Complex cortical dysplasia with other brain malformations 6

Summary

Complex cortical dysplasia with other brain malformations 6 (MONDO:0014341) is a disease caused by TUBB (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: TUBB (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 34

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	complex cortical dysplasia with other brain malformations 6
Mondo ID	MONDO:0014341
OMIM	615771
DOID	DOID:0090136
UMLS	C4014283
MedGen	862720
Is cancer (heuristic)	no

Also known as: CDCBM6 · complex cortical dysplasia with other brain malformations caused by mutation in TUBB · complex cortical dysplasia with other brain malformations type 6 · cortical dysplasia, complex, with other brain malformations 6 · cortical dysplasia, Complex, with Other brain malformations type 6 · TUBB complex cortical dysplasia with other brain malformations

Data availability: 34 ClinVar variants · 3 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 6

Related subtypes (11): complex cortical dysplasia with other brain malformations 7, 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, 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

34 retrieved; paginated sample, class counts are floors:

13 uncertain significance, 9 likely pathogenic, 5 pathogenic, 4 pathogenic/likely pathogenic, 3 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
127189	NM_178014.4(TUBB):c.895A>G (p.Met299Val)	TUBB	Pathogenic	criteria provided, multiple submitters, no conflicts
127190	NM_178014.4(TUBB):c.1057G>A (p.Val353Ile)	TUBB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
127191	NM_178014.4(TUBB):c.1201G>A (p.Glu401Lys)	TUBB	Pathogenic	criteria provided, multiple submitters, no conflicts
1806220	NM_178014.4(TUBB):c.331G>A (p.Glu111Lys)	TUBB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2136013	NM_178014.4(TUBB):c.155A>G (p.Asn52Ser)	TUBB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
235892	NM_178014.4(TUBB):c.662C>T (p.Thr221Ile)	TUBB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3256783	NM_178014.4(TUBB):c.869C>T (p.Thr290Ile)	TUBB	Pathogenic	criteria provided, single submitter
4528358	NM_178014.4(TUBB):c.626A>G (p.Asp209Gly)	TUBB	Pathogenic	criteria provided, single submitter
977846	NM_178014.4(TUBB):c.1261G>A (p.Glu421Lys)	TUBB	Pathogenic	no assertion criteria provided
1172521	NM_178014.4(TUBB):c.316T>G (p.Tyr106Asp)	TUBB	Likely pathogenic	criteria provided, single submitter
1339905	NM_178014.4(TUBB):c.917G>C (p.Arg306Pro)	TUBB	Likely pathogenic	criteria provided, single submitter
1709915	NM_178014.4(TUBB):c.670G>T (p.Asp224Tyr)	TUBB	Likely pathogenic	criteria provided, single submitter
2443069	NM_178014.4(TUBB):c.260C>T (p.Pro87Leu)	TUBB	Likely pathogenic	criteria provided, single submitter
3256579	NM_178014.4(TUBB):c.670G>C (p.Asp224His)	TUBB	Likely pathogenic	criteria provided, single submitter
3256784	NM_178014.4(TUBB):c.91G>A (p.Asp31Asn)	TUBB	Likely pathogenic	no assertion criteria provided
3600528	NM_178014.4(TUBB):c.245G>T (p.Gly82Val)	TUBB	Likely pathogenic	criteria provided, single submitter
807517	NM_178014.4(TUBB):c.448C>T (p.Leu150Phe)	TUBB	Likely pathogenic	criteria provided, single submitter
976678	NM_178014.4(TUBB):c.139A>G (p.Ile47Val)	TUBB	Likely pathogenic	criteria provided, single submitter
1172672	NM_178014.4(TUBB):c.961A>G (p.Met321Val)	TUBB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1308242	NM_178014.4(TUBB):c.352G>T (p.Asp118Tyr)	TUBB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
438586	NM_178014.4(TUBB):c.860C>T (p.Pro287Leu)	TUBB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030361	NM_178014.4(TUBB):c.599A>G (p.Tyr200Cys)	TUBB	Uncertain significance	criteria provided, multiple submitters, no conflicts
1031753	NM_178014.4(TUBB):c.161C>T (p.Ala54Val)	TUBB	Uncertain significance	criteria provided, multiple submitters, no conflicts
1251922	NM_178014.4(TUBB):c.299A>G (p.Asn100Ser)	TUBB	Uncertain significance	criteria provided, multiple submitters, no conflicts
1333849	NM_178014.4(TUBB):c.710C>G (p.Thr237Ser)	TUBB	Uncertain significance	criteria provided, single submitter
1705480	NM_178014.4(TUBB):c.506T>C (p.Val169Ala)	TUBB	Uncertain significance	criteria provided, single submitter
2500912	NM_178014.4(TUBB):c.852del (p.Thr285fs)	TUBB	Uncertain significance	criteria provided, single submitter
2572464	NM_178014.4(TUBB):c.443G>C (p.Gly148Ala)	TUBB	Uncertain significance	criteria provided, single submitter
3237496	NM_178014.4(TUBB):c.801G>T (p.Met267Ile)	TUBB	Uncertain significance	criteria provided, single submitter
3899279	NM_178014.4(TUBB):c.421G>A (p.Gly141Arg)	TUBB	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 1 · 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
TUBB	Strong	Autosomal dominant	complex cortical dysplasia with other brain malformations 6	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TUBB	Orphanet:2505	Multiple benign circumferential skin creases on limbs

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
TUBB	HGNC:20778	ENSG00000196230	P07437	Tubulin beta chain	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.

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)
TUBB	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
TUBB	133	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
TUBB	1,512

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TUBB	P07437	21

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 24. 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
Centrosome maturation	1	253.8×	0.018	TUBB
Loss of Nlp from mitotic centrosomes	1	158.6×	0.018	TUBB
Loss of proteins required for interphase microtubule organization from the centrosome	1	158.6×	0.018	TUBB
AURKA Activation by TPX2	1	152.3×	0.018	TUBB
Recruitment of mitotic centrosome proteins and complexes	1	135.9×	0.018	TUBB
Regulation of PLK1 Activity at G2/M Transition	1	126.9×	0.018	TUBB
Mitotic G2-G2/M phases	1	126.9×	0.018	TUBB
G2/M Transition	1	126.9×	0.018	TUBB
Recruitment of NuMA to mitotic centrosomes	1	116.5×	0.018	TUBB
Potential therapeutics for SARS	1	114.2×	0.018	TUBB
Anchoring of the basal body to the plasma membrane	1	113.1×	0.018	TUBB
Cilium Assembly	1	108.8×	0.018	TUBB
Mitotic Prometaphase	1	69.2×	0.024	TUBB
Organelle biogenesis and maintenance	1	66.0×	0.024	TUBB
M Phase	1	66.0×	0.024	TUBB
SARS-CoV Infections	1	55.4×	0.027	TUBB
Cell Cycle, Mitotic	1	48.2×	0.029	TUBB
Cell Cycle	1	36.0×	0.037	TUBB
Viral Infection Pathways	1	30.8×	0.041	TUBB
Innate Immune System	1	25.5×	0.046	TUBB
Infectious disease	1	24.8×	0.046	TUBB
Neutrophil degranulation	1	23.1×	0.047	TUBB
Disease	1	13.1×	0.077	TUBB
Immune System	1	13.0×	0.077	TUBB

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
odontoblast differentiation	1	2106.5×	0.003	TUBB
microtubule-based process	1	991.3×	0.003	TUBB
cytoskeleton-dependent intracellular transport	1	936.2×	0.003	TUBB
regulation of synapse organization	1	648.1×	0.003	TUBB
spindle assembly	1	443.5×	0.003	TUBB
natural killer cell mediated cytotoxicity	1	432.1×	0.003	TUBB
mitotic cell cycle	1	133.8×	0.009	TUBB
microtubule cytoskeleton organization	1	121.2×	0.009	TUBB
cell division	1	46.2×	0.022	TUBB

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
TUBB	COLCHICINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TUBB	22	4

Drugs targeting cohort genes (top 30)

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

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TUBB	1,780	Binding:1740, 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
TUBB	1,780

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

22 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	TUBB
VINBLASTINE	4	TUBB
LEVOFLOXACIN ANHYDROUS	4	TUBB
DOCETAXEL	4	TUBB
NOSCAPINE	4	TUBB
VINBLASTINE SULFATE	4	TUBB
PACLITAXEL	4	TUBB
LEVOFLOXACIN	4	TUBB
VINORELBINE	4	TUBB
TIRBANIBULIN	4	TUBB
PODOFILOX	4	TUBB
VINCRISTINE	4	TUBB
DOCETAXEL ANHYDROUS	4	TUBB
PATUPILONE	3	TUBB
ABT-751	2	TUBB
MAYTANSINE	2	TUBB
DOLASTATIN-10	2	TUBB
INDIBULIN	2	TUBB
PARBENDAZOLE	2	TUBB
NOCODAZOLE	2	TUBB
MOLIBRESIB	2	TUBB
COMBRETASTATIN	1	TUBB

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TUBB
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.