Expanding the phenotypic spectrum associated with ZIC1 variants: a neurodevelopmental disorder with and without craniosynostosis.
Watts LM., Chang MSM., Lewis-Orr E., Walton IS., Leinhos L., Tooze RS., Pei Y., Calpena E., Vedovato-Dos-Santos JH., Steel D., Reid KM., Kurian MA., Mohammad SS., Cantagrel V., Siquier K., Boddaert N., Rio M., Blyth M., Kraus A., Al Mutairi F., Holder SE., Clowes VE., Cobben JM., Timberlake AT., Elias ER., Stewart H., Johnson D., Cohen JS., Barañano KW., Ceulemans S., Jones MC., Ortega Rico RI., Haug MG., Berland S., Bombei HM., Paulson A., Sidhu A., Gooch CF., da Rocha KM., Passos Bueno MR., Ţopa A., Muslimovic AZ., Maltese G., Tan TY., McCann E., Lord H., Chin H-L., 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 AM., Johnson D., Wilkie AOM., Arkell RM., Shears DJ., Twigg SRF.
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.