Lissencephaly 4

Summary

Lissencephaly 4 (MONDO:0013527) is a disease caused by NDE1 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: NDE1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 139

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	lissencephaly 4
Mondo ID	MONDO:0013527
OMIM	614019
DOID	DOID:0112235
UMLS	C3151461
MedGen	462811
GARD	0024934
Is cancer (heuristic)	no

Also known as: LIS4 · lissencephaly (disease) caused by mutation in NDE1 · lissencephaly 4 · lissencephaly 4 (with microcephaly) · lissencephaly type 4 · NDE1 lissencephaly (disease)

Data availability: 139 ClinVar variants · 4 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 › microlissencephaly › lissencephaly 4

Related subtypes (2): Norman-Roberts syndrome, lissencephaly 6 with microcephaly

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

139 retrieved; paginated sample, class counts are floors:

70 uncertain significance, 20 benign, 17 conflicting classifications of pathogenicity, 16 benign/likely benign, 9 likely benign, 6 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
159015	NM_017668.3(NDE1):c.658C>T (p.Arg220Ter)	NDE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1696425	NM_017668.3(NDE1):c.54G>A (p.Trp18Ter)	NDE1	Pathogenic	no assertion criteria provided
30787	NM_017668.3(NDE1):c.684_685del (p.Pro229fs)	NDE1	Pathogenic	criteria provided, multiple submitters, no conflicts
30789	NM_017668.3(NDE1):c.733dup (p.Leu245fs)	NDE1	Pathogenic	criteria provided, single submitter
435939	NM_017668.3(NDE1):c.83+1G>T	NDE1	Pathogenic	criteria provided, single submitter
620567	NM_017668.3(NDE1):c.109C>T (p.Arg37Ter)	NDE1	Pathogenic	criteria provided, multiple submitters, no conflicts
625823	GRCh37/hg19 16p13.11(chr16:15758011-15761384)	NDE1	Pathogenic	criteria provided, single submitter
201034	NM_002474.3(MYH11):c.4116+11del	MYH11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
201039	NM_002474.3(MYH11):c.5528C>T (p.Ser1843Leu)	MYH11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
201068	NM_002474.3(MYH11):c.3928G>A (p.Val1310Met)	MYH11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
201073	NM_002474.3(MYH11):c.4240G>A (p.Ala1414Thr)	MYH11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
257258	NM_002474.3(MYH11):c.3897C>T (p.Ala1299=)	MYH11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
318120	NM_002474.3(MYH11):c.4116+110C>T	MYH11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
318135	NM_002474.3(MYH11):c.3859-158G>T	MYH11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
159018	NM_017668.3(NDE1):c.744G>A (p.Ala248=)	NDE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
159020	NM_017668.3(NDE1):c.872C>T (p.Ser291Phe)	NDE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
288031	NM_017668.3(NDE1):c.386+9G>A	NDE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
318045	NM_017668.3(NDE1):c.12C>T (p.Ser4=)	NDE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
318052	NM_017668.3(NDE1):c.95C>T (p.Thr32Met)	NDE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
318059	NM_017668.3(NDE1):c.309C>G (p.Thr103=)	NDE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
318063	NM_017668.3(NDE1):c.700C>T (p.Arg234Cys)	NDE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
318064	NM_017668.3(NDE1):c.720C>T (p.Thr240=)	NDE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
386002	NM_017668.3(NDE1):c.624C>T (p.Ala208=)	NDE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
884703	NM_017668.3(NDE1):c.291G>A (p.Glu97=)	NDE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
884574	NM_001143979.1(NDE1):c.-794C>T	MIR484	Uncertain significance	criteria provided, single submitter
884575	NM_001143979.1(NDE1):c.-765C>T	MIR484	Uncertain significance	criteria provided, single submitter
159022	NM_002474.3(MYH11):c.4327G>A (p.Val1443Met)	MYH11	Uncertain significance	criteria provided, multiple submitters, no conflicts
201071	NM_002474.3(MYH11):c.4016G>A (p.Arg1339His)	MYH11	Uncertain significance	criteria provided, multiple submitters, no conflicts
318114	NM_017668.3(NDE1):c.*193G>A	MYH11	Uncertain significance	criteria provided, single submitter
318117	NM_017668.3(NDE1):c.*259G>T	MYH11	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 7 · 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
NDE1	Definitive	Autosomal recessive	lissencephaly 4	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NDE1	Orphanet:2177	Hydranencephaly
NDE1	Orphanet:443162	NDE1-related microhydranencephaly
NDE1	Orphanet:89844	Lissencephaly syndrome, Norman-Roberts type
MYH11	Orphanet:2241	Megacystis-microcolon-intestinal hypoperistalsis syndrome
MYH11	Orphanet:229	Familial aortic dissection
MYH11	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
MYH11	Orphanet:98829	Acute myeloid leukemia with abnormal bone marrow eosinophils inv(16)(p13q22) or t(16;16)(p13;q22)

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NDE1	HGNC:17619	ENSG00000072864	Q9NXR1	Nuclear distribution protein nudE homolog 1	gencc,clinvar
MIR484	HGNC:32341	ENSG00000283736		microRNA 484	clinvar
MYH11	HGNC:7569	ENSG00000133392	P35749	Myosin-11	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NDE1	Nuclear distribution protein nudE homolog 1	Required for centrosome duplication and formation and function of the mitotic spindle.
MYH11	Myosin-11	Muscle contraction.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Scaffold/PPI	1	5.8×	0.327
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NDE1	Other/Unknown	no		NUDE_dom, NUDE
MIR484	Other/Unknown	no
MYH11	Scaffold/PPI	no		IQ_motif_EF-hand-BS, Myosin_head_motor_dom-like, Myosin_tail

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)	1
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
colonic epithelium	1
corpus callosum	1
ventricular zone	1
blood	1
esophagogastric junction muscularis propria	1
right hemisphere of cerebellum	1
lower esophagus	1
lower esophagus muscularis layer	1
right coronary artery	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NDE1	134	ubiquitous	marker	colonic epithelium, ventricular zone, corpus callosum
MIR484	4		yes	blood, esophagogastric junction muscularis propria, right hemisphere of cerebellum
MYH11	143	broad	marker	right coronary artery, lower esophagus, lower esophagus muscularis layer

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MYH11	3,818
NDE1	1,761
MIR484	0

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NDE1	Q9NXR1	1
MYH11	P35749	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 45. Enrichment computed across 3 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
RHO GTPase Effectors	2	68.0×	0.010	NDE1, MYH11
Signaling by Rho GTPases	2	34.2×	0.013	NDE1, MYH11
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	2	33.5×	0.013	NDE1, MYH11
Sema4D in semaphorin signaling	1	335.9×	0.018	MYH11
RHO GTPases activate CIT	1	300.5×	0.018	MYH11
RHO GTPases Activate ROCKs	1	300.5×	0.018	MYH11
Sema4D induced cell migration and growth-cone collapse	1	285.5×	0.018	MYH11
RHO GTPases activate PAKs	1	271.9×	0.018	MYH11
Developmental Lineage of Mammary Gland Myoepithelial Cells	1	271.9×	0.018	MYH11
Semaphorin interactions	1	196.9×	0.021	MYH11
EPHA-mediated growth cone collapse	1	190.3×	0.021	MYH11
RHO GTPases activate PKNs	1	158.6×	0.024	MYH11
Smooth Muscle Contraction	1	132.8×	0.025	MYH11
Centrosome maturation	1	126.9×	0.025	NDE1
Amplification of signal from the kinetochores	1	98.5×	0.028	NDE1
EPH-Ephrin signaling	1	82.8×	0.028	MYH11
Loss of Nlp from mitotic centrosomes	1	79.3×	0.028	NDE1
Loss of proteins required for interphase microtubule organization from the centrosome	1	79.3×	0.028	NDE1
Mitotic Spindle Checkpoint	1	79.3×	0.028	NDE1
AURKA Activation by TPX2	1	76.1×	0.028	NDE1
Signal Transduction	2	10.2×	0.028	NDE1, MYH11
Recruitment of mitotic centrosome proteins and complexes	1	68.0×	0.028	NDE1
Regulation of PLK1 Activity at G2/M Transition	1	63.4×	0.028	NDE1
Mitotic G2-G2/M phases	1	63.4×	0.028	NDE1
G2/M Transition	1	63.4×	0.028	NDE1
Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal	1	58.3×	0.028	NDE1
Recruitment of NuMA to mitotic centrosomes	1	58.3×	0.028	NDE1
Anchoring of the basal body to the plasma membrane	1	56.5×	0.028	NDE1
Cilium Assembly	1	54.4×	0.028	NDE1
Mitotic Metaphase and Anaphase	1	48.4×	0.030	NDE1

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
chromosome localization	1	4213.0×	0.003	NDE1
skeletal muscle myosin thick filament assembly	1	2808.7×	0.003	MYH11
mitotic centrosome separation	1	1404.3×	0.004	NDE1
elastic fiber assembly	1	766.0×	0.006	MYH11
centrosome duplication	1	468.1×	0.006	NDE1
vesicle transport along microtubule	1	443.5×	0.006	NDE1
centrosome localization	1	443.5×	0.006	NDE1
smooth muscle contraction	1	401.2×	0.006	MYH11
microtubule nucleation	1	312.1×	0.006	NDE1
cardiac muscle cell development	1	312.1×	0.006	MYH11
actomyosin structure organization	1	280.9×	0.006	MYH11
establishment of mitotic spindle orientation	1	240.7×	0.006	NDE1
neuroblast proliferation	1	183.2×	0.008	NDE1
cerebral cortex development	1	102.8×	0.012	NDE1
chromosome segregation	1	86.9×	0.014	NDE1
neuron migration	1	66.9×	0.017	NDE1
cell migration	1	30.8×	0.034	NDE1
cell division	1	23.1×	0.043	NDE1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
NDE1	0	0
MIR484	0	0
MYH11	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	3	NDE1, MIR484, MYH11

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NDE1	0	—
MIR484	0	—
MYH11	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.