM_005993.5(TBCD):c.1661C>T (p.Ala554Val)	TBCD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
624104	NM_005993.5(TBCD):c.230A>G (p.His77Arg)	TBCD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
692021	NM_005993.5(TBCD):c.967C>T (p.Arg323Ter)	TBCD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2570653	NM_005993.5(TBCD):c.2077C>A (p.Pro693Thr)	LOC126862673	Likely pathogenic	criteria provided, single submitter
1496655	NM_005993.5(TBCD):c.2007-2A>G	TBCD	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2570652	NM_005993.5(TBCD):c.2472-2A>G	TBCD	Likely pathogenic	criteria provided, single submitter
2582324	NM_005993.5(TBCD):c.345_346del (p.Tyr115_Lys116delinsTer)	TBCD	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2633532	NM_005993.5(TBCD):c.2983del (p.Glu995fs)	TBCD	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3339394	NM_005993.5(TBCD):c.435+1del	TBCD	Likely pathogenic	criteria provided, single submitter
3382166	NM_005993.5(TBCD):c.1723_1724dup (p.Trp575fs)	TBCD	Likely pathogenic	criteria provided, single submitter
3393126	NM_005993.5(TBCD):c.950+2T>C	TBCD	Likely pathogenic	criteria provided, single submitter
3583156	NM_005993.5(TBCD):c.2260G>T (p.Glu754Ter)	TBCD	Likely pathogenic	criteria provided, single submitter
3583157	NM_005993.5(TBCD):c.2892_2901del (p.Gln964fs)	TBCD	Likely pathogenic	criteria provided, single submitter
3583158	NM_005993.5(TBCD):c.3311_3320delinsGT (p.Asp1104fs)	TBCD	Likely pathogenic	criteria provided, single submitter
807699	NM_005993.5(TBCD):c.1504C>G (p.Arg502Gly)	TBCD	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 4 · 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
TBCD	Definitive	Autosomal recessive	early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome	5
TBCE	Strong	Autosomal recessive	early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TBCD	Orphanet:496641	Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome
TBCE	Orphanet:2323	Sanjad-Sakati syndrome
TBCE	Orphanet:496756	Early-onset progressive encephalopathy-spastic ataxia-distal spinal muscular atrophy syndrome
TBCE	Orphanet:93324	Autosomal recessive Kenny-Caffey syndrome

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
TBCD	HGNC:11581	ENSG00000141556	Q9BTW9	Tubulin-specific chaperone D	gencc,clinvar
TBCE	HGNC:11582	ENSG00000284770	Q15813	Tubulin-specific chaperone E	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TBCD	Tubulin-specific chaperone D	Tubulin-folding protein implicated in the first step of the tubulin folding pathway and required for tubulin complex assembly.
TBCE	Tubulin-specific chaperone E	Tubulin-folding protein; involved in the second step of the tubulin folding pathway and in the regulation of tubulin heterodimer dissociation.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TBCD	Other/Unknown	no		ARM-like, ARM-type_fold, TBCD_C
TBCE	Other/Unknown	no		Ubiquitin-like_dom, CAP-Gly_domain, Ubiquitin-like_domsf

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
right hemisphere of cerebellum	1
right lobe of thyroid gland	1
cortical plate	1
hindlimb stylopod muscle	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TBCD	165	ubiquitous	marker	right lobe of thyroid gland, apex of heart, right hemisphere of cerebellum
TBCE	134	ubiquitous	yes	ventricular zone, hindlimb stylopod muscle, cortical plate

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TBCD	2,066
TBCE	1,068

Intra-cohort edges

A	B	Sources
TBCD	TBCE	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TBCD	Q9BTW9	6
TBCE	Q15813	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Post-chaperonin tubulin folding pathway	2	475.8×	1e-05	TBCD, TBCE
Protein folding	2	259.6×	2e-05	TBCD, TBCE
Metabolism of proteins	2	12.4×	0.007	TBCD, TBCE

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
post-chaperonin tubulin folding pathway	2	2808.7×	2e-06	TBCD, TBCE
tubulin complex assembly	2	1685.2×	3e-06	TBCD, TBCE
microtubule cytoskeleton organization	2	121.2×	4e-04	TBCD, TBCE
protein folding	2	103.4×	4e-04	TBCD, TBCE
muscle atrophy	1	4213.0×	8e-04	TBCE
peripheral nervous system neuron axonogenesis	1	2106.5×	0.001	TBCE
cell morphogenesis involved in neuron differentiation	1	766.0×	0.003	TBCD
negative regulation of microtubule polymerization	1	648.1×	0.003	TBCD
adherens junction assembly	1	648.1×	0.003	TBCD
negative regulation of cell-substrate adhesion	1	526.6×	0.003	TBCD
developmental growth	1	366.4×	0.004	TBCE
bicellular tight junction assembly	1	165.2×	0.008	TBCD
adult locomotory behavior	1	150.5×	0.008	TBCE
mitotic spindle organization	1	135.9×	0.008	TBCE
post-embryonic development	1	102.8×	0.010	TBCE
mitotic cell cycle	1	66.9×	0.015	TBCD

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TBCD	0	0
TBCE	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TBCD	1	Binding:1

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	TBCD, TBCE

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)
TBCD	1	—
TBCE	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.