Complex cortical dysplasia with other brain malformations 7

Summary

Complex cortical dysplasia with other brain malformations 7 (MONDO:0012399) is a disease caused by TUBB2B (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TUBB2B (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 73
• Phenotypes (HPO): 30

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		36	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

30 HPO clinical features (Orphanet curated; top 30 by frequency):

HPO ID	Term	Frequency
HP:0002126	Polymicrogyria	Very frequent (80-99%)
HP:0002539	Cortical dysplasia	Very frequent (80-99%)
HP:0100543	Cognitive impairment	Very frequent (80-99%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001269	Hemiparesis	Frequent (30-79%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001272	Cerebellar atrophy	Occasional (5-29%)
HP:0001273	Abnormal corpus callosum morphology	Occasional (5-29%)
HP:0001302	Pachygyria	Occasional (5-29%)
HP:0002079	Hypoplasia of the corpus callosum	Occasional (5-29%)
HP:0002282	Gray matter heterotopia	Occasional (5-29%)
HP:0002339	Abnormal caudate nucleus morphology	Occasional (5-29%)
HP:0002363	Abnormal brainstem morphology	Occasional (5-29%)
HP:0002389	Cavum septum pellucidum	Occasional (5-29%)
HP:0006956	Dilation of lateral ventricles	Occasional (5-29%)
HP:0007018	Attention deficit hyperactivity disorder	Occasional (5-29%)
HP:0007301	Oromotor apraxia	Occasional (5-29%)
HP:0007359	Focal-onset seizure	Occasional (5-29%)
HP:0008947	Floppy infant	Occasional (5-29%)
HP:0012110	Hypoplasia of the pons	Occasional (5-29%)
HP:0012377	Hemianopia	Occasional (5-29%)
HP:0012650	Perisylvian polymicrogyria	Occasional (5-29%)
HP:0025102	Dysgenesis of the basal ganglia	Occasional (5-29%)
HP:0025160	Abnormal temper tantrums	Occasional (5-29%)
HP:0001274	Agenesis of corpus callosum	Very rare (<1-4%)
HP:0001339	Lissencephaly	Very rare (<1-4%)
HP:0010636	Schizencephaly	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	complex cortical dysplasia with other brain malformations 7
Mondo ID	MONDO:0012399
OMIM	610031
Orphanet	300573
DOID	DOID:0090132
UMLS	C3552236
MedGen	765150
GARD	0017375
Is cancer (heuristic)	no

Also known as: CDCBM7 · complex cortical dysplasia with other brain malformations caused by mutation in TUBB2B · complex cortical dysplasia with other brain malformations type 7 · PMGYSA · polymicrogyria due to TUBB2B mutation · polymicrogyria, symmetric or asymmetric · TUBB2B complex cortical dysplasia with other brain malformations

Data availability: 73 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › complex cortical dysplasia with other brain malformations › complex cortical dysplasia with other brain malformations 7

Related subtypes (11): polymicrogyria with optic nerve hypoplasia, complex cortical dysplasia with other brain malformations 1, complex cortical dysplasia with other brain malformations 2, complex cortical dysplasia with other brain malformations 3, complex cortical dysplasia with other brain malformations 4, complex cortical dysplasia with other brain malformations 5, complex cortical dysplasia with other brain malformations 6, cortical dysplasia, complex, with other brain malformations 9, cortical dysplasia, complex, with other brain malformations 10, cortical dysplasia, complex, with other brain malformations 11, cortical dysplasia, complex, with other brain malformations 12

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

73 retrieved; paginated sample, class counts are floors:

24 likely pathogenic, 18 uncertain significance, 12 pathogenic, 11 conflicting classifications of pathogenicity, 3 pathogenic/likely pathogenic, 2 not provided, 2 likely benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1214258	NM_178012.5(TUBB2B):c.1138C>T (p.Arg380Cys)	TUBB2B	Pathogenic	criteria provided, multiple submitters, no conflicts
1676461	NM_178012.5(TUBB2B):c.518C>G (p.Pro173Arg)	TUBB2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1708143	NM_178012.5(TUBB2B):c.776C>T (p.Pro259Leu)	TUBB2B	Pathogenic	criteria provided, multiple submitters, no conflicts
236255	NM_178012.5(TUBB2B):c.716G>T (p.Cys239Phe)	TUBB2B	Pathogenic	no assertion criteria provided
2498169	NM_178012.5(TUBB2B):c.1139G>A (p.Arg380His)	TUBB2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3777181	NM_178012.5(TUBB2B):c.1106G>T (p.Gly369Val)	TUBB2B	Pathogenic	criteria provided, single submitter
39720	NM_178012.5(TUBB2B):c.1249G>A (p.Asp417Asn)	TUBB2B	Pathogenic	no assertion criteria provided
4086071	NM_178012.5(TUBB2B):c.4C>T (p.Arg2Cys)	TUBB2B	Pathogenic	criteria provided, single submitter
426	NM_178012.5(TUBB2B):c.514T>C (p.Ser172Pro)	TUBB2B	Pathogenic	no assertion criteria provided
427	NM_178012.5(TUBB2B):c.683T>C (p.Leu228Pro)	TUBB2B	Pathogenic	criteria provided, single submitter
428	NM_178012.5(TUBB2B):c.793T>C (p.Phe265Leu)	TUBB2B	Pathogenic	no assertion criteria provided
4526588	NM_178012.5(TUBB2B):c.795C>A (p.Phe265Leu)	TUBB2B	Pathogenic	criteria provided, single submitter
692087	NM_178012.5(TUBB2B):c.1070C>T (p.Pro357Leu)	TUBB2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
800842	NM_178012.5(TUBB2B):c.4C>A (p.Arg2Ser)	TUBB2B	Pathogenic	criteria provided, multiple submitters, no conflicts
88897	NM_178012.5(TUBB2B):c.1261G>A (p.Glu421Lys)	TUBB2B	Pathogenic	criteria provided, single submitter
1048606	NM_178012.5(TUBB2B):c.1162A>C (p.Met388Leu)	TUBB2B	Likely pathogenic	criteria provided, single submitter
160177	NM_178012.5(TUBB2B):c.1139G>T (p.Arg380Leu)	TUBB2B	Likely pathogenic	criteria provided, multiple submitters, no conflicts
160187	NM_178012.5(TUBB2B):c.965C>T (p.Ser322Phe)	TUBB2B	Likely pathogenic	criteria provided, single submitter
1679255	NM_178012.5(TUBB2B):c.908G>A (p.Cys303Tyr)	TUBB2B	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3024227	NM_178012.5(TUBB2B):c.632G>A (p.Cys211Tyr)	TUBB2B	Likely pathogenic	criteria provided, single submitter
3235893	NM_178012.5(TUBB2B):c.845G>C (p.Arg282Pro)	TUBB2B	Likely pathogenic	criteria provided, single submitter
3236667	NM_178012.5(TUBB2B):c.622T>A (p.Tyr208Asn)	TUBB2B	Likely pathogenic	criteria provided, single submitter
3255101	NM_178012.5(TUBB2B):c.243C>G (p.Phe81Leu)	TUBB2B	Likely pathogenic	criteria provided, single submitter
3366292	NM_178012.5(TUBB2B):c.212G>A (p.Gly71Asp)	TUBB2B	Likely pathogenic	criteria provided, single submitter
3774397	NM_178012.5(TUBB2B):c.670G>T (p.Asp224Tyr)	TUBB2B	Likely pathogenic	criteria provided, single submitter
3775014	NM_178012.5(TUBB2B):c.539T>C (p.Val180Ala)	TUBB2B	Likely pathogenic	criteria provided, single submitter
39722	NM_178012.5(TUBB2B):c.350T>C (p.Leu117Pro)	TUBB2B	Likely pathogenic	criteria provided, single submitter
4076115	NM_178012.5(TUBB2B):c.43C>T (p.Gln15Ter)	TUBB2B	Likely pathogenic	criteria provided, single submitter
4077397	NM_178012.5(TUBB2B):c.145G>A (p.Val49Ile)	TUBB2B	Likely pathogenic	criteria provided, single submitter
4278262	NM_178012.5(TUBB2B):c.55A>G (p.Lys19Glu)	TUBB2B	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · 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
TUBB2B	Definitive	Autosomal dominant	complex cortical dysplasia with other brain malformations	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TUBB2B	HGNC:30829	ENSG00000137285	Q9BVA1	Tubulin beta-2B chain	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TUBB2B	Other/Unknown	no		Tubulin, Beta_tubulin, Tubulin_FtsZ_GTPase

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	1
ganglionic eminence	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TUBB2B	265	ubiquitous	marker	cortical plate, ganglionic eminence, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TUBB2B	4,736

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TUBB2B	Q9BVA1	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 86. Enrichment computed across 1 evidence-associated genes (1 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 1 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	543.8×	0.016	TUBB2B
Transport of connexons to the plasma membrane	1	543.8×	0.016	TUBB2B
Gap junction trafficking and regulation	1	475.8×	0.016	TUBB2B
Gap junction trafficking	1	475.8×	0.016	TUBB2B
Post-chaperonin tubulin folding pathway	1	475.8×	0.016	TUBB2B
Formation of tubulin folding intermediates by CCT/TriC	1	423.0×	0.016	TUBB2B
Cooperation of Prefoldin and TriC/CCT in actin and tubulin folding	1	407.9×	0.016	TUBB2B
Prefoldin mediated transfer of substrate to CCT/TriC	1	393.8×	0.016	TUBB2B
Activation of AMPK downstream of NMDARs	1	380.7×	0.016	TUBB2B
RHO GTPases activate IQGAPs	1	346.1×	0.016	TUBB2B
Sealing of the nuclear envelope (NE) by ESCRT-III	1	346.1×	0.016	TUBB2B
HCMV Infection	1	326.3×	0.016	TUBB2B
Chaperonin-mediated protein folding	1	300.5×	0.016	TUBB2B
Gap junction assembly	1	292.8×	0.016	TUBB2B
Nuclear Envelope (NE) Reassembly	1	292.8×	0.016	TUBB2B
Selective autophagy	1	278.5×	0.016	TUBB2B
Protein folding	1	259.6×	0.016	TUBB2B
Assembly and cell surface presentation of NMDA receptors	1	253.8×	0.016	TUBB2B
Cargo trafficking to the periciliary membrane	1	248.3×	0.016	TUBB2B
Aggrephagy	1	248.3×	0.016	TUBB2B
Carboxyterminal post-translational modifications of tubulin	1	237.9×	0.016	TUBB2B
Recycling pathway of L1	1	223.9×	0.016	TUBB2B
COPI-independent Golgi-to-ER retrograde traffic	1	207.6×	0.016	TUBB2B
Post NMDA receptor activation events	1	203.9×	0.016	TUBB2B
Intraflagellar transport	1	200.3×	0.016	TUBB2B
Antimicrobial mechanism of IFN-stimulated genes	1	196.9×	0.016	TUBB2B
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	1	193.6×	0.016	TUBB2B
Activation of NMDA receptors and postsynaptic events	1	184.2×	0.016	TUBB2B
Signaling by Hedgehog	1	184.2×	0.016	TUBB2B
Hedgehog ‘off’ state	1	178.4×	0.016	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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of axon guidance	1	8426.0×	9e-04	TUBB2B
microtubule-based process	1	991.3×	0.003	TUBB2B
embryonic brain development	1	802.5×	0.003	TUBB2B
cerebral cortex development	1	205.5×	0.008	TUBB2B
modulation of chemical synaptic transmission	1	183.2×	0.008	TUBB2B
mitotic cell cycle	1	133.8×	0.008	TUBB2B
neuron migration	1	133.8×	0.008	TUBB2B
microtubule cytoskeleton organization	1	121.2×	0.008	TUBB2B

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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
TUBB2B	COLCHICINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TUBB2B	21	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
COLCHICINE	4	TUBB2B
VINBLASTINE	4	TUBB2B
LEVOFLOXACIN ANHYDROUS	4	TUBB2B
DOCETAXEL	4	TUBB2B
NOSCAPINE	4	TUBB2B
VINBLASTINE SULFATE	4	TUBB2B
PACLITAXEL	4	TUBB2B
LEVOFLOXACIN	4	TUBB2B
VINORELBINE	4	TUBB2B
TIRBANIBULIN	4	TUBB2B
PODOFILOX	4	TUBB2B
VINCRISTINE	4	TUBB2B
DOCETAXEL ANHYDROUS	4	TUBB2B
PATUPILONE	3	TUBB2B
ABT-751	2	TUBB2B
MAYTANSINE	2	TUBB2B
DOLASTATIN-10	2	TUBB2B
INDIBULIN	2	TUBB2B
PARBENDAZOLE	2	TUBB2B
NOCODAZOLE	2	TUBB2B
COMBRETASTATIN	1	TUBB2B

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TUBB2B	1,757	Binding:1717, 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
TUBB2B	1,757

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	TUBB2B
VINBLASTINE	4	TUBB2B
LEVOFLOXACIN ANHYDROUS	4	TUBB2B
DOCETAXEL	4	TUBB2B
NOSCAPINE	4	TUBB2B
VINBLASTINE SULFATE	4	TUBB2B
PACLITAXEL	4	TUBB2B
LEVOFLOXACIN	4	TUBB2B
VINORELBINE	4	TUBB2B
TIRBANIBULIN	4	TUBB2B
PODOFILOX	4	TUBB2B
VINCRISTINE	4	TUBB2B
DOCETAXEL ANHYDROUS	4	TUBB2B
PATUPILONE	3	TUBB2B
ABT-751	2	TUBB2B
MAYTANSINE	2	TUBB2B
DOLASTATIN-10	2	TUBB2B
INDIBULIN	2	TUBB2B
PARBENDAZOLE	2	TUBB2B
NOCODAZOLE	2	TUBB2B
COMBRETASTATIN	1	TUBB2B

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TUBB2B
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.