Expanding the phenotypic spectrum associated with ZIC1 variants: a neurodevelopmental disorder with and without craniosynostosis

Journal article

Purpose: ZIC1 encodes a transcription factor with critical roles in vertebrate neural and skeletal development. Heterozygous deletions encompassing ZIC1 and ZIC4 cause Dandy-Walker malformation, whilst in the final exon heterozygous ZIC1 variants result in a distinct phenotype of craniosynostosis with variable intellectual disability via a gain-of-function mechanism. We describe the largest group of individuals harboring ZIC1 variants to date, significantly expanding the phenotypic spectrum and allowing genotype-phenotype correlation.

Methods: Through international collaboration we identified 18 different heterozygous ZIC1 variants from 22 families, comprising 30 individuals.

Results: Twelve families segregated a phenotype comprising craniosynostosis with facial dysmorphism, structural brain abnormalities and developmental delay, while 10 families had a neurodevelopmental disorder alone without craniosynostosis. Variants associated with craniosynostosis were clustered in the final exon (3) and were predominantly truncating variants predicted to escape nonsense-mediated decay. Variants associated with neurodevelopmental disorder alone included missense substitutions within exons 1 and 2 predicted to disrupt the normal function of the zinc finger domain, leading to loss of ZIC1 function which was confirmed in a functional assay.

Conclusion: This study presents evidence for a ZIC1 genotype-phenotype correlation differentiating variants that cause a neurodevelopmental phenotype with and without craniosynostosis.

Authors: Watts, LM; Chang, MSM; Lewis-Orr, E; Walton, IS; Leinhos, L

• Publication status: In press
• Peer review status: Peer reviewed
• Publisher: Elsevier
• Journal: Genetics in Medicine
• Article number: 102585
• Publication date: 2026-04-22
• Acceptance date: 2026-02-11
• DOI: 10.1016/j.gim.2026.102585
• EISSN: 1530-0366
• ISSN: 1098-3600
• Language: English
• Keywords: craniosynostosis; neurodevelopmental disorder; ZIC1; loss-of-function; gain-of-function