Pathogenic variants in the paired-related homeobox 1 gene (PRRX1) cause craniosynostosis with incomplete penetrance

Rebecca S. Tooze, Kerry A. Miller, Sigrid M.A. Swagemakers, Eduardo Calpena, Simon J. McGowan, Odile Boute, Corinne Collet, David Johnson, Fanny Laffargue, Nicole de Leeuw, Jenny V. Morton, Peter Noons, Charlotte W. Ockeloen, Julie M. Phipps, Tiong Yang Tan, Andrew T. Timberlake, Clemence Vanlerberghe, Steven A. Wall, Astrid Weber, Louise C. WilsonElaine H. Zackai, Irene M.J. Mathijssen, Stephen R.F. Twigg*, Andrew O.M. Wilkie

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)
23 Downloads (Pure)


Purpose: Studies have previously implicated PRRX1 in craniofacial development, including demonstration of murine Prrx1 expression in the preosteogenic cells of the cranial sutures. We investigated the role of heterozygous missense and loss-of-function (LoF) variants in PRRX1 associated with craniosynostosis. Methods: Trio-based genome, exome, or targeted sequencing were used to screen PRRX1 in patients with craniosynostosis; immunofluorescence analyses were used to assess nuclear localization of wild-type and mutant proteins. Results: Genome sequencing identified 2 of 9 sporadically affected individuals with syndromic/multisuture craniosynostosis, who were heterozygous for rare/undescribed variants in PRRX1. Exome or targeted sequencing of PRRX1 revealed a further 9 of 1449 patients with craniosynostosis harboring deletions or rare heterozygous variants within the homeodomain. By collaboration, 7 additional individuals (4 families) were identified with putatively pathogenic PRRX1 variants. Immunofluorescence analyses showed that missense variants within the PRRX1 homeodomain cause abnormal nuclear localization. Of patients with variants considered likely pathogenic, bicoronal or other multisuture synostosis was present in 11 of 17 cases (65%). Pathogenic variants were inherited from unaffected relatives in many instances, yielding a 12.5% penetrance estimate for craniosynostosis. Conclusion: This work supports a key role for PRRX1 in cranial suture development and shows that haploinsufficiency of PRRX1 is a relatively frequent cause of craniosynostosis.

Original languageEnglish
Article number100883
JournalGenetics in Medicine
Issue number9
Publication statusPublished - Sept 2023

Bibliographical note

Funding Information:
This work was supported by a 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.). The research conducted at the Murdoch Children’s Research Institute was supported by the Victorian Government’s Operational Infrastructure Support Program; the “Undiagnosed Diseases Project Victoria” (UDP-Vic; RCH HREC 36291A) acknowledges financial support from the Murdoch Children’s Research Institute and the Harbig Foundation (T.Y.T.). T.Y.T. was supported by Victorian Clinical Genetics Services and Murdoch Children’s Research Institute to undertake a sabbatical with A.O.M.W. Work in Oxford was supported by the National Institute for Health and Care Research Oxford Biomedical Research Centre Program (A.O.M.W.), the WIMM Strategic Alliance (G0902418 and MC UU 12025), Wellcome (102731 to A.O.M.W.), the VTCT Foundation (S.R.F.T., A.O.M.W.), and the MRC through Project Grant MR/T031670/1 (A.O.M.W.).

Publisher Copyright:
© 2023 The Authors


Dive into the research topics of 'Pathogenic variants in the paired-related homeobox 1 gene (PRRX1) cause craniosynostosis with incomplete penetrance'. Together they form a unique fingerprint.

Cite this