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Fetal anomalies

Gene: ZIC1

Green List (high evidence)
ZIC1 (Zic family member 1)
EnsemblGeneIds (GRCh38): ENSG00000152977
EnsemblGeneIds (GRCh37): ENSG00000152977
OMIM: 600470, Gene2Phenotype
ZIC1 is in 7 panels

2 reviews

Crystle Lee (Victorian Clinical Genetics Services)

I don't know

Single paper from 2015 with reports of variants in ZIC1 - unsure if JS phenotype? Amber/Red

PMID: 26340333; Reported 5 families with coronal craniosynotosis and learning disabilities with inconsistent brain abnormalities (1 pt with abnormalities of the cerebellum and pons). 4 nonsense and 1 missense reported to cause disease through GoF mechanism

PMID: 9412507; Zic1 deficient mice presented with ataxia and cerebellar hypoplasia (1998)

PMID: 14981711; This 2004 paper acknowledges that null mice shows JS phenotype, but excluded ZIC1 as causative gene because no pathogenic variants found in cohort of 47 JS patients
Created: 4 May 2020, 12:12 a.m. | Last Modified: 4 May 2020, 12:17 a.m.
Panel Version: 0.20

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Structural brain anomalies with impaired intellectual development and craniosynostosis (MIM#618736)

Publications

Mode of pathogenicity
Other

Created: 4 May 2020, 12:06 a.m.
Last Modified: 4 May 2020, 12:17 a.m.
Panel version: Imported from Joubert syndrome and other neurological ciliopathies panel version 0.20

Chirag Patel (Genetic Health Queensland)

Green List (high evidence)

5 families with heterozygous mutations located in the final (third) exon of ZIC1 who have a distinct phenotype in which severe craniosynostosis, specifically involving the coronal sutures, and variable learning disability are the most characteristic features. The location of the nonsense mutations predicts escape of mutant ZIC1 transcripts from nonsense-mediated decay, which was confirmed in a cell line from an affected individual. Both nonsense and missense mutations are associated with altered and/or enhanced expression of a target gene, engrailed-2, in a Xenopus embryo assay. Analysis of mouse embryos revealed a localized domain of Zic1 expression at embryonic days 11.5-12.5 in a region overlapping the supraorbital regulatory center, which patterns the coronal suture.

2 sibs with BAIDCS, Vandervore et al. (2018) identified heterozygosity for a frameshift mutation in the ZIC1 gene. Neither parent had evidence of the mutation by whole-exome sequencing, suggesting that gonadal mosaicism for the mutation was present in one of the parents. Expression of the mutated allele was detected in patient fibroblasts by RT-PCR, evidence that the mutant mRNA did not undergo nonsense-mediated decay and probably generates an abnormal protein.


Also heterozygous deletions of ZIC1 on chromosome 3q25.1 are associated with Dandy-Walker malformation of the cerebellum. Loss of the orthologous Zic1 gene in the mouse causes cerebellar hypoplasia and vertebral defects.
Sources: Expert list
Created: 12 Feb 2020, 12:58 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Structural brain anomalies with impaired intellectual development and craniosynostosis; OMIM #618736 

Publications

Created: 12 Feb 2020, 12:58 a.m.

Panel version: Imported from Intellectual disability syndromic and non-syndromic panel version 0.2117

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Genomics England PanelApp
  • Expert list
  • Victorian Clinical Genetics Services
Phenotypes
  • Structural brain anomalies with impaired intellectual development and craniosynostosis
  • OMIM#618736
OMIM
600470
Clinvar variants
Variants in ZIC1
Penetrance
None
Publications
Panels with this gene

History Filter Activity

19 Jan 2022, Gel status: 3

Entity classified by Genomics England curator

Seb Lunke (Victorian Clinical Genetics Services)

Gene: zic1 has been classified as Green List (High Evidence).

19 Jan 2022, Gel status: 3

Set Phenotypes

Seb Lunke (Victorian Clinical Genetics Services)

Phenotypes for gene: ZIC1 were changed from CRANIOSYNOSTOSIS 6 to Structural brain anomalies with impaired intellectual development and craniosynostosis; OMIM#618736

19 Jan 2022, Gel status: 3

Set publications

Seb Lunke (Victorian Clinical Genetics Services)

Publications for gene: ZIC1 were set to

19 Jan 2022, Gel status: 3

Set mode of inheritance

Seb Lunke (Victorian Clinical Genetics Services)

Mode of inheritance for gene: ZIC1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

24 Oct 2021, Gel status: 3

Created, Added New Source, Set mode of inheritance, Set Phenotypes

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

gene: ZIC1 was added gene: ZIC1 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: ZIC1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: ZIC1 were set to CRANIOSYNOSTOSIS 6