Cerebral cortical dysplasia

Summary

Cerebral cortical dysplasia (MONDO:0017094) is a disease with 6 cohort genes and 3 clinical trials.

At a glance

• Prevalence: Unknown (Worldwide)
• Cohort genes: 6
• ClinVar variants: 6
• Clinical trials: 3

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cerebral cortical dysplasia
Mondo ID	MONDO:0017094
MeSH	D054220
Orphanet	268950
ICD-11	1352548261
NCIT	C42088
SNOMED CT	253153000
UMLS	C0431380
MedGen	98129
GARD	0020982
Is cancer (heuristic)	no

Also known as: brain cortical dysplasia · cortical dysplasia

Data availability: 6 ClinVar variants · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › cerebral cortical dysplasia

Related subtypes (70): leukoencephalopathy, megalencephalic, encephalopathy, acute, infection-induced, diabetic encephalopathy, complex cortical dysplasia with other brain malformations, hydrocephalus, brain compression, cerebral sarcoidosis, hepatic encephalopathy, visual pathway disorder, central nervous system origin vertigo, cerebellar disorder, cerebritis, olfactory nerve disorder, thalamic disorder, pituitary gland disorder, disorder of optic chiasm, basal ganglia disorder, epilepsy, mental disorder, central nervous system cyst, migraine disorder, multiple sclerosis, prion disease, carbon monoxide-induced delayed encephalopathy, cerebral malaria, akinetic mutism, bulbar polio, Reye syndrome, brain edema, encephalomalacia, intracranial hypertension, intracranial hypotension, Wernicke encephalopathy, encephalopathy, recurrent, of childhood, XK aprosencephaly, progressive bulbar palsy, cerebrovascular disorder, glycine encephalopathy, autosomal recessive frontotemporal pachygyria, occipital pachygyria and polymicrogyria, insomnia, narcolepsy-cataplexy syndrome, megalencephaly, meningoencephalocele, encephaloclastic disorder, bilirubin encephalopathy, autoimmune encephalopathy with parasomnia and obstructive sleep apnea, narcolepsy without cataplexy, hypothalamic hamartomas with gelastic seizures, encephalitis, cerebral lipidosis with dementia, brain neoplasm, colpocephaly, corpus callosum agenesis of blepharophimosis robin type, corpus callosum dysgenesis X-linked recessive, corpus callosum dysgenesis cleft spasm, corpus callosum dysgenesis hypopituitarism, cerebral degeneration, acute bilirubin encephalopathy, chronic bilirubin encephalopathy, atelencephaly, aprosencephaly, brain injury, traumatic encephalopathy, cluster headache syndrome, cerebral cortex disorder, midbrain disorder, encephalopathy due to mitochondrial and peroxisomal fission defect, brain malformations with or without urinary tract defects, encephalopathy, acute transient

Subtypes (2): central bilateral macrogyria, isolated focal cortical dysplasia

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

6 retrieved; paginated sample, class counts are floors:

4 likely pathogenic, 1 uncertain significance, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
49135	NM_000368.5(TSC1):c.989dup (p.Ser331fs)	TSC1	Pathogenic	criteria provided, multiple submitters, no conflicts
4076967	NM_001242896.3(DEPDC5):c.279+1G>T	DEPDC5	Likely pathogenic	criteria provided, single submitter
183311	NM_020223.4(FAM20C):c.1225C>T (p.Arg409Cys)	FAM20C	Likely pathogenic	no assertion criteria provided
3384044	NM_004522.3(KIF5C):c.404A>G (p.Tyr135Cys)	KIF5C	Likely pathogenic	criteria provided, multiple submitters, no conflicts
523684	NM_006593.4(TBR1):c.1652dup (p.Gln552fs)	TBR1	Likely pathogenic	criteria provided, single submitter
267862	46;XY;t(1;3)(p22;q21)dn		Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 1 · Orphanet: 10 · 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
PLXNC1	Limited	Autosomal dominant	cerebral cortical dysplasia

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TBR1	Orphanet:1617	Developmental delay-language impairment-dopa responsive dystonia-parkinsonism syndrome due to 2q24 microdeletion
TBR1	Orphanet:528084	Non-specific syndromic intellectual disability
TSC1	Orphanet:210159	Adult hepatocellular carcinoma
TSC1	Orphanet:269008	Isolated focal cortical dysplasia type IIb
TSC1	Orphanet:538	Lymphangioleiomyomatosis
TSC1	Orphanet:805	Tuberous sclerosis complex
DEPDC5	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
DEPDC5	Orphanet:98784	Sleep-related hypermotor epilepsy
DEPDC5	Orphanet:98820	Familial focal epilepsy with variable foci
FAM20C	Orphanet:1832	Osteosclerotic bone dysplasia

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PLXNC1	HGNC:9106	ENSG00000136040	O60486	Plexin-C1	gencc
TBR1	HGNC:11590	ENSG00000136535	Q16650	T-box brain protein 1	clinvar
TSC1	HGNC:12362	ENSG00000165699	Q92574	Hamartin	clinvar
DEPDC5	HGNC:18423	ENSG00000100150	O75140	GATOR1 complex protein DEPDC5	clinvar
FAM20C	HGNC:22140	ENSG00000177706	Q8IXL6	Extracellular serine/threonine protein kinase FAM20C	clinvar
KIF5C	HGNC:6325	ENSG00000168280	O60282	Kinesin heavy chain isoform 5C	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PLXNC1	Plexin-C1	Receptor for SEMA7A, for smallpox semaphorin A39R, vaccinia virus semaphorin A39R and for herpesvirus Sema protein.
TBR1	T-box brain protein 1	Transcriptional repressor involved in multiple aspects of cortical development, including neuronal migration, laminar and areal identity, and axonal projection.
TSC1	Hamartin	Non-catalytic component of the TSC-TBC complex, a multiprotein complex that acts as a negative regulator of the canonical mTORC1 complex, an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolec…
DEPDC5	GATOR1 complex protein DEPDC5	As a component of the GATOR1 complex functions as an inhibitor of the amino acid-sensing branch of the mTORC1 pathway.
FAM20C	Extracellular serine/threonine protein kinase FAM20C	Golgi serine/threonine protein kinase that phosphorylates secretory pathway proteins within Ser-x-Glu/pSer motifs and plays a key role in biomineralization of bones and teeth.
KIF5C	Kinesin heavy chain isoform 5C	Microtubule-associated force-producing protein that may play a role in organelle transport.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 4 · Druggable fraction: 0.17

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
Antibody/Immunoglobulin	1	4.9×	0.539
Transcription factor	1	1.4×	0.539
Other/Unknown	4	1.2×	0.539

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PLXNC1	Antibody/Immunoglobulin	yes		Semap_dom, Plexin_repeat, IPT_dom
TBR1	Transcription factor	no		TF_T-box, p53-like_TF_DNA-bd_sf, TF_T-box_CS
TSC1	Other/Unknown	no		Hamartin
DEPDC5	Other/Unknown	no		DEP_dom, IML1, WH-like_DNA-bd_sf
FAM20C	Other/Unknown	no		FAM20_C, FAM20
KIF5C	Other/Unknown	no		Kinesin_motor_dom, Kinesin_motor_CS, P-loop_NTPase

Expression context

Cohort genes with no expression data: 0.

6 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 10	2
frontal pole	2
paraflocculus	2
blood	1
bone marrow cell	1
buccal mucosa cell	1
cortical plate	1
ganglionic eminence	1
gluteal muscle	1
lateral globus pallidus	1
substantia nigra pars compacta	1
middle frontal gyrus	1
adult mammalian kidney	1
lower esophagus muscularis layer	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PLXNC1	279	ubiquitous	marker	buccal mucosa cell, blood, bone marrow cell
TBR1	58	tissue_specific	marker	cortical plate, ganglionic eminence, Brodmann (1909) area 10
TSC1	297	ubiquitous	marker	substantia nigra pars compacta, gluteal muscle, lateral globus pallidus
DEPDC5	236	ubiquitous	marker	paraflocculus, frontal pole, middle frontal gyrus
FAM20C	134	ubiquitous	marker	right lobe of liver, adult mammalian kidney, lower esophagus muscularis layer
KIF5C	229	broad	marker	Brodmann (1909) area 10, paraflocculus, frontal pole

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TSC1	5,445
KIF5C	2,900
TBR1	2,438
FAM20C	1,530
DEPDC5	1,273
PLXNC1	1,118

Structural data

PDB: 4 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DEPDC5	O75140	11
TSC1	Q92574	5
PLXNC1	O60486	4
FAM20C	Q8IXL6	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KIF5C	O60282	78.70
TBR1	Q16650	56.17

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 6 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Inhibition of TSC complex formation by AKT (PKB)	1	456.8×	0.026	TSC1
Other semaphorin interactions	1	120.2×	0.038	PLXNC1
Insulin processing	1	91.4×	0.038	KIF5C
Energy dependent regulation of mTOR by LKB1-AMPK	1	78.8×	0.038	TSC1
Peptide hormone metabolism	1	54.4×	0.038	KIF5C
TBC/RABGAPs	1	51.9×	0.038	TSC1
Amino acids regulate mTORC1	1	40.1×	0.042	DEPDC5
TP53 Regulates Metabolic Genes	1	25.9×	0.057	TSC1
Macroautophagy	1	23.1×	0.057	TSC1
Post-translational protein phosphorylation	1	20.0×	0.059	FAM20C
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	17.3×	0.062	FAM20C
Metabolism of proteins	1	2.5×	0.344	KIF5C

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
specification of animal organ identity	1	2808.7×	0.007	TBR1
regulation of phosphorus metabolic process	1	2808.7×	0.007	FAM20C
negative regulation of TORC1 signaling	2	108.0×	0.007	TSC1, DEPDC5
cerebral cortex development	2	68.5×	0.007	TBR1, TSC1
osteoclast maturation	1	1404.3×	0.010	FAM20C
conditioned taste aversion	1	936.2×	0.010	TBR1
memory T cell differentiation	1	936.2×	0.010	TSC1
anterograde dendritic transport of messenger ribonucleoprotein complex	1	936.2×	0.010	KIF5C
cellular response to decreased oxygen levels	1	702.2×	0.011	TSC1
organelle organization	1	561.7×	0.011	KIF5C
amygdala development	1	468.1×	0.011	TBR1
commitment of neuronal cell to specific neuron type in forebrain	1	468.1×	0.011	TBR1
regulation of fibroblast growth factor receptor signaling pathway	1	401.2×	0.011	FAM20C
anterograde dendritic transport of neurotransmitter receptor complex	1	401.2×	0.011	KIF5C
regulation of axon guidance	1	401.2×	0.011	TBR1
intracellular mRNA localization	1	351.1×	0.011	KIF5C
odontoblast differentiation	1	351.1×	0.011	FAM20C
dentinogenesis	1	351.1×	0.011	FAM20C
anterograde axonal protein transport	1	351.1×	0.011	KIF5C
regulation of synapse pruning	1	351.1×	0.011	PLXNC1
negative regulation of ATP-dependent activity	1	280.9×	0.012	TSC1
negative regulation of cell size	1	280.9×	0.012	TSC1
regulation of cell-matrix adhesion	1	216.1×	0.015	TSC1
enamel mineralization	1	200.6×	0.016	FAM20C
negative regulation of macroautophagy	1	187.2×	0.016	TSC1
hindbrain development	1	187.2×	0.016	TBR1
regulation of stress fiber assembly	1	165.2×	0.017	TSC1
obsolete D-glucose import	1	140.4×	0.019	TSC1
synaptic vesicle transport	1	140.4×	0.019	KIF5C
activation of GTPase activity	1	122.1×	0.021	TSC1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 6

Druggability breadth: 2 of 6 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PLXNC1	0	0
TBR1	0	0
TSC1	0	0
DEPDC5	0	0
FAM20C	0	0
KIF5C	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
KIF5C	3	Binding:3
FAM20C	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; 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	PLXNC1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	5	TBR1, TSC1, DEPDC5, FAM20C, KIF5C

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PLXNC1	0	—
TBR1	0	—
TSC1	0	—
DEPDC5	0	—
FAM20C	2	—
KIF5C	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06915649	Not specified	RECRUITING	Exploration and Evaluation of Amygdalo-Hippocampectomy According to Prof. Coubes’ Technique: An Anatomical, Clinical, and Educational Approach
NCT02261753	Not specified	TERMINATED	Evaluating Dietary Intervention Before surgicaL Treatment for Epilepsy
NCT02654340	Not specified	TERMINATED	Biomarkers for Tuberous Sclerosis Complex (BioTuScCom)