Craniosynostosis 6

Summary

Craniosynostosis 6 (MONDO:0014705) is a disease caused by ZIC1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: ZIC1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 3

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	craniosynostosis 6
Mondo ID	MONDO:0014705
OMIM	616602
Orphanet	672985
DOID	DOID:0061008
UMLS	C4225269
MedGen	904675
GARD	0018048
Is cancer (heuristic)	no

Also known as: craniosynostosis 6 · craniosynostosis caused by mutation in ZIC1 · craniosynostosis type 6 · CRS6 · ZIC1 craniosynostosis

Data availability: 3 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone development disease › dysostosis › synostosis › craniosynostosis › isolated craniosynostosis › isolated oxycephaly › craniosynostosis 6

Related subtypes (1): TWIST1-related craniosynostosis

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

3 retrieved; paginated sample, class counts are floors:

1 uncertain significance, 1 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
372164	NM_003412.4(ZIC1):c.1198G>C (p.Gly400Arg)	ZIC1	Pathogenic	no assertion criteria provided
981197	NM_003412.4(ZIC1):c.1153G>T (p.Glu385Ter)	ZIC1	Likely pathogenic	criteria provided, single submitter
1333899	NM_003412.4(ZIC1):c.1097T>A (p.Met366Lys)	ZIC1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 3 · 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
ZIC1	Definitive	Autosomal dominant	craniosynostosis 6	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ZIC1	Orphanet:269212	Isolated Dandy-Walker malformation with hydrocephalus
ZIC1	Orphanet:269215	Isolated Dandy-Walker malformation without hydrocephalus
ZIC1	Orphanet:35099	Non-syndromic bicoronal craniosynostosis

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
ZIC1	HGNC:12872	ENSG00000152977	Q15915	Zinc finger protein ZIC 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ZIC1	Zinc finger protein ZIC 1	Acts as a transcriptional activator.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ZIC1	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Znf_ZIC

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
cerebellum	1
cranial nerve II	1
paraflocculus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ZIC1	196	broad	marker	paraflocculus, cranial nerve II, cerebellum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ZIC1	2,710

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ZIC1	Q15915	55.77

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Specification of the neural plate border	1	634.4×	0.003	ZIC1
Transcriptional and post-translational regulation of MITF-M expression and activity	1	178.4×	0.006	ZIC1

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
maintenance of cell number	1	8426.0×	0.002	ZIC1
olfactory bulb development	1	766.0×	0.005	ZIC1
regulation of smoothened signaling pathway	1	624.1×	0.005	ZIC1
spinal cord development	1	510.7×	0.005	ZIC1
adult walking behavior	1	495.6×	0.005	ZIC1
pattern specification process	1	468.1×	0.005	ZIC1
positive regulation of protein import into nucleus	1	421.3×	0.005	ZIC1
inner ear morphogenesis	1	300.9×	0.006	ZIC1
hippocampus development	1	230.8×	0.007	ZIC1
central nervous system development	1	115.4×	0.013	ZIC1
gene expression	1	79.9×	0.016	ZIC1
brain development	1	79.5×	0.016	ZIC1
cell differentiation	1	29.1×	0.038	ZIC1
positive regulation of DNA-templated transcription	1	27.9×	0.038	ZIC1
regulation of transcription by RNA polymerase II	1	11.7×	0.086	ZIC1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
ZIC1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	1	ZIC1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ZIC1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.