Classic lissencephaly

Summary

Classic lissencephaly (MONDO:0015146) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 4

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	classic lissencephaly
Mondo ID	MONDO:0015146
Orphanet	102009
ICD-11	570001324
UMLS	C0431375
MedGen	98463
GARD	0005049
Is cancer (heuristic)	no

Also known as: ILS · lissencephaly classic · lissencephaly sequence isolated · lissencephaly type 1

Data availability: 4 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 › classic lissencephaly

Related subtypes (14): craniotelencephalic dysplasia, X-linked lissencephaly with abnormal genitalia, lissencephaly 7 with cerebellar hypoplasia, lissencephaly 8, lissencephaly type 3, 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): Miller-Dieker lissencephaly syndrome, lissencephaly type 1 due to doublecortin gene mutation, lissencephaly due to LIS1 mutation, isolated lissencephaly type 1 without known genetic defects

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

4 retrieved; paginated sample, class counts are floors:

2 pathogenic, 1 likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2413703	NM_002291.3(LAMB1):c.4188+1G>C	LAMB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2682216	NC_000007.13:g.(107626809_107635331)_(107635406_107638801)del	LAMB1	Pathogenic	criteria provided, single submitter
3907425	NM_002291.3(LAMB1):c.5066_5072delCTTTAGA	LAMB1	Pathogenic	criteria provided, single submitter
1605218	NM_000430.4(PAFAH1B1):c.1070C>G (p.Ala357Gly)	PAFAH1B1	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LAMB1	Orphanet:352682	Cobblestone lissencephaly without muscular or ocular involvement
PAFAH1B1	Orphanet:217385	17p13.3 microduplication syndrome
PAFAH1B1	Orphanet:531	Miller-Dieker syndrome
PAFAH1B1	Orphanet:95232	Lissencephaly due to LIS1 mutation
PAFAH1B1	Orphanet:99796	Subcortical band heterotopia

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
LAMB1	HGNC:6486	ENSG00000091136	P07942	Laminin subunit beta-1	clinvar
PAFAH1B1	HGNC:8574	ENSG00000007168	P43034	Platelet-activating factor acetylhydrolase IB subunit beta	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LAMB1	Laminin subunit beta-1	Binding to cells via a high affinity receptor, laminin is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components.
PAFAH1B1	Platelet-activating factor acetylhydrolase IB subunit beta	Regulatory subunit (beta subunit) of the cytosolic type I platelet-activating factor (PAF) acetylhydrolase (PAF-AH (I)), an enzyme that catalyzes the hydrolyze of the acetyl group at the sn-2 position of PAF and its analogs and participate…

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Scaffold/PPI	1	8.6×	0.225
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LAMB1	Other/Unknown	no		EGF, LE_dom, Laminin_N
PAFAH1B1	Scaffold/PPI	no		WD40_rpt, LisH, WD40/YVTN_repeat-like_dom_sf

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
nerve	1
omental fat pad	1
tibial nerve	1
male germ cell	1
middle temporal gyrus	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LAMB1	284	ubiquitous	marker	nerve, tibial nerve, omental fat pad
PAFAH1B1	295	ubiquitous	marker	sperm, male germ cell, middle temporal gyrus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PAFAH1B1	3,181
LAMB1	1,970

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PAFAH1B1	P43034	21
LAMB1	P07942	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 56. 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
MET promotes cell motility	1	300.5×	0.035	LAMB1
Attachment of bacteria to epithelial cells	1	248.3×	0.035	LAMB1
Laminin interactions	1	190.3×	0.035	LAMB1
MET activates PTK2 signaling	1	190.3×	0.035	LAMB1
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	184.2×	0.035	LAMB1
Signaling by MET	1	158.6×	0.035	LAMB1
Formation of the dystrophin-glycoprotein complex (DGC)	1	154.3×	0.035	LAMB1
Centrosome maturation	1	126.9×	0.035	PAFAH1B1
Developmental Lineage of Pancreatic Ductal Cells	1	114.2×	0.035	LAMB1
COPI-independent Golgi-to-ER retrograde traffic	1	103.8×	0.035	PAFAH1B1
Amplification of signal from the kinetochores	1	98.5×	0.035	PAFAH1B1
Loss of Nlp from mitotic centrosomes	1	79.3×	0.035	PAFAH1B1
Loss of proteins required for interphase microtubule organization from the centrosome	1	79.3×	0.035	PAFAH1B1
Mitotic Spindle Checkpoint	1	79.3×	0.035	PAFAH1B1
Non-integrin membrane-ECM interactions	1	77.2×	0.035	LAMB1
AURKA Activation by TPX2	1	76.1×	0.035	PAFAH1B1
ECM proteoglycans	1	75.1×	0.035	LAMB1
Recruitment of mitotic centrosome proteins and complexes	1	68.0×	0.035	PAFAH1B1
Golgi-to-ER retrograde transport	1	66.4×	0.035	PAFAH1B1
Regulation of PLK1 Activity at G2/M Transition	1	63.4×	0.035	PAFAH1B1
Mitotic G2-G2/M phases	1	63.4×	0.035	PAFAH1B1
G2/M Transition	1	63.4×	0.035	PAFAH1B1
L1CAM interactions	1	60.1×	0.035	LAMB1
Degradation of the extracellular matrix	1	58.9×	0.035	LAMB1
Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal	1	58.3×	0.035	PAFAH1B1
Recruitment of NuMA to mitotic centrosomes	1	58.3×	0.035	PAFAH1B1
Anchoring of the basal body to the plasma membrane	1	56.5×	0.035	PAFAH1B1
Cilium Assembly	1	54.4×	0.035	PAFAH1B1
Intra-Golgi and retrograde Golgi-to-ER traffic	1	52.4×	0.035	PAFAH1B1
Post-translational protein phosphorylation	1	50.1×	0.035	LAMB1

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
neuronal-glial interaction involved in cerebral cortex radial glia guided migration	1	8426.0×	0.004	LAMB1
platelet activating factor metabolic process	1	2808.7×	0.004	PAFAH1B1
microtubule sliding	1	2808.7×	0.004	PAFAH1B1
nuclear membrane disassembly	1	2808.7×	0.004	PAFAH1B1
microtubule cytoskeleton organization involved in establishment of planar polarity	1	2808.7×	0.004	PAFAH1B1
ameboidal-type cell migration	1	2106.5×	0.004	PAFAH1B1
establishment of planar polarity of embryonic epithelium	1	2106.5×	0.004	PAFAH1B1
myeloid leukocyte migration	1	2106.5×	0.004	PAFAH1B1
radial glia-guided pyramidal neuron migration	1	2106.5×	0.004	PAFAH1B1
maintenance of centrosome location	1	1404.3×	0.005	PAFAH1B1
regulation of basement membrane organization	1	1404.3×	0.005	LAMB1
corpus callosum morphogenesis	1	1203.7×	0.005	PAFAH1B1
osteoclast development	1	1053.2×	0.005	PAFAH1B1
stem cell division	1	936.2×	0.005	PAFAH1B1
cortical microtubule organization	1	936.2×	0.005	PAFAH1B1
auditory receptor cell development	1	936.2×	0.005	PAFAH1B1
positive regulation of cytokine-mediated signaling pathway	1	842.6×	0.005	PAFAH1B1
establishment of centrosome localization	1	842.6×	0.005	PAFAH1B1
retrograde axonal transport	1	766.0×	0.005	PAFAH1B1
interneuron migration	1	766.0×	0.005	PAFAH1B1
microtubule organizing center organization	1	702.2×	0.005	PAFAH1B1
positive regulation of integrin-mediated signaling pathway	1	648.1×	0.005	LAMB1
cerebral cortex neuron differentiation	1	601.9×	0.005	PAFAH1B1
reelin-mediated signaling pathway	1	601.9×	0.005	PAFAH1B1
layer formation in cerebral cortex	1	561.7×	0.005	PAFAH1B1
positive regulation of embryonic development	1	561.7×	0.005	PAFAH1B1
positive regulation of muscle cell differentiation	1	561.7×	0.005	LAMB1
microtubule-based process	1	495.6×	0.005	PAFAH1B1
vesicle transport along microtubule	1	443.5×	0.005	PAFAH1B1
positive regulation of dendritic spine morphogenesis	1	443.5×	0.005	PAFAH1B1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LAMB1	0	0
PAFAH1B1	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
LAMB1	1	Binding:1

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	LAMB1, PAFAH1B1

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)
LAMB1	1	—
PAFAH1B1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.