Submission Details

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).