ZIC1

protein-coding

Zic family member 1, the group of Zinc fingers C2H2-type

Gene summary

This gene encodes a member of the ZIC family of C2H2-type zinc finger proteins. Members of this family are important during development. Aberrant expression of this gene is seen in medulloblastoma, a childhood brain tumor. This gene is closely linked to the gene encoding zinc finger protein of the cerebellum 4, a related family member on chromosome 3. This gene encodes a transcription factor that can bind and transactivate the apolipoprotein E gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_003412.4

Inheritance

ClinVar variants

P:14U:105B:80

Top phenotype

Craniosynostosis 6; Structural brain anomalies with impaired intellectual development and craniosynostosis

gnomAD constraint

pLI —, LoF o/e 0.08

Max pathogenic AF

—

Genomic locus

chr3:147,393,422-147,510,293

External References & Databases

Ensembl (ENSG00000152977)

Transcript & Mutation Effects

hg38 • Region Span ~116.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

craniosynostosis 6DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014705

Submitter: ClinGen

ZIC1 was first reported in relation to autosomal dominant craniosynostosis 6 in 2015 (Twigg et al., PMID: 26340333). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism, inheritance pattern, and phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities craniosynostosis 6 (OMIM: 616602) and structural brain anomalies without craniosynostosis (no OMIM term). The split curation for autosomal recessive structural brain anomalies without craniosynostosis will be curated separately. Ten variants (missense, frameshift, nonsense) that have been reported in at least 17 probands in 8 publications (PMIDs: 26340333, 27884935, 30391508, 32975022, 33288889, 35591945, 36118902, 37086723) are included in this curation. The variants associated with this disease are all in the C-terminal region, the disruption of which enhances en-2 expression. The mechanism of pathogenicity is reported to be gain-of-function. This gene-disease relationship is also supported by experimental evidence (GTEx expression data, Xenopus oocyte functional evidence; PMID: 26340333). In summary, there is definitive evidence supporting the relationship between ZIC1 and autosomal dominant craniosynostosis 6. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Craniofacial Malformations GCEP on the meeting date 1/18/2024 (SOP Version 10).

structural brain anomalies with impaired intellectual development and craniosynostosisLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0032892

Submitter: Labcorp Genetics (formerly Invitae)

Dandy-Walker syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0009072

Submitter: Ambry Genetics

craniosynostosis 6STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014705

Submitter: Labcorp Genetics (formerly Invitae)

craniosynostosis 6DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014705

Submitter: G2P

craniosynostosis 6MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0014705

Submitter: Ambry Genetics

structural brain anomalies with impaired intellectual development and craniosynostosisSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032892

Submitter: PanelApp Australia

craniosynostosis 6STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014705

Submitter: PanelApp Australia

structural brain anomalies with impaired intellectual development and craniosynostosisMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0032892

Submitter: Ambry Genetics

isolated brachycephalySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018114

Submitter: Orphanet

Clinical Genomic Database (CGD)

Craniosynostosis 6; Structural brain anomalies with impaired intellectual development and craniosynostosisAD

Manifestation: Craniofacial; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 26340333; 30391508

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ZIC1 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 171

Inborn genetic diseasesTotal: 29

not specifiedTotal: 17

Structural brain anomalies with impaired intellectual development and craniosynostosisTotal: 11

ZIC1-related disorderTotal: 10

Craniosynostosis 6Total: 4

See casesTotal: 1

Cerebral cortex disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003412.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	61 clinvar	5 clinvar	67
missense	1 clinvar	5 clinvar	98 clinvar	9 clinvar	5 clinvar	118
nonsense	2 clinvar	5 clinvar	1 clinvar			8
start loss						0
frameshift	1 clinvar		5 clinvar			6
splice donor/acceptor (+/-2bp)						0
Total	4	10	105	70	10	199

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 4 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003412.4	RefSeq	NP_003403.2	3	MANE Select
ENST00000282928.5	Ensembl	ENSP00000282928.4	3	MANE Select
ENST00000488404.5	Ensembl	ENSP00000419664.1	3	Standard
ENST00001145117.1	Ensembl	ENSP00000804494.1	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
zic1	Danio rerio	Structure: optic fissure Quality: closure incomplete abnormal

Gene / Model

Organism

Observed Phenotype

zic1

Danio rerio

Structure: optic fissure

Quality: closure incomplete

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Neural Crest Differentiation
Differentiation of white and brown adipocyte

Biological Process

pattern specification process
central nervous system development
brain development
adult walking behavior
regulation of smoothened signaling pathway

Molecular Function

RNA polymerase II regulatory region sequence-specific DNA binding
RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription activator activity, RNA polymerase II-specific
DNA-binding transcription factor activity

Cellular Component

nucleus
cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000282928
Coding exons: 3
Length: 116872
Individuals with no LoFs: 123380
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 123381
p: 0.00000405

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.57	160	281	0.569	0.0000127	2935
Missense (PolyPhen)		57	128.05	0.44512		1389
Synonymous	-2.81	161	122	1.32	0.00000596	889
Loss of Function	3.09	1	13.0	0.0767	5.65e-7	138

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Acts as a transcriptional activator. Involved in neurogenesis. Plays important roles in the early stage of organogenesis of the CNS, as well as during dorsal spinal cord development and maturation of the cerebellum. Involved in the spatial distribution of mossy fiber (MF) neurons within the pontine gray nucleus (PGN). Plays a role in the regulation of MF axon pathway choice. Promotes MF migration towards ipsilaterally- located cerebellar territories. May have a role in shear flow mechanotransduction in osteocytes. Retains nuclear GLI1 and GLI3 in the cytoplasm. Binds to the minimal GLI-consensus sequence 5'- TGGGTGGTC-3' (By similarity). {ECO:0000250|UniProtKB:P46684}.;
Disease: DISEASE: Craniosynostosis 6 (CRS6) [MIM:616602]: A form of craniosynostosis, a primary abnormality of skull growth involving premature fusion of one or more cranial sutures. The growth velocity of the skull often cannot match that of the developing brain resulting in an abnormal head shape and, in some cases, increased intracranial pressure, which must be treated promptly to avoid permanent neurodevelopmental disability. {ECO:0000269|PubMed:26340333}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.281

Intolerance Scores

LoFtool: 0.0318
RVIS EVS: -0.49
RVIS percentile EVS: 22.09

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.995

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium