Lissencephaly type 3

Summary

Lissencephaly type 3 (MONDO:0015148) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 8

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	lissencephaly type 3
Mondo ID	MONDO:0015148
Orphanet	102011
DOID	DOID:0112232
ICD-11	1533765623
UMLS	C1969029
MedGen	369910
GARD	0019821
Is cancer (heuristic)	no

Data availability: 8 ClinVar variants.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › lissencephaly spectrum disorders › lissencephaly type 3

Related subtypes (14): craniotelencephalic dysplasia, X-linked lissencephaly with abnormal genitalia, lissencephaly 7 with cerebellar hypoplasia, lissencephaly 8, classic lissencephaly, microlissencephaly, Warburg micro syndrome, Baraitser-Winter cerebrofrontofacial syndrome, cobblestone lissencephaly, lissencephaly with cerebellar hypoplasia, lissencephaly 10, cortical dysplasia, complex, with other brain malformations 9, massa casaer ceulemans syndrome, lissencephaly spectrum disorder with complex brainstem malformation

Subtypes (4): Neu-Laxova syndrome, lissencephaly type 3-metacarpal bone dysplasia syndrome, lissencephaly due to TUBA1A mutation, lissencephaly type 3-familial fetal akinesia sequence syndrome

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

8 retrieved; paginated sample, class counts are floors:

4 pathogenic, 2 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
279750	NM_018451.5(CPAP):c.289dup (p.Thr97fs)	CPAP	Pathogenic	criteria provided, multiple submitters, no conflicts
503611	NM_018451.5(CPAP):c.1132C>T (p.Arg378Ter)	CPAP	Pathogenic	criteria provided, multiple submitters, no conflicts
2637677	NM_006009.4(TUBA1A):c.637_640del (p.Cys213fs)	TUBA1A	Pathogenic	criteria provided, single submitter
3063674	NM_006009.4(TUBA1A):c.1225G>T (p.Val409Phe)	TUBA1A	Pathogenic	criteria provided, single submitter
431845	NM_006009.4(TUBA1A):c.235C>T (p.Arg79Cys)	TUBA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
957529	NM_006009.4(TUBA1A):c.878A>G (p.Asn293Ser)	TUBA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265283	NM_006009.4(TUBA1A):c.790C>G (p.Arg264Gly)	TUBA1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3061839	NM_006009.4(TUBA1A):c.1136G>A (p.Ser379Asn)	TUBA1A	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 6 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CPAP	Orphanet:2512	Autosomal recessive primary microcephaly
CPAP	Orphanet:808	Seckel syndrome
TUBA1A	Orphanet:171680	Lissencephaly due to TUBA1A mutation
TUBA1A	Orphanet:45358	Congenital fibrosis of extraocular muscles
TUBA1A	Orphanet:467166	Tubulinopathy-associated dysgyria
TUBA1A	Orphanet:994	Fetal akinesia deformation sequence

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
CPAP	HGNC:17272	ENSG00000151849	Q9HC77	Centrosomal P4.1-associated protein	clinvar
TUBA1A	HGNC:20766	ENSG00000167552	Q71U36	Tubulin alpha-1A chain	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CPAP	Centrosomal P4.1-associated protein	Plays an important role in cell division and centrosome function by participating in centriole duplication.
TUBA1A	Tubulin alpha-1A 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: 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)
CPAP	Other/Unknown	no		CENPJ_C_dom, TCP10L/CENPJ, Tcp10_C_sf
TUBA1A	Other/Unknown	no		Tubulin, Alpha_tubulin, Tubulin_FtsZ_GTPase

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
left lobe of thyroid gland	1
right lobe of thyroid gland	1
sperm	1
cortical plate	1
endothelial cell	1
ganglionic eminence	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CPAP	246	ubiquitous	marker	sperm, left lobe of thyroid gland, right lobe of thyroid gland
TUBA1A	288	ubiquitous	marker	endothelial cell, cortical plate, ganglionic eminence

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CPAP	2,242
TUBA1A	1,436

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TUBA1A	Q71U36	15
CPAP	Q9HC77	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 94. 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
Loss of Nlp from mitotic centrosomes	2	158.6×	0.001	CPAP, TUBA1A
Loss of proteins required for interphase microtubule organization from the centrosome	2	158.6×	0.001	CPAP, TUBA1A
AURKA Activation by TPX2	2	152.3×	0.001	CPAP, TUBA1A
Recruitment of mitotic centrosome proteins and complexes	2	135.9×	0.001	CPAP, TUBA1A
Regulation of PLK1 Activity at G2/M Transition	2	126.9×	0.001	CPAP, TUBA1A
Recruitment of NuMA to mitotic centrosomes	2	116.5×	0.001	CPAP, TUBA1A
Anchoring of the basal body to the plasma membrane	2	113.1×	0.001	CPAP, TUBA1A
Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane	1	271.9×	0.026	TUBA1A
Transport of connexons to the plasma membrane	1	271.9×	0.026	TUBA1A
TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain	1	259.6×	0.026	CPAP
Gap junction trafficking and regulation	1	237.9×	0.026	TUBA1A
Gap junction trafficking	1	237.9×	0.026	TUBA1A
Post-chaperonin tubulin folding pathway	1	237.9×	0.026	TUBA1A
Formation of tubulin folding intermediates by CCT/TriC	1	211.5×	0.026	TUBA1A
Cooperation of Prefoldin and TriC/CCT in actin and tubulin folding	1	203.9×	0.026	TUBA1A
Prefoldin mediated transfer of substrate to CCT/TriC	1	196.9×	0.026	TUBA1A
Activation of AMPK downstream of NMDARs	1	190.3×	0.026	TUBA1A
RHO GTPases activate IQGAPs	1	173.0×	0.026	TUBA1A
Sealing of the nuclear envelope (NE) by ESCRT-III	1	173.0×	0.026	TUBA1A
HCMV Infection	1	163.1×	0.026	TUBA1A
Chaperonin-mediated protein folding	1	150.3×	0.026	TUBA1A
Gap junction assembly	1	146.4×	0.026	TUBA1A
Nuclear Envelope (NE) Reassembly	1	146.4×	0.026	TUBA1A
Selective autophagy	1	139.3×	0.026	TUBA1A
Protein folding	1	129.8×	0.026	TUBA1A
Centrosome maturation	1	126.9×	0.026	TUBA1A
Assembly and cell surface presentation of NMDA receptors	1	126.9×	0.026	TUBA1A
Cargo trafficking to the periciliary membrane	1	124.1×	0.026	TUBA1A
Aggrephagy	1	124.1×	0.026	TUBA1A
Carboxyterminal post-translational modifications of tubulin	1	119.0×	0.026	TUBA1A

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
microtubule polymerization	2	887.0×	6e-05	CPAP, TUBA1A
smoothened signaling pathway	2	181.2×	8e-04	CPAP, TUBA1A
astral microtubule nucleation	1	8426.0×	0.002	CPAP
centriole elongation	1	2106.5×	0.004	CPAP
pyramidal neuron differentiation	1	1685.2×	0.004	TUBA1A
positive regulation of centriole replication	1	1685.2×	0.004	CPAP
cerebellar cortex morphogenesis	1	1404.3×	0.004	TUBA1A
positive regulation of establishment of protein localization	1	1404.3×	0.004	CPAP
positive regulation of centriole elongation	1	1203.7×	0.004	CPAP
positive regulation of spindle assembly	1	1053.2×	0.004	CPAP
neuron projection arborization	1	936.2×	0.004	TUBA1A
positive regulation of non-motile cilium assembly	1	936.2×	0.004	CPAP
regulation of centriole replication	1	842.6×	0.004	CPAP
response to L-glutamate	1	842.6×	0.004	TUBA1A
cell division	2	46.2×	0.004	CPAP, TUBA1A
forebrain morphogenesis	1	702.2×	0.004	TUBA1A
organelle transport along microtubule	1	601.9×	0.005	TUBA1A
startle response	1	561.7×	0.005	TUBA1A
microtubule-based process	1	495.6×	0.005	TUBA1A
locomotory exploration behavior	1	495.6×	0.005	TUBA1A
cytoskeleton-dependent intracellular transport	1	468.1×	0.005	TUBA1A
glial cell differentiation	1	443.5×	0.005	TUBA1A
regulation of mitotic spindle organization	1	421.3×	0.005	CPAP
centriole replication	1	366.4×	0.006	CPAP
regulation of synapse organization	1	324.1×	0.006	TUBA1A
microtubule nucleation	1	312.1×	0.006	CPAP
dentate gyrus development	1	312.1×	0.006	TUBA1A
response to tumor necrosis factor	1	312.1×	0.006	TUBA1A
motile cilium assembly	1	290.6×	0.006	CPAP
motor behavior	1	280.9×	0.006	TUBA1A

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
TUBA1A	COLCHICINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TUBA1A	22	4
CPAP	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
COLCHICINE	4	TUBA1A
VINBLASTINE	4	TUBA1A
LEVOFLOXACIN ANHYDROUS	4	TUBA1A
DOCETAXEL	4	TUBA1A
NOSCAPINE	4	TUBA1A
VINBLASTINE SULFATE	4	TUBA1A
PACLITAXEL	4	TUBA1A
LEVOFLOXACIN	4	TUBA1A
VINORELBINE	4	TUBA1A
TIRBANIBULIN	4	TUBA1A
PODOFILOX	4	TUBA1A
VINCRISTINE	4	TUBA1A
DOCETAXEL ANHYDROUS	4	TUBA1A
PATUPILONE	3	TUBA1A
ABT-751	2	TUBA1A
MAYTANSINE	2	TUBA1A
DOLASTATIN-10	2	TUBA1A
INDIBULIN	2	TUBA1A
PARBENDAZOLE	2	TUBA1A
NOCODAZOLE	2	TUBA1A
MOLIBRESIB	2	TUBA1A
COMBRETASTATIN	1	TUBA1A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TUBA1A	1,696	Binding:1655, Functional:35, ADMET:6

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
TUBA1A	1,696

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

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	TUBA1A
VINBLASTINE	4	TUBA1A
LEVOFLOXACIN ANHYDROUS	4	TUBA1A
DOCETAXEL	4	TUBA1A
NOSCAPINE	4	TUBA1A
VINBLASTINE SULFATE	4	TUBA1A
PACLITAXEL	4	TUBA1A
LEVOFLOXACIN	4	TUBA1A
VINORELBINE	4	TUBA1A
TIRBANIBULIN	4	TUBA1A
PODOFILOX	4	TUBA1A
VINCRISTINE	4	TUBA1A
DOCETAXEL ANHYDROUS	4	TUBA1A
PATUPILONE	3	TUBA1A
ABT-751	2	TUBA1A
MAYTANSINE	2	TUBA1A
DOLASTATIN-10	2	TUBA1A
INDIBULIN	2	TUBA1A
PARBENDAZOLE	2	TUBA1A
NOCODAZOLE	2	TUBA1A
MOLIBRESIB	2	TUBA1A
COMBRETASTATIN	1	TUBA1A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TUBA1A
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	1	CPAP

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CPAP	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.