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

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.

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

Twelve families segregated a phenotype comprising craniosynostosis with facial dysmorphism, structural brain abnormalities and developmental delay, whereas 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.

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