ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000003.11) (NC_000003.12)
  • Haploinsufficiency score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Haploinsufficiency phenotype comments:

Deletions that encompass only ZIC1 have not been reported, and the clinical consequence of haploinsufficiency for ZIC1 alone is therefore unknown. For this reason, the haploinsufficiency score is 0. Heterozygous nonsense variants in the last exon of ZIC1, or last 50 nucleotides of the penultimate exon, have been reported in six apparently unrelated individuals with craniosynostosis (additional developmental/neurodevelopmental phenotypes in PMIDs: 27884935, 25985138, 26340333). The variants arose de novo in 5/5 cases where parental samples were available for testing, and are not expected to result in nonsense mediated decay. Twigg et al. (2015), PMID: 26340333 confirmed expression of cDNA transcripts containing the premature stop codon in cultured scalp fibroblasts from four subjects with nonsense variants. Expression levels were approximately equal to that of the wildtype transcript. Injection of ZIC1 RNA constructs that modeled patient variants into zebrafish embryos resulted in disruption of 66-79% of embryos, compared to just 8% when full length ZIC1 RNA was injected. The authors suggest the variants result in gain-of-function. For discussion of haploinsufficiency of the 3q24 Region (includes ZIC1), please see the linked region (ISCA-46553).

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

Case reports of whole gene duplications including only the ZIC1 gene have not been been reported. Therefore, the triplosensitivity score is 0.