Cobblestone lissencephaly without muscular or ocular involvement

Summary

Cobblestone lissencephaly without muscular or ocular involvement (MONDO:0014077) is a disease caused by LAMB1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: LAMB1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 61
• Phenotypes (HPO): 13

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		6	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0000238	Hydrocephalus	Frequent (30-79%)
HP:0000648	Optic atrophy	Frequent (30-79%)
HP:0001321	Cerebellar hypoplasia	Frequent (30-79%)
HP:0002085	Occipital encephalocele	Frequent (30-79%)
HP:0002282	Gray matter heterotopia	Frequent (30-79%)
HP:0002365	Hypoplasia of the brainstem	Frequent (30-79%)
HP:0002500	Abnormal cerebral white matter morphology	Frequent (30-79%)
HP:0007260	Type II lissencephaly	Frequent (30-79%)
HP:0011344	Severe global developmental delay	Frequent (30-79%)
HP:0012447	Abnormal myelination	Frequent (30-79%)
HP:0032398	Dysgyria	Frequent (30-79%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0003457	EMG abnormality	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	cobblestone lissencephaly without muscular or ocular involvement
Mondo ID	MONDO:0014077
OMIM	615191
Orphanet	352682
DOID	DOID:0112230
UMLS	C3554657
MedGen	767571
GARD	0017526
Is cancer (heuristic)	no

Also known as: cobblestone lissencephaly without muscular or eye involvement · cobblestone lissencephaly without muscular or ocular involvement · LIS5 · lissencephaly 5 · lissencephaly type 2 without muscular or eye involvement · lissencephaly type 2 without muscular or ocular involvement · lissencephaly type 5

Data availability: 61 ClinVar variants · 7 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › lissencephaly spectrum disorders › cobblestone lissencephaly › cobblestone lissencephaly without muscular or ocular involvement

Related subtypes (1): muscle-eye-brain disease with bilateral multicystic leucodystrophy

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

61 retrieved; paginated sample, class counts are floors:

33 uncertain significance, 12 pathogenic, 8 likely pathogenic, 6 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1323179	NM_002291.3(LAMB1):c.1752_1756dup (p.Ala586fs)	LAMB1	Pathogenic	criteria provided, single submitter
1427340	NM_002291.3(LAMB1):c.1189C>T (p.Arg397Ter)	LAMB1	Pathogenic	criteria provided, multiple submitters, no conflicts
225687	NM_002291.3(LAMB1):c.2931del (p.Gln977fs)	LAMB1	Pathogenic	no assertion criteria provided
225688	NM_002291.3(LAMB1):c.1442G>T (p.Cys481Phe)	LAMB1	Pathogenic	no assertion criteria provided
2413703	NM_002291.3(LAMB1):c.4188+1G>C	LAMB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2506519	NM_002291.3(LAMB1):c.1526del (p.Pro509fs)	LAMB1	Pathogenic	criteria provided, single submitter
42014	NM_002291.3(LAMB1):c.3145_3158delinsCCAGTGCTTGTGTCTTCCTAATGTGCTTGTGTCTTCCTAAT (p.Lys1049_Gln1053delinsProValLeuValSerSerTer)	LAMB1	Pathogenic	no assertion criteria provided
42015	NM_002291.3(LAMB1):c.2109+1G>T	LAMB1	Pathogenic	no assertion criteria provided
4532054	NM_002291.3(LAMB1):c.3803_3804dup (p.Val1269fs)	LAMB1	Pathogenic	criteria provided, single submitter
4533329	C1182Y	LAMB1	Pathogenic	no assertion criteria provided
4533330	LAMB1, ASN788SER	LAMB1	Pathogenic	no assertion criteria provided
4533331	LAMB1, NT5201_5224+28DEL	LAMB1	Pathogenic	no assertion criteria provided
4533332	LAMB1, EX23-EX24DEL	LAMB1	Pathogenic	no assertion criteria provided
1701785	NM_002291.3(LAMB1):c.4363_4376del (p.Leu1455fs)	LAMB1	Likely pathogenic	criteria provided, single submitter
1701786	NM_002291.3(LAMB1):c.1974_1975dup (p.Pro659fs)	LAMB1	Likely pathogenic	criteria provided, single submitter
2498207	GRCh38/hg38 7q31.1(chr7:107951205-107952243)x0	LAMB1	Likely pathogenic	criteria provided, single submitter
3075956	NM_002291.3(LAMB1):c.1000+1G>T	LAMB1	Likely pathogenic	criteria provided, single submitter
3779807	NM_002291.3(LAMB1):c.963G>A (p.Trp321Ter)	LAMB1	Likely pathogenic	criteria provided, single submitter
4056575	NM_002291.3(LAMB1):c.880-1G>A	LAMB1	Likely pathogenic	criteria provided, single submitter
4532053	NM_002291.3(LAMB1):c.4537+1G>A	LAMB1	Likely pathogenic	criteria provided, single submitter
4849325	NM_002291.3(LAMB1):c.-86-2A>C	LAMB1	Likely pathogenic	criteria provided, single submitter
1353429	NM_002291.3(LAMB1):c.4088G>A (p.Arg1363Gln)	LAMB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3242128	NM_002291.3(LAMB1):c.979C>T (p.Arg327Ter)	LAMB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
709400	NM_002291.3(LAMB1):c.2723T>C (p.Ile908Thr)	LAMB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
930970	NM_002291.3(LAMB1):c.4648C>T (p.Arg1550Ter)	LAMB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
973338	NM_002291.3(LAMB1):c.4277G>C (p.Gly1426Ala)	LAMB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
981899	NM_002291.3(LAMB1):c.2315-28A>G	LAMB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029432	NM_002291.3(LAMB1):c.2092T>A (p.Tyr698Asn)	LAMB1	Uncertain significance	criteria provided, single submitter
1029433	NM_002291.3(LAMB1):c.2402G>A (p.Arg801Lys)	LAMB1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1029434	NM_002291.3(LAMB1):c.4188G>C (p.Met1396Ile)	LAMB1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
LAMB1	Strong	Autosomal recessive	cobblestone lissencephaly without muscular or ocular involvement	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LAMB1	Orphanet:352682	Cobblestone lissencephaly without muscular or ocular involvement

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
LAMB1	HGNC:6486	ENSG00000091136	P07942	Laminin subunit beta-1	gencc,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.

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)
LAMB1	Other/Unknown	no		EGF, LE_dom, Laminin_N

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
nerve	1
omental fat pad	1
tibial nerve	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

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LAMB1	1,970

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LAMB1	P07942	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 22. 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
MET promotes cell motility	1	601.0×	0.010	LAMB1
Attachment of bacteria to epithelial cells	1	496.5×	0.010	LAMB1
Laminin interactions	1	380.7×	0.010	LAMB1
MET activates PTK2 signaling	1	380.7×	0.010	LAMB1
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	368.4×	0.010	LAMB1
Signaling by MET	1	317.2×	0.010	LAMB1
Formation of the dystrophin-glycoprotein complex (DGC)	1	308.6×	0.010	LAMB1
Developmental Lineage of Pancreatic Ductal Cells	1	228.4×	0.012	LAMB1
Non-integrin membrane-ECM interactions	1	154.3×	0.015	LAMB1
ECM proteoglycans	1	150.3×	0.015	LAMB1
L1CAM interactions	1	120.2×	0.016	LAMB1
Degradation of the extracellular matrix	1	117.7×	0.016	LAMB1
Post-translational protein phosphorylation	1	100.2×	0.017	LAMB1
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	86.5×	0.018	LAMB1
Extracellular matrix organization	1	63.1×	0.023	LAMB1
Signaling by Receptor Tyrosine Kinases	1	51.7×	0.027	LAMB1
Axon guidance	1	45.1×	0.028	LAMB1
Nervous system development	1	42.9×	0.028	LAMB1
Post-translational protein modification	1	19.2×	0.060	LAMB1
Developmental Biology	1	14.5×	0.076	LAMB1
Metabolism of proteins	1	12.4×	0.085	LAMB1
Signal Transduction	1	10.2×	0.098	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 1 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	16852.0×	0.001	LAMB1
regulation of basement membrane organization	1	2808.7×	0.003	LAMB1
positive regulation of integrin-mediated signaling pathway	1	1296.3×	0.004	LAMB1
positive regulation of muscle cell differentiation	1	1123.5×	0.004	LAMB1
odontogenesis	1	526.6×	0.005	LAMB1
endodermal cell differentiation	1	495.6×	0.005	LAMB1
negative regulation of cell adhesion	1	383.0×	0.005	LAMB1
embryo implantation	1	351.1×	0.005	LAMB1
substrate adhesion-dependent cell spreading	1	343.9×	0.005	LAMB1
regulation of embryonic development	1	330.4×	0.005	LAMB1
regulation of cell adhesion	1	306.4×	0.005	LAMB1
positive regulation of cell adhesion	1	271.8×	0.006	LAMB1
positive regulation of epithelial cell proliferation	1	244.2×	0.006	LAMB1
regulation of cell migration	1	157.5×	0.008	LAMB1
neuron projection development	1	122.1×	0.010	LAMB1
positive regulation of cell migration	1	61.7×	0.018	LAMB1
cell adhesion	1	37.5×	0.028	LAMB1
signal transduction	1	16.1×	0.062	LAMB1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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

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: 1; 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	1	LAMB1

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)
LAMB1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.