Journal article
Expanding the phenotypic spectrum associated with ZIC1 variants: a neurodevelopmental disorder with and without craniosynostosis
Genetics in medicine, Vol.28(6), 102585
06/2026
DOI: 10.1016/j.gim.2026.102585
PMID: 42028696
Abstract
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, 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.
This study presents evidence for a ZIC1 genotype-phenotype correlation differentiating variants that cause a neurodevelopmental phenotype with and without craniosynostosis.
Details
- Title: Subtitle
- Expanding the phenotypic spectrum associated with ZIC1 variants: a neurodevelopmental disorder with and without craniosynostosis
- Creators
- Laura M. Watts - Oxford University Hospitals NHS TrustMichelle S.M. Chang - Australian National UniversityElizabeth Lewis-Orr - University of OxfordIsaac S. Walton - University of OxfordLisa Leinhos - University of OxfordRebecca S. Tooze - University of OxfordYang Pei - University of OxfordEduardo Calpena - Instituto de Investigación Sanitaria La FeJ. Heather Vedovato-dos-Santos - University of OxfordDora Steel - Great Ormond Street HospitalKimberley M. Reid - Great Ormond Street HospitalManju A. Kurian - Great Ormond Street HospitalShekeeb S. Mohammad - The University of SydneyVincent Cantagrel - InsermKarine Siquier - InsermNathalie Boddaert - InsermMarlene Rio - Hôpital Necker-Enfants MaladesMoira Blyth - University of AberdeenAlison Kraus - Chapel Allerton HospitalFuad Al Mutairi - King Saud bin Abdulaziz University for Health SciencesSusan E. Holder - London North West Healthcare NHS TrustVirginia E. Clowes - London North West Healthcare NHS TrustJan M. Cobben - Genomics EnglandAndrew T. Timberlake - NYU Langone HealthEllen R. Elias - University of Colorado Anschutz Medical CampusHelen Stewart - Oxford University Hospitals NHS TrustDiana Johnson - John Radcliffe HospitalJulie S. Cohen - Kennedy Krieger InstituteKristin W. Barañano - Johns Hopkins UniversitySophia Ceulemans - Rady Children's Hospital-San DiegoMarilyn C. Jones - Rady Children's Hospital-San DiegoRita I. Ortega Rico - Fundación Centro Colombiano de Epilepsia y Enfermedades Neurológicas, FIRE, Cartagena de Indias, ColombiaMarte G. Haug - St Olav's University HospitalSiren Berland - Haukeland University HospitalHannah M. Bombei - University of IowaAnna Paulson - University of Iowa Health CareAlpa Sidhu - University of IowaCatherine F. Gooch - Washington University in St. LouisKátia M. da Rocha - Institute of Human GeneticsMaria Rita Passos Bueno - Universidade de São PauloAlexandra Ţopa - Sahlgrenska University HospitalAida Z. Muslimovic - Sahlgrenska University HospitalGiovanni Maltese - University of GothenburgTiong Yang Tan - Victorian Clinical Genetics ServicesEmma McCann - University of LiverpoolHelen Lord - Churchill HospitalHui-lin Chin - Division of Genetics and Metabolism, Khoo Teck Puat-National University Children’s Medical Institute, National University Hospital, SingaporeJeremy Lin - National University of SingaporeDenise Li-Meng Goh - Division of Genetics and Metabolism, Khoo Teck Puat-National University Children’s Medical Institute, National University Hospital, SingaporeBoris Keren - Sorbonne UniversitéPerrine Charles - Sorbonne UniversitéTrayan Delchev - Medical University of SofiaDaniela Avdjieva-Tzavella - Medical University of SofiaSalem Alawbathani - Centogene (Germany)Ligia Almeida - Centogene (Germany)Ameni Kdissa - Centogene (Germany)Ruslan Al-Ali - Centogene (Germany)Aida M. Bertoli-Avella - Centogene (Germany)David Johnson - John Radcliffe HospitalAndrew O.M. Wilkie - Oxford BioMedica (United Kingdom)Ruth M. Arkell - Australian National UniversityDeborah J. Shears - Oxford University Hospitals NHS TrustStephen R.F. Twigg - MRC Weatherall Institute of Molecular Medicine
- Resource Type
- Journal article
- Publication Details
- Genetics in medicine, Vol.28(6), 102585
- DOI
- 10.1016/j.gim.2026.102585
- PMID
- 42028696
- NLM abbreviation
- Genet Med
- ISSN
- 1098-3600
- eISSN
- 1530-0366
- Publisher
- Elsevier Inc; AMSTERDAM
- Grant note
- NIHR Radcliffe Department of Medicine Exeter College (Oxford) MRC Clarendon Fund Mary Somerville Graduate Scholarship Instituto de Salud Carlos III (ISCIII, Spain): CP23/00073 European Social Fund Plus (ESF+) from the European Union ANR: ANR-10-IAHU-01 MSDAVENIR fund: DEVODECODE project NIHR Oxford Biomedical Research Centre VTCT Foundation MRC: MR/T031670/1 MRC National Mouse Genetics Network: MC_PC_21044
This work was supported by an NIHR Academic Clinical Fellowship (L.W.); Doctoral Training Program studentship funded jointly by the Radcliffe Department of Medicine, the Exeter College (Oxford) Usher Cunningham Scholarship, and the MRC (R.S.T.); Doctoral Training Program studentship funded jointly by the Radcliffe Department of Medicine, Clarendon Fund, Mary Somerville Graduate Scholarship, and MRC (I.W.); a Miguel Servet fellowship (CP23/00073) from Instituto de Salud Carlos III (ISCIII, Spain) and cofunded by the European Social Fund Plus (ESF+) from the European Union (E.C.); ANR ''Investissements d'avenir'' program: ANR-10-IAHU-01, and the MSDAVENIR fund: DEVODECODE project (VC), the NIHR Oxford Biomedical Research Centre Program (S.R.F.T., A.O.M.W), the VTCT Foundation (S.R.F.T., A.O.M.W.), and the MRC: Project Grant MR/T031670/1 (A.O.M.W.), MRC National Mouse Genetics Network (MC_PC_21044; S.R.F.T.).
- Language
- English
- Electronic publication date
- 04/22/2026
- Date published
- 06/2026
- Academic Unit
- Stead Family Department of Pediatrics; Medical Genetics and Genomics
- Record Identifier
- 9985157610702771
Metrics
1 Record Views