Microcephaly and chorioretinopathy 2

Summary

Microcephaly and chorioretinopathy 2 (MONDO:0014516) is a disease caused by PLK4 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: PLK4 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 15

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	microcephaly and chorioretinopathy 2
Mondo ID	MONDO:0014516
OMIM	616171
DOID	DOID:0080106
UMLS	C4015388
MedGen	863825
GARD	0024997
Is cancer (heuristic)	no

Also known as: MCCRP2 · microcephaly and chorioretinopathy caused by mutation in PLK4 · microcephaly and chorioretinopathy type 2 · microcephaly and chorioretinopathy, autosomal recessive, 2 · microcephaly and chorioretinopathy, autosomal recessive, type 2 · PLK4 microcephaly and chorioretinopathy

Data availability: 15 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › disorder of development or morphogenesis › microcephaly › microcephaly and chorioretinopathy › microcephaly and chorioretinopathy 2

Related subtypes (2): microcephaly and chorioretinopathy 1, microcephaly and chorioretinopathy 3

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

15 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 2 likely pathogenic, 2 benign, 2 pathogenic/likely pathogenic, 2 conflicting classifications of pathogenicity, 1 likely benign, 1 pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1381731	NM_014264.5(PLK4):c.1163_1166del (p.Gln388fs)	PLK4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
162400	NM_014264.5(PLK4):c.2811-5C>G	PLK4	Pathogenic	no assertion criteria provided
3069188	NM_014264.5(PLK4):c.1658del (p.Pro553fs)	PLK4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1031259	NM_014264.5(PLK4):c.2562+1G>C	PLK4	Likely pathogenic	criteria provided, single submitter
3064399	NM_014264.5(PLK4):c.1177_1181del (p.Thr393fs)	PLK4	Likely pathogenic	criteria provided, single submitter
162401	NM_014264.5(PLK4):c.1299_1303del (p.Phe433fs)	PLK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
739801	NM_014264.5(PLK4):c.926A>G (p.Lys309Arg)	PLK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1032615	NM_014264.5(PLK4):c.176A>G (p.Asn59Ser)	PLK4	Uncertain significance	criteria provided, single submitter
1041556	NM_014264.5(PLK4):c.2368G>A (p.Glu790Lys)	PLK4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1505068	NM_014264.5(PLK4):c.160G>A (p.Val54Ile)	PLK4	Uncertain significance	criteria provided, multiple submitters, no conflicts
939314	NM_014264.5(PLK4):c.1935+4A>T	PLK4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1157346	NM_014264.5(PLK4):c.609A>G (p.Thr203=)	PLK4	Likely benign	criteria provided, multiple submitters, no conflicts
1166823	NM_014264.5(PLK4):c.694T>A (p.Ser232Thr)	PLK4	Benign	criteria provided, multiple submitters, no conflicts
1166824	NM_014264.5(PLK4):c.2490G>T (p.Glu830Asp)	PLK4	Benign	criteria provided, multiple submitters, no conflicts
741394	NM_014264.5(PLK4):c.2109C>A (p.Ile703=)	PLK4	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · 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
PLK4	Definitive	Autosomal recessive	microcephaly and chorioretinopathy 2	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PLK4	Orphanet:2518	Autosomal recessive chorioretinopathy-microcephaly syndrome
PLK4	Orphanet:808	Seckel syndrome

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
PLK4	HGNC:11397	ENSG00000142731	O00444	Serine/threonine-protein kinase PLK4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PLK4	Serine/threonine-protein kinase PLK4	Serine/threonine-protein kinase that plays a central role in centriole duplication.

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)
PLK4	Kinase	yes	2.7.11.21	Prot_kinase_dom, POLO_box_dom, Tyr_kinase_AS

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
ganglionic eminence	1
primordial germ cell in gonad	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PLK4	201	ubiquitous	marker	ventricular zone, ganglionic eminence, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PLK4	3,694

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PLK4	O00444	19

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
Loss of Nlp from mitotic centrosomes	1	158.6×	0.009	PLK4
Loss of proteins required for interphase microtubule organization from the centrosome	1	158.6×	0.009	PLK4
AURKA Activation by TPX2	1	152.3×	0.009	PLK4
Recruitment of mitotic centrosome proteins and complexes	1	135.9×	0.009	PLK4
Regulation of PLK1 Activity at G2/M Transition	1	126.9×	0.009	PLK4
Recruitment of NuMA to mitotic centrosomes	1	116.5×	0.009	PLK4
Anchoring of the basal body to the plasma membrane	1	113.1×	0.009	PLK4

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 centriole replication	1	3370.4×	9e-04	PLK4
de novo centriole assembly involved in multi-ciliated epithelial cell differentiation	1	3370.4×	9e-04	PLK4
trophoblast giant cell differentiation	1	1203.7×	0.002	PLK4
centriole replication	1	732.7×	0.002	PLK4
cilium assembly	1	73.6×	0.015	PLK4
protein phosphorylation	1	68.0×	0.015	PLK4

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
PLK4	MOMELOTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PLK4	65	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOMELOTINIB	4	PLK4
FEDRATINIB	4	PLK4
AXITINIB	4	PLK4
SORAFENIB	4	PLK4
RUXOLITINIB	4	PLK4
ENTRECTINIB	4	PLK4
DABRAFENIB	4	PLK4
FOSTAMATINIB	4	PLK4
CERITINIB	4	PLK4
VANDETANIB	4	PLK4
GILTERITINIB	4	PLK4
PAZOPANIB	4	PLK4
NINTEDANIB	4	PLK4
SUNITINIB	4	PLK4
DASATINIB	4	PLK4
ERLOTINIB	4	PLK4
CRIZOTINIB	4	PLK4
MIDOSTAURIN	4	PLK4
IMATINIB	4	PLK4
LINIFANIB	3	PLK4
RIPASUDIL	3	PLK4
ALVOCIDIB	3	PLK4
ALISERTIB	3	PLK4
CEDIRANIB	3	PLK4
DOVITINIB	3	PLK4
LESTAURTINIB	3	PLK4
RUBOXISTAURIN	3	PLK4
FORETINIB	2	PLK4
AZD-1480	2	PLK4
TANDUTINIB	2	PLK4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PLK4	303	Binding:293, Functional:10

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PLK4	2.7.11.21	polo kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
PLK4	303

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)
MOMELOTINIB	4	PLK4
FEDRATINIB	4	PLK4
AXITINIB	4	PLK4
SORAFENIB	4	PLK4
RUXOLITINIB	4	PLK4
ENTRECTINIB	4	PLK4
DABRAFENIB	4	PLK4
FOSTAMATINIB	4	PLK4
CERITINIB	4	PLK4
VANDETANIB	4	PLK4
GILTERITINIB	4	PLK4
PAZOPANIB	4	PLK4
NINTEDANIB	4	PLK4
SUNITINIB	4	PLK4
DASATINIB	4	PLK4
ERLOTINIB	4	PLK4
CRIZOTINIB	4	PLK4
MIDOSTAURIN	4	PLK4
IMATINIB	4	PLK4
LINIFANIB	3	PLK4
RIPASUDIL	3	PLK4
ALVOCIDIB	3	PLK4
ALISERTIB	3	PLK4
CEDIRANIB	3	PLK4
DOVITINIB	3	PLK4
LESTAURTINIB	3	PLK4
RUBOXISTAURIN	3	PLK4
FORETINIB	2	PLK4
AZD-1480	2	PLK4
TANDUTINIB	2	PLK4

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PLK4
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.