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

Watts, L.; Chang, M.; Lewis-Orr, E.; Walton, I.; Leinhos, L.; Tooze, R.; Pei, Y.; Calpena, E.; Vedovato-Dos-Santos, J.; Steel, D.; Reid, K.; Kurian, M.; Mohammad, S.; Cantagrel, V.; Siquier, K.; Boddaert, N.; Rio, M.; Blyth, M.; Kraus, A.; Al Mutairi, F.; Holder, S.; Clowes, V.; Cobben, J.; Timberlake, A.; Elias, E.; Stewart, H.; Johnson, D.; Cohen, J.; Baranano, K.; Ceulemans, S.; Jones, M.; Ortega Rico, R.; Haug, M.; Berland, S.; Bombei, H.; Paulson, A.; Sidhu, A.; Gooch, C.; da Rocha, K.; Passos Bueno, M.; Topa, A.; Muslimovic, A.; Maltese, G.; Tan, T.; McCann, E.; Lord, H.; Chin, H.; Lin, J.; Li-Meng Goh, D.; Keren, B.; Charles, P.; Delchev, T.; Avdjieva-Tzavella, D.; Alawbathani, S.; Almeida, L.; Kdissa, A.; Al-Ali, R.; Bertoli-Avella, A.; Wilkie, A.; Arkell, R.; Shears, D.; Twigg, S.

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

All Authors

Watts, L.

Chang, M.

Lewis-Orr, E.

Walton, I.

Leinhos, L.

Tooze, R.

Pei, Y.

Calpena, E.

Vedovato-Dos-Santos, J.

Steel, D.

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LTHT Author

Kraus, Alison

LTHT Department

Pathology
Clinical Genetics
Yorkshire Regional Genetics Service

Publication Date

2026

Item Type

Journal Article

Abstract

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.