Intellectual disability
Gene: ZIC1

ZIC1 (Zic family member 1)
EnsemblGeneIds (GRCh38): ENSG00000152977
EnsemblGeneIds (GRCh37): ENSG00000152977
OMIM: 600470, Gene2Phenotype
ZIC1 is in 5 panels

5 reviews

Sarah Leigh (Genomics England Curator)

The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Created: 9 Mar 2022, 3:40 p.m. | Last Modified: 9 Mar 2022, 3:40 p.m.

Panel Version: 3.1510

Created: 9 Mar 2022, 3:40 p.m.
Last Modified: 9 Mar 2022, 3:40 p.m.
Panel version: 3.1510

Arina Puzriakova (Genomics England Curator)

Green List (high evidence)

Comment on list classification: There is sufficient evidence for this gene to be rated Green at the next GMS panel update (added 'for-review' tag)
Created: 28 Oct 2020, 11:53 a.m. | Last Modified: 28 Oct 2020, 11:53 a.m.

Panel Version: 3.490

Associated with phenotype in OMIM, and a 'confirmed' gene for Craniosynostosis 6 in Gene2Phenotype.

At least 5 variants reported in 6 unrelated families with intellectual disability (2 mild, 1 moderate, 2 moderate-severe, 1 severe) among other variable CNS abnormalities including craniosynostosis, callosal dysgenesis, anomaly in cerebellar hemispheres, vermis and pons, spinal dysraphism, as well as skull abnormalities not associated with craniosynostosis.

Predicted that both gain- and loss-of-function variants can be deleterious.
Created: 28 Oct 2020, 11:47 a.m. | Last Modified: 28 Oct 2020, 12:12 p.m.

Panel Version: 3.491

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

Phenotypes
?Craniosynostosis 6, 616602; Structural brain anomalies with impaired intellectual development and craniosynostosis, 618736

Publications

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Created: 28 Oct 2020, 11:47 a.m.
Last Modified: 28 Oct 2020, 12:12 p.m.
Panel version: 3.489

Zornitza Stark (Australian Genomics)

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.
Created: 4 Mar 2020, 1:40 a.m. | Last Modified: 4 Mar 2020, 1:40 a.m.

Panel Version: 3.3

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

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

Publications

Variants in this GENE are reported as part of current diagnostic practice

Created: 4 Mar 2020, 1:40 a.m.
Last Modified: 4 Mar 2020, 1:40 a.m.
Panel version: 3.3

BRIDGE consortium (NIHRBR-RD)

Green List (high evidence)

This is a pertinent gene from the NIHR BioResource - Rare Diseases Study (NIHRBR-RD) BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene is on the SPEED_NEURO_20170705 gene list. Evidences used for SPEED NEURO gene list: in_ddg2p_2_4_2017;in_ddg2p_2_4_2017_conf . Main mutation mechanism : activating
Created: 27 Jul 2017, 8:58 p.m.

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

Publications

25529582

Mode of pathogenicity
Other

Created: 2 Aug 2017, 11:28 p.m.

Panel version: 1.354

Louise Daugherty (Genomics England Curator)

Comment on list classification: This gene is from an expert list and needs further assessment by the Genomics England curation team to access inclusion and pertinence to this panel.
Created: 28 Jul 2017, 5:13 p.m.

Created: 28 Jul 2017, 5:13 p.m.

Panel version: 1.351

Details

Mode of Inheritance

MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Sources

Expert Review Green

Phenotypes

Structural brain anomalies with impaired intellectual development and craniosynostosis, 618736
?Craniosynostosis 6, 616602

OMIM

600470

Clinvar variants

Variants in ZIC1

Penetrance

Complete

Publications

Mode of Pathogenicity

Other - please provide details in the comments

Panels with this gene