Complex cortical dysplasia with other brain malformations 4

Summary

Complex cortical dysplasia with other brain malformations 4 (MONDO:0014171) is a disease caused by TUBG1 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: TUBG1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 24

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	complex cortical dysplasia with other brain malformations 4
Mondo ID	MONDO:0014171
OMIM	615412
DOID	DOID:0090138
UMLS	C3809420
MedGen	815750
Is cancer (heuristic)	no

Also known as: CDCBM4 · complex cortical dysplasia with other brain malformations caused by mutation in TUBG1 · complex cortical dysplasia with other brain malformations type 4 · cortical dysplasia, complex, with other brain malformations 4 · cortical dysplasia, Complex, with Other brain malformations type 4 · TUBG1 complex cortical dysplasia with other brain malformations

Data availability: 24 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 4

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 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

24 retrieved; paginated sample, class counts are floors:

9 uncertain significance, 7 likely pathogenic, 2 conflicting classifications of pathogenicity, 2 pathogenic, 1 pathogenic/likely pathogenic, 1 benign, 1 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
373145	NM_001070.5(TUBG1):c.1021C>T (p.Arg341Trp)	TUBG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
65397	NM_001070.5(TUBG1):c.1160T>C (p.Leu387Pro)	TUBG1	Pathogenic	no assertion criteria provided
65399	NM_001070.5(TUBG1):c.991A>C (p.Thr331Pro)	TUBG1	Pathogenic	no assertion criteria provided
3338057	NM_001070.5(TUBG1):c.664A>C (p.Asn222His)	RETREG3	Likely pathogenic	criteria provided, single submitter
1526152	NM_001070.5(TUBG1):c.821C>A (p.Thr274Asn)	TUBG1	Likely pathogenic	criteria provided, single submitter
1703182	NM_001070.5(TUBG1):c.725C>T (p.Thr242Ile)	TUBG1	Likely pathogenic	criteria provided, single submitter
2430135	NM_001070.5(TUBG1):c.421A>C (p.Ile141Leu)	TUBG1	Likely pathogenic	criteria provided, single submitter
3236666	NM_001070.5(TUBG1):c.202G>T (p.Asp68Tyr)	TUBG1	Likely pathogenic	criteria provided, single submitter
3376145	NM_001070.5(TUBG1):c.843+2_843+5del	TUBG1	Likely pathogenic	criteria provided, single submitter
65398	NM_001070.5(TUBG1):c.275A>G (p.Tyr92Cys)	TUBG1	Likely pathogenic	criteria provided, single submitter
1916205	NM_001070.5(TUBG1):c.607-7C>T	TUBG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
452987	NM_001070.5(TUBG1):c.1022G>A (p.Arg341Gln)	TUBG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2438438	NM_001070.5(TUBG1):c.459C>T (p.Leu153=)	TUBG1	Uncertain significance	criteria provided, single submitter
2438439	NM_001070.5(TUBG1):c.1157C>T (p.Ser386Leu)	TUBG1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2571995	NM_001070.5(TUBG1):c.757C>T (p.Leu253Phe)	TUBG1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2690399	NM_001070.5(TUBG1):c.1136C>G (p.Ala379Gly)	TUBG1	Uncertain significance	criteria provided, single submitter
3236665	NM_001070.5(TUBG1):c.1131G>T (p.Met377Ile)	TUBG1	Uncertain significance	criteria provided, single submitter
3382385	NM_001070.5(TUBG1):c.931C>T (p.Arg311Cys)	TUBG1	Uncertain significance	criteria provided, single submitter
3393315	NM_001070.5(TUBG1):c.677C>T (p.Ser226Phe)	TUBG1	Uncertain significance	criteria provided, single submitter
4813471	NM_001070.5(TUBG1):c.952A>T (p.Ile318Phe)	TUBG1	Uncertain significance	criteria provided, single submitter
813950	NM_001070.5(TUBG1):c.618C>G (p.Asp206Glu)	TUBG1	Uncertain significance	criteria provided, single submitter
380875	NM_001070.5(TUBG1):c.1029C>G (p.Arg343=)	TUBG1	Benign	criteria provided, multiple submitters, no conflicts
782914	NM_001070.5(TUBG1):c.813C>T (p.Thr271=)	TUBG1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
977875	NM_001070.5(TUBG1):c.925C>T (p.Arg309Ter)	TUBG1	Likely benign	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
TUBG1	Strong	Autosomal dominant	complex cortical dysplasia with other brain malformations 4	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TUBG1	Orphanet:261183	15q11.2 microdeletion 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
TUBG1	HGNC:12417	ENSG00000131462	P23258	Tubulin gamma-1 chain	gencc,clinvar
RETREG3	HGNC:27258	ENSG00000141699	Q86VR2	Reticulophagy regulator 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TUBG1	Tubulin gamma-1 chain	Tubulin is the major constituent of microtubules, protein filaments consisting of alpha- and beta-tubulin heterodimers.
RETREG3	Reticulophagy regulator 3	Endoplasmic reticulum (ER)-anchored autophagy regulator which exists in an inactive state under basal conditions but is activated following cellular stress.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TUBG1	Enzyme (other)	yes	3.6.5.6	Tubulin, Gamma_tubulin, Tubulin_FtsZ_GTPase
RETREG3	Other/Unknown	no		RETREG1/3, RETR3_RHD, RETREG1-3-like_RHD

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adult organism	1
left testis	1
right testis	1
epithelium of nasopharynx	1
nasopharynx	1
parotid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TUBG1	289	ubiquitous	marker	left testis, right testis, adult organism
RETREG3	295	ubiquitous	marker	parotid gland, epithelium of nasopharynx, nasopharynx

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TUBG1	3,048
RETREG3	2,259

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TUBG1	P23258	32

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RETREG3	Q86VR2	61.61

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 2 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×	0.013	TUBG1
Loss of Nlp from mitotic centrosomes	1	158.6×	0.013	TUBG1
Loss of proteins required for interphase microtubule organization from the centrosome	1	158.6×	0.013	TUBG1
AURKA Activation by TPX2	1	152.3×	0.013	TUBG1
Recruitment of mitotic centrosome proteins and complexes	1	135.9×	0.013	TUBG1
Regulation of PLK1 Activity at G2/M Transition	1	126.9×	0.013	TUBG1
Mitotic G2-G2/M phases	1	126.9×	0.013	TUBG1
G2/M Transition	1	126.9×	0.013	TUBG1
Recruitment of NuMA to mitotic centrosomes	1	116.5×	0.013	TUBG1
Anchoring of the basal body to the plasma membrane	1	113.1×	0.013	TUBG1
Cilium Assembly	1	108.8×	0.013	TUBG1
Mitotic Prometaphase	1	69.2×	0.017	TUBG1
Organelle biogenesis and maintenance	1	66.0×	0.017	TUBG1
M Phase	1	66.0×	0.017	TUBG1
Cell Cycle, Mitotic	1	48.2×	0.022	TUBG1
Cell Cycle	1	36.0×	0.028	TUBG1

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
meiotic spindle organization	1	1203.7×	0.009	TUBG1
endoplasmic reticulum tubular network organization	1	561.7×	0.009	RETREG3
reticulophagy	1	351.1×	0.009	RETREG3
microtubule nucleation	1	312.1×	0.009	TUBG1
mitotic sister chromatid segregation	1	240.7×	0.009	TUBG1
collagen catabolic process	1	195.9×	0.009	RETREG3
cytoplasmic microtubule organization	1	172.0×	0.009	TUBG1
mitotic spindle organization	1	135.9×	0.010	TUBG1
positive regulation of neuron projection development	1	68.5×	0.016	RETREG3
mitotic cell cycle	1	66.9×	0.016	TUBG1
microtubule cytoskeleton organization	1	60.6×	0.016	TUBG1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TUBG1	0	0
RETREG3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TUBG1	3.6.5.6	tubulin GTPase

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	1	TUBG1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	RETREG3

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)
TUBG1	0	—
RETREG3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.