Microlissencephaly

Summary

Microlissencephaly (MONDO:0015204) is a disease with 3 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Cohort genes: 3
• ClinVar variants: 1
• Phenotypes (HPO): 22

Clinical features

Signs & symptoms

Clinical features (HPO)

22 HPO clinical features (Orphanet curated; top 22 by frequency):

HPO ID	Term	Frequency
HP:0000252	Microcephaly	Obligate (100%)
HP:0000750	Delayed speech and language development	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0002079	Hypoplasia of the corpus callosum	Very frequent (80-99%)
HP:0007190	Neuronal loss in the cerebral cortex	Very frequent (80-99%)
HP:0007266	Cerebral dysmyelination	Very frequent (80-99%)
HP:0010864	Intellectual disability, severe	Very frequent (80-99%)
HP:0025190	Bilateral tonic-clonic seizure with generalized onset	Very frequent (80-99%)
HP:0001276	Hypertonia	Frequent (30-79%)
HP:0001339	Lissencephaly	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0001999	Abnormal facial shape	Frequent (30-79%)
HP:0002119	Ventriculomegaly	Frequent (30-79%)
HP:0002120	Cerebral cortical atrophy	Frequent (30-79%)
HP:0006891	Thick cerebral cortex	Frequent (30-79%)
HP:0001272	Cerebellar atrophy	Occasional (5-29%)
HP:0001302	Pachygyria	Occasional (5-29%)
HP:0002090	Pneumonia	Occasional (5-29%)
HP:0002126	Polymicrogyria	Occasional (5-29%)
HP:0007165	Periventricular heterotopia	Occasional (5-29%)
HP:0009879	Simplified gyral pattern	Occasional (5-29%)
HP:0032391	Subcortical heterotopia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	microlissencephaly
Mondo ID	MONDO:0015204
Orphanet	1083
DOID	DOID:0112234
ICD-11	169315445
UMLS	C1956147
MedGen	365439
GARD	0016555
Is cancer (heuristic)	no

Data availability: 1 ClinVar variant · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 3 Mondo subtypes.

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

Related subtypes (14): craniotelencephalic dysplasia, X-linked lissencephaly with abnormal genitalia, lissencephaly 7 with cerebellar hypoplasia, lissencephaly 8, classic lissencephaly, lissencephaly type 3, 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 (3): Norman-Roberts syndrome, lissencephaly 4, 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

1 retrieved; paginated sample, class counts are floors:

1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
635849	NM_001163809.2(WDR81):c.4668_4669del (p.Gly1557fs)	WDR81	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · 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
KATNB1	Supportive	Autosomal recessive	microlissencephaly	6
NDE1	Supportive	Autosomal recessive	microlissencephaly	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
KATNB1	Orphanet:89844	Lissencephaly syndrome, Norman-Roberts type
WDR81	Orphanet:1766	Dysequilibrium syndrome
WDR81	Orphanet:269505	Congenital communicating hydrocephalus
WDR81	Orphanet:269510	Congenital non-communicating hydrocephalus

Cohort genes → proteins

3 cohort genes, 3 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
KATNB1	HGNC:6217	ENSG00000140854	Q9BVA0	Katanin p80 WD40 repeat-containing subunit B1	gencc
WDR81	HGNC:26600	ENSG00000167716	Q562E7	WD repeat-containing protein 81	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.
KATNB1	Katanin p80 WD40 repeat-containing subunit B1	Participates in a complex which severs microtubules in an ATP-dependent manner.
WDR81	WD repeat-containing protein 81	Functions as a negative regulator of the PI3 kinase/PI3K activity associated with endosomal membranes via BECN1, a core subunit of the PI3K complex.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

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
Kinase	1	9.2×	0.246
Scaffold/PPI	1	5.8×	0.246
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NDE1	Other/Unknown	no		NUDE_dom, NUDE
KATNB1	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_CS
WDR81	Kinase	yes		BEACH_dom, WD40_rpt, Kinase-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
colonic epithelium	1
corpus callosum	1
ventricular zone	1
middle temporal gyrus	1
right frontal lobe	1
right uterine tube	1
granulocyte	1
left ovary	1
right ovary	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
KATNB1	280	ubiquitous	marker	middle temporal gyrus, right frontal lobe, right uterine tube
WDR81	138	ubiquitous	marker	granulocyte, left ovary, right ovary

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NDE1	1,761
WDR81	1,404
KATNB1	1,325

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NDE1	Q9NXR1	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KATNB1	Q9BVA0	79.58
WDR81	Q562E7	69.23

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 31. 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
Centrosome maturation	1	126.9×	0.037	NDE1
Amplification of signal from the kinetochores	1	98.5×	0.037	NDE1
Loss of Nlp from mitotic centrosomes	1	79.3×	0.037	NDE1
Loss of proteins required for interphase microtubule organization from the centrosome	1	79.3×	0.037	NDE1
Mitotic Spindle Checkpoint	1	79.3×	0.037	NDE1
AURKA Activation by TPX2	1	76.1×	0.037	NDE1
Recruitment of mitotic centrosome proteins and complexes	1	68.0×	0.037	NDE1
Regulation of PLK1 Activity at G2/M Transition	1	63.4×	0.037	NDE1
Mitotic G2-G2/M phases	1	63.4×	0.037	NDE1
G2/M Transition	1	63.4×	0.037	NDE1
Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal	1	58.3×	0.037	NDE1
Recruitment of NuMA to mitotic centrosomes	1	58.3×	0.037	NDE1
Anchoring of the basal body to the plasma membrane	1	56.5×	0.037	NDE1
Cilium Assembly	1	54.4×	0.037	NDE1
Mitotic Metaphase and Anaphase	1	48.4×	0.037	NDE1
Mitotic Anaphase	1	48.4×	0.037	NDE1
EML4 and NUDC in mitotic spindle formation	1	46.4×	0.037	NDE1
Cell Cycle Checkpoints	1	44.3×	0.037	NDE1
Resolution of Sister Chromatid Cohesion	1	43.3×	0.037	NDE1
RHO GTPases Activate Formins	1	38.8×	0.037	NDE1
CDC42 GTPase cycle	1	36.1×	0.037	WDR81
Mitotic Prometaphase	1	34.6×	0.037	NDE1
RHO GTPase Effectors	1	34.0×	0.037	NDE1
Organelle biogenesis and maintenance	1	33.0×	0.037	NDE1
M Phase	1	33.0×	0.037	NDE1
Separation of Sister Chromatids	1	30.4×	0.039	NDE1
Cell Cycle, Mitotic	1	24.1×	0.047	NDE1
Cell Cycle	1	18.0×	0.061	NDE1
Signaling by Rho GTPases	1	17.1×	0.061	NDE1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	16.7×	0.061	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 3 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	2808.7×	0.007	NDE1
mitotic chromosome movement towards spindle pole	1	1123.5×	0.007	KATNB1
positive regulation of microtubule depolymerization	1	1123.5×	0.007	KATNB1
mitotic centrosome separation	1	936.2×	0.007	NDE1
cell division	2	30.8×	0.007	NDE1, KATNB1
aggrephagy	1	561.7×	0.008	WDR81
microtubule severing	1	432.1×	0.008	KATNB1
microtubule depolymerization	1	351.1×	0.008	KATNB1
centrosome duplication	1	312.1×	0.008	NDE1
vesicle transport along microtubule	1	295.6×	0.008	NDE1
centrosome localization	1	295.6×	0.008	NDE1
early endosome to late endosome transport	1	216.1×	0.010	WDR81
microtubule nucleation	1	208.1×	0.010	NDE1
negative regulation of microtubule depolymerization	1	165.2×	0.011	KATNB1
establishment of mitotic spindle orientation	1	160.5×	0.011	NDE1
protein targeting	1	122.1×	0.013	KATNB1
neuroblast proliferation	1	122.1×	0.013	NDE1
cytoplasmic microtubule organization	1	114.6×	0.013	KATNB1
cerebral cortex development	1	68.5×	0.021	NDE1
chromosome segregation	1	57.9×	0.023	NDE1
mitochondrion organization	1	50.6×	0.025	WDR81
positive regulation of neuron projection development	1	45.7×	0.026	KATNB1
neuron migration	1	44.6×	0.026	NDE1
ubiquitin-dependent protein catabolic process	1	24.8×	0.045	WDR81
protein stabilization	1	22.3×	0.048	WDR81
cell migration	1	20.5×	0.050	NDE1
positive regulation of apoptotic process	1	18.9×	0.052	KATNB1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 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
NDE1	0	0
KATNB1	0	0
WDR81	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
KATNB1	2	Binding:2

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	1	WDR81
E	Difficult family or no structure, no drug	2	NDE1, KATNB1

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	—
KATNB1	2	—
WDR81	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.