Lissencephaly 7 with cerebellar hypoplasia

Summary

Lissencephaly 7 with cerebellar hypoplasia (MONDO:0014596) is a disease caused by CDK5 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: CDK5 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	lissencephaly 7 with cerebellar hypoplasia
Mondo ID	MONDO:0014596
OMIM	616342
DOID	DOID:0112231
UMLS	C4225359
MedGen	895680
GARD	0025004
Is cancer (heuristic)	no

Also known as: LIS7 · lissencephaly 7 with cerebellar hypoplasia

Data availability: 2 ClinVar variants · 3 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 › lissencephaly 7 with cerebellar hypoplasia

Related subtypes (14): craniotelencephalic dysplasia, X-linked lissencephaly with abnormal genitalia, lissencephaly 8, classic lissencephaly, 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

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

2 retrieved; paginated sample, class counts are floors:

1 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
190117	NM_004935.4(CDK5):c.580+1G>A	CDK5	Pathogenic	no assertion criteria provided
2683824	NM_004935.4(CDK5):c.149G>A (p.Arg50Gln)	CDK5	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 0 · 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
CDK5	Strong	Autosomal recessive	lissencephaly 7 with cerebellar hypoplasia	3

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
CDK5	HGNC:1774	ENSG00000164885	Q00535	Cyclin-dependent kinase 5	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CDK5	Cyclin-dependent kinase 5	Proline-directed serine/threonine-protein kinase essential for neuronal cell cycle arrest and differentiation and may be involved in apoptotic cell death in neuronal diseases by triggering abortive cell cycle re-entry.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CDK5	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf

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
nucleus accumbens	1
prefrontal cortex	1
right frontal lobe	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CDK5	235	ubiquitous	marker	right frontal lobe, prefrontal cortex, nucleus accumbens

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CDK5	3,850

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CDK5	Q00535	10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 40. 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
Phosphorylation and nuclear translocation of BMAL1 (ARNTL) and CLOCK	1	2284.0×	0.007	CDK5
Activated NTRK2 signals through CDK5	1	1903.3×	0.007	CDK5
Signaling by NTRK2 (TRKB)	1	1631.4×	0.007	CDK5
Neurodegenerative Diseases	1	878.5×	0.007	CDK5
Phosphorylation and nuclear translocation of the CRY:PER:kinase complex	1	815.7×	0.007	CDK5
Defective Intrinsic Pathway for Apoptosis	1	761.3×	0.007	CDK5
CRMPs in Sema3A signaling	1	634.4×	0.007	CDK5
Diseases of programmed cell death	1	634.4×	0.007	CDK5
Transcriptional Regulation by NPAS4	1	571.0×	0.007	CDK5
Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer’s disease models	1	519.1×	0.007	CDK5
NPAS4 regulates expression of target genes	1	496.5×	0.007	CDK5
DARPP-32 events	1	475.8×	0.007	CDK5
Semaphorin interactions	1	393.8×	0.008	CDK5
Nuclear Events (kinase and transcription factor activation)	1	346.1×	0.008	CDK5
NGF-stimulated transcription	1	285.5×	0.009	CDK5
Opioid Signalling	1	265.6×	0.009	CDK5
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1	215.5×	0.011	CDK5
Signaling by NTRK1 (TRKA)	1	196.9×	0.011	CDK5
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	1	196.9×	0.011	CDK5
Signaling by NTRKs	1	181.3×	0.011	CDK5
Epigenetic regulation by WDR5-containing histone modifying complexes	1	154.3×	0.012	CDK5
Regulation of TP53 Activity	1	132.8×	0.014	CDK5
Regulation of TP53 Activity through Phosphorylation	1	117.7×	0.015	CDK5
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	1	82.8×	0.020	CDK5
Epigenetic regulation of gene expression	1	71.4×	0.022	CDK5
Factors involved in megakaryocyte development and platelet production	1	66.4×	0.023	CDK5
Transcriptional Regulation by TP53	1	62.1×	0.024	CDK5
Signaling by Receptor Tyrosine Kinases	1	51.7×	0.028	CDK5
Axon guidance	1	45.1×	0.030	CDK5
GPCR downstream signalling	1	43.4×	0.030	CDK5

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
positive regulation of presynaptic cytosolic calcium concentration	1	16852.0×	0.002	CDK5
negative regulation of calcium ion-dependent exocytosis of neurotransmitter	1	16852.0×	0.002	CDK5
regulation of synaptic vesicle recycling	1	8426.0×	0.002	CDK5
cerebellar cortex formation	1	5617.3×	0.003	CDK5
negative regulation of synaptic plasticity	1	3370.4×	0.004	CDK5
synaptic transmission, dopaminergic	1	2106.5×	0.004	CDK5
negative regulation of protein export from nucleus	1	2106.5×	0.004	CDK5
regulation of cell cycle phase transition	1	1872.4×	0.004	CDK5
positive regulation of calcium ion-dependent exocytosis	1	1296.3×	0.004	CDK5
layer formation in cerebral cortex	1	1123.5×	0.004	CDK5
receptor catabolic process	1	1123.5×	0.004	CDK5
Schwann cell development	1	1053.2×	0.004	CDK5
corpus callosum development	1	842.6×	0.004	CDK5
behavioral response to cocaine	1	842.6×	0.004	CDK5
synaptic vesicle transport	1	842.6×	0.004	CDK5
regulation of dendritic spine morphogenesis	1	842.6×	0.004	CDK5
central nervous system neuron development	1	802.5×	0.004	CDK5
calcium ion import	1	802.5×	0.004	CDK5
synaptic vesicle exocytosis	1	766.0×	0.004	CDK5
protein localization to synapse	1	766.0×	0.004	CDK5
negative regulation of axon extension	1	732.7×	0.004	CDK5
motor neuron axon guidance	1	702.2×	0.004	CDK5
negative regulation of proteolysis	1	674.1×	0.004	CDK5
regulation of protein localization to plasma membrane	1	648.1×	0.004	CDK5
receptor clustering	1	624.1×	0.004	CDK5
positive regulation of protein targeting to membrane	1	561.7×	0.004	CDK5
regulation of synaptic transmission, glutamatergic	1	510.7×	0.004	CDK5
axon extension	1	495.6×	0.004	CDK5
excitatory postsynaptic potential	1	443.5×	0.004	CDK5
synaptic vesicle endocytosis	1	432.1×	0.004	CDK5

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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
CDK5	PALBOCICLIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CDK5	58	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PALBOCICLIB	4	CDK5
ABEMACICLIB	4	CDK5
SORAFENIB	4	CDK5
DABRAFENIB	4	CDK5
SUNITINIB	4	CDK5
DINACICLIB	3	CDK5
EPIGALOCATECHIN GALLATE	3	CDK5
ALVOCIDIB	3	CDK5
QUERCETIN	3	CDK5
CRENOLANIB	3	CDK5
DEFACTINIB	3	CDK5
FASUDIL	3	CDK5
LESTAURTINIB	3	CDK5
INDIRUBIN	2	CDK5
SELICICLIB	2	CDK5
LUTEOLIN	2	CDK5
ZOTIRACICLIB	2	CDK5
NARAZACICLIB	2	CDK5
FISETIN	2	CDK5
CYC-065	2	CDK5
AT-7519	2	CDK5
CULMERCICLIB	2	CDK5
INIXACICLIB	2	CDK5
ISTISOCICLIB	2	CDK5
MILCICLIB	2	CDK5
DORAMAPIMOD	2	CDK5
SILMITASERTIB	2	CDK5
REBASTINIB	2	CDK5
CENISERTIB	2	CDK5
ADAVOSERTIB	2	CDK5

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CDK5	1,044	Binding:1036, ADMET:4, Functional:3, Toxicity:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CDK5	2.7.11.1, 2.7.11.22	non-specific serine/threonine protein kinase, cyclin-dependent kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CDK5	1,044

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

30 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)
PALBOCICLIB	4	CDK5
ABEMACICLIB	4	CDK5
SORAFENIB	4	CDK5
DABRAFENIB	4	CDK5
SUNITINIB	4	CDK5
DINACICLIB	3	CDK5
EPIGALOCATECHIN GALLATE	3	CDK5
ALVOCIDIB	3	CDK5
QUERCETIN	3	CDK5
CRENOLANIB	3	CDK5
DEFACTINIB	3	CDK5
FASUDIL	3	CDK5
LESTAURTINIB	3	CDK5
INDIRUBIN	2	CDK5
SELICICLIB	2	CDK5
LUTEOLIN	2	CDK5
ZOTIRACICLIB	2	CDK5
NARAZACICLIB	2	CDK5
FISETIN	2	CDK5
CYC-065	2	CDK5
AT-7519	2	CDK5
CULMERCICLIB	2	CDK5
INIXACICLIB	2	CDK5
ISTISOCICLIB	2	CDK5
MILCICLIB	2	CDK5
DORAMAPIMOD	2	CDK5
SILMITASERTIB	2	CDK5
REBASTINIB	2	CDK5
CENISERTIB	2	CDK5
ADAVOSERTIB	2	CDK5

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CDK5
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.