Microcephaly and chorioretinopathy 1

Summary

Microcephaly and chorioretinopathy 1 (MONDO:0009624) is a disease caused by TUBGCP6 (GenCC Definitive), with 4 cohort genes. The dominant Reactome pathway is Recruitment of mitotic centrosome proteins and complexes (3 cohort genes).

At a glance

• Causal gene: TUBGCP6 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 101
• 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	Very frequent (80-99%)
HP:0007703	Abnormality of retinal pigmentation	Very frequent (80-99%)
HP:0000307	Pointed chin	Frequent (30-79%)
HP:0000340	Sloping forehead	Frequent (30-79%)
HP:0000411	Protruding ear	Frequent (30-79%)
HP:0000431	Wide nasal bridge	Frequent (30-79%)
HP:0000463	Anteverted nares	Frequent (30-79%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0000499	Abnormal eyelash morphology	Frequent (30-79%)
HP:0000505	Visual impairment	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0000648	Optic atrophy	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001276	Hypertonia	Frequent (30-79%)
HP:0001511	Intrauterine growth retardation	Frequent (30-79%)
HP:0002120	Cerebral cortical atrophy	Frequent (30-79%)
HP:0002269	Abnormality of neuronal migration	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0004422	Biparietal narrowing	Frequent (30-79%)
HP:0007360	Aplasia/Hypoplasia of the cerebellum	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	microcephaly and chorioretinopathy 1
Mondo ID	MONDO:0009624
OMIM	251270
Orphanet	2518
DOID	DOID:0080105
NCIT	C129306
UMLS	C3278481
MedGen	480111
GARD	0016603
Is cancer (heuristic)	no

Also known as: autosomal recessive chorioretinopathy-microcephaly-intellectual disability syndrome · MCCRP1 · microcephaly and chorioretinopathy 1 · microcephaly and chorioretinopathy caused by mutation in TUBGCP6 · microcephaly and chorioretinopathy type 1 · microcephaly and chorioretinopathy, autosomal recessive, 1 · microcephaly and chorioretinopathy, autosomal recessive, type 1 · Pseudotoxoplasmosis syndrome · TUBGCP6 microcephaly and chorioretinopathy

Data availability: 101 ClinVar variants · 7 GenCC gene-disease records · 3 cell lines.

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 1

Related subtypes (2): microcephaly and chorioretinopathy 2, 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

101 retrieved; paginated sample, class counts are floors:

43 uncertain significance, 15 likely pathogenic, 12 conflicting classifications of pathogenicity, 9 benign, 9 pathogenic, 7 pathogenic/likely pathogenic, 4 benign/likely benign, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
977910	NM_004523.4(KIF11):c.2514_2518del (p.Asn838fs)	KIF11	Pathogenic	criteria provided, multiple submitters, no conflicts
1215472	NM_020461.4(TUBGCP6):c.2221_2222del (p.Arg741fs)	TUBGCP6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1325319	NM_020461.4(TUBGCP6):c.2155C>T (p.Arg719Ter)	TUBGCP6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452125	NM_020461.4(TUBGCP6):c.4165_4166del (p.Gln1389fs)	TUBGCP6	Pathogenic	criteria provided, multiple submitters, no conflicts
1455867	NM_020461.4(TUBGCP6):c.2234dup (p.Lys746fs)	TUBGCP6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1503780	NM_020461.4(TUBGCP6):c.4108+2T>C	TUBGCP6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
162402	NM_020461.4(TUBGCP6):c.4333_4334insT (p.His1445fs)	TUBGCP6	Pathogenic	no assertion criteria provided
162403	NM_020461.4(TUBGCP6):c.2215C>T (p.Arg739Ter)	TUBGCP6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
162405	NM_020461.4(TUBGCP6):c.3565G>T (p.Gly1189Ter)	TUBGCP6	Pathogenic	no assertion criteria provided
162406	NM_020461.4(TUBGCP6):c.3163C>T (p.His1055Tyr)	TUBGCP6	Pathogenic	no assertion criteria provided
212517	NM_020461.4(TUBGCP6):c.895C>T (p.Arg299Ter)	TUBGCP6	Pathogenic	criteria provided, multiple submitters, no conflicts
2627912	NM_020461.4(TUBGCP6):c.4664del (p.Pro1555fs)	TUBGCP6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2813272	NM_020461.4(TUBGCP6):c.4306G>T (p.Glu1436Ter)	TUBGCP6	Pathogenic	criteria provided, multiple submitters, no conflicts
30809	NM_020461.4(TUBGCP6):c.5458T>G (p.Ter1820Gly)	TUBGCP6	Pathogenic	no assertion criteria provided
372990	NM_020461.4(TUBGCP6):c.3893dup (p.Gly1299fs)	TUBGCP6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
977849	NM_020461.4(TUBGCP6):c.1615_1616del (p.Trp539fs)	TUBGCP6	Pathogenic	criteria provided, multiple submitters, no conflicts
2504122	NM_020461.4(TUBGCP6):c.741+1G>A	TUBGCP6	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2682639	NM_020461.4(TUBGCP6):c.3267_3672del (p.Ser1089fs)	TUBGCP6	Likely pathogenic	criteria provided, single submitter
3339917	NM_020461.4(TUBGCP6):c.905+1G>C	TUBGCP6	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3780774	NM_020461.4(TUBGCP6):c.5320C>T (p.Gln1774Ter)	TUBGCP6	Likely pathogenic	criteria provided, single submitter
4076280	NM_020461.4(TUBGCP6):c.1242dup (p.Leu415fs)	TUBGCP6	Likely pathogenic	criteria provided, single submitter
4076281	NM_020461.4(TUBGCP6):c.4174dup (p.Thr1392fs)	TUBGCP6	Likely pathogenic	criteria provided, single submitter
4077725	NM_020461.4(TUBGCP6):c.508_509del (p.Leu170fs)	TUBGCP6	Likely pathogenic	criteria provided, single submitter
4292387	NM_020461.4(TUBGCP6):c.2118dup (p.Gln707fs)	TUBGCP6	Likely pathogenic	criteria provided, single submitter
4849296	NM_020461.4(TUBGCP6):c.3817_3818del (p.Pro1273fs)	TUBGCP6	Likely pathogenic	criteria provided, single submitter
495284	NM_020461.3(TUBGCP6):c.4315+2_4315+3delTG	TUBGCP6	Likely pathogenic	criteria provided, single submitter
694004	NM_020461.4(TUBGCP6):c.1075G>A (p.Val359Ile)	TUBGCP6	Likely pathogenic	no assertion criteria provided
694005	NM_020461.4(TUBGCP6):c.2968G>A (p.Gly990Arg)	TUBGCP6	Likely pathogenic	no assertion criteria provided
977834	NM_020461.4(TUBGCP6):c.4838dup (p.Asn1613fs)	TUBGCP6	Likely pathogenic	no assertion criteria provided
977919	NM_020461.4(TUBGCP6):c.3907C>T (p.Gln1303Ter)	TUBGCP6	Likely pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 5 · 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
TUBGCP6	Definitive	Autosomal recessive	microcephaly and chorioretinopathy 1	5
TUBGCP4	Strong	Autosomal recessive	microcephaly and chorioretinopathy 3	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TUBGCP6	Orphanet:2518	Autosomal recessive chorioretinopathy-microcephaly syndrome
PLK4	Orphanet:2518	Autosomal recessive chorioretinopathy-microcephaly syndrome
PLK4	Orphanet:808	Seckel syndrome
TUBGCP4	Orphanet:2518	Autosomal recessive chorioretinopathy-microcephaly syndrome
KIF11	Orphanet:2526	Microcephaly-lymphedema-chorioretinopathy syndrome

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TUBGCP6	HGNC:18127	ENSG00000128159	Q96RT7	Gamma-tubulin complex component 6	gencc,clinvar
PLK4	HGNC:11397	ENSG00000142731	O00444	Serine/threonine-protein kinase PLK4	gencc
TUBGCP4	HGNC:16691	ENSG00000137822	Q9UGJ1	Gamma-tubulin complex component 4	gencc
KIF11	HGNC:6388	ENSG00000138160	P52732	Kinesin-like protein KIF11	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TUBGCP6	Gamma-tubulin complex component 6	Component of the gamma-tubulin ring complex (gTuRC) which mediates microtubule nucleation.
PLK4	Serine/threonine-protein kinase PLK4	Serine/threonine-protein kinase that plays a central role in centriole duplication.
TUBGCP4	Gamma-tubulin complex component 4	Component of the gamma-tubulin ring complex (gTuRC) which mediates microtubule nucleation.
KIF11	Kinesin-like protein KIF11	Motor protein required for establishing a bipolar spindle and thus contributing to chromosome congression during mitosis.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.5

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	6.9×	0.410
Enzyme (other)	1	3.0×	0.441
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TUBGCP6	Other/Unknown	no		GCP, GCP_C, GCP_N
PLK4	Kinase	yes	2.7.11.21	Prot_kinase_dom, POLO_box_dom, Tyr_kinase_AS
TUBGCP4	Other/Unknown	no		GCP, GCP_C, GCP_N
KIF11	Enzyme (other)	yes	5.6.1.3	Kinesin_motor_dom, Kinesin_motor_CS, Kinesin-assoc_MT-bd_dom

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ganglionic eminence	2
ventricular zone	2
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
primordial germ cell in gonad	1
male germ cell	1
secondary oocyte	1
sperm	1
embryo	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TUBGCP6	185	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
PLK4	201	ubiquitous	marker	ventricular zone, ganglionic eminence, primordial germ cell in gonad
TUBGCP4	259	ubiquitous	marker	sperm, secondary oocyte, male germ cell
KIF11	205	ubiquitous	marker	ventricular zone, ganglionic eminence, embryo

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KIF11	3,788
PLK4	3,694
TUBGCP6	1,875
TUBGCP4	1,322

Intra-cohort edges

A	B	Sources
PLK4	TUBGCP6	string_interaction
TUBGCP4	TUBGCP6	intact, string_interaction

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KIF11	P52732	62
TUBGCP6	Q96RT7	30
TUBGCP4	Q9UGJ1	28
PLK4	O00444	19

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Recruitment of mitotic centrosome proteins and complexes	3	102.0×	2e-05	TUBGCP6, PLK4, TUBGCP4
Recruitment of NuMA to mitotic centrosomes	3	87.4×	2e-05	TUBGCP6, PLK4, TUBGCP4
Kinesins	1	44.6×	0.062	KIF11
Loss of Nlp from mitotic centrosomes	1	39.6×	0.062	PLK4
Loss of proteins required for interphase microtubule organization from the centrosome	1	39.6×	0.062	PLK4
AURKA Activation by TPX2	1	38.1×	0.062	PLK4
Golgi-to-ER retrograde transport	1	33.2×	0.062	KIF11
Regulation of PLK1 Activity at G2/M Transition	1	31.7×	0.062	PLK4
Anchoring of the basal body to the plasma membrane	1	28.3×	0.062	PLK4
COPI-dependent Golgi-to-ER retrograde traffic	1	27.7×	0.062	KIF11
Intra-Golgi and retrograde Golgi-to-ER traffic	1	26.2×	0.062	KIF11
MHC class II antigen presentation	1	22.3×	0.066	KIF11
Factors involved in megakaryocyte development and platelet production	1	16.6×	0.082	KIF11
Membrane Trafficking	1	9.3×	0.124	KIF11
Hemostasis	1	9.0×	0.124	KIF11
Vesicle-mediated transport	1	8.7×	0.124	KIF11
Adaptive Immune System	1	7.5×	0.135	KIF11
Immune System	1	3.2×	0.275	KIF11

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mitotic cell cycle	3	100.3×	3e-05	TUBGCP6, TUBGCP4, KIF11
microtubule nucleation	2	312.1×	1e-04	TUBGCP6, TUBGCP4
spindle assembly	2	221.7×	2e-04	TUBGCP6, TUBGCP4
cytoplasmic microtubule organization	2	172.0×	2e-04	TUBGCP6, TUBGCP4
meiotic cell cycle	2	122.1×	4e-04	TUBGCP6, TUBGCP4
spindle elongation	1	1404.3×	0.002	KIF11
positive regulation of centriole replication	1	842.6×	0.003	PLK4
regulation of mitotic centrosome separation	1	842.6×	0.003	KIF11
de novo centriole assembly involved in multi-ciliated epithelial cell differentiation	1	842.6×	0.003	PLK4
mitotic centrosome separation	1	702.2×	0.003	KIF11
trophoblast giant cell differentiation	1	300.9×	0.006	PLK4
spindle organization	1	247.8×	0.007	KIF11
centriole replication	1	183.2×	0.008	PLK4
mitotic spindle assembly	1	86.0×	0.017	KIF11
microtubule-based movement	1	73.9×	0.018	KIF11
mitotic spindle organization	1	68.0×	0.018	KIF11
protein-containing complex assembly	1	28.5×	0.041	TUBGCP4
cilium assembly	1	18.4×	0.059	PLK4
protein phosphorylation	1	17.0×	0.061	PLK4
cell division	1	11.5×	0.084	KIF11

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 2

Druggability breadth: 3 of 4 evidence-associated genes (75%) 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
KIF11	6	3
TUBGCP6	0	0
TUBGCP4	0	0

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
GOSSYPOL	3	KIF11
FORETINIB	2	PLK4
AZD-1480	2	PLK4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
PLK4	303	Binding:293, Functional:10
KIF11	193	Binding:185, Functional:8
TUBGCP4	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PLK4	2.7.11.21	polo kinase
KIF11	5.6.1.3	plus-end-directed kinesin ATPase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
PLK4	303
KIF11	193

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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
GOSSYPOL	3	KIF11
FORETINIB	2	PLK4
AZD-1480	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	1	KIF11
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	TUBGCP6, TUBGCP4

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TUBGCP6	0	—
TUBGCP4	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.