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

Tooze, RS; Miller, KA; Swagemakers, SMA; Calpena, E; McGowan, SJ; Boute, O; Collet, C; Johnson, D; Laffargue, F; de Leeuw, N; Morton, JV; Noons, P; Ockeloen, CW; Phipps, JM; Tan, TY; Timberlake, AT; Vanlerberghe, C; Wall, SA; Weber, A; Wilson, LC; Zackai, EH; Mathijssen, IMJ; Twigg, SRF; Wilkie, AOM

Journal article

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

Abstract:: Purpose
Studies previously implicated PRRX1 in craniofacial development, including demonstration of murine Prrx1 expression in the pre-osteogenic cells of the cranial sutures. We investigated the role of heterozygous missense and loss-of-function 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 9/1449 patients with craniosynostosis harboring deletions or rare heterozygous variants within the homeodomain. By collaboration, seven additional individuals (four 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 multi-suture synostosis was present in 11/17 (65% of the cases). 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.

Publication status:: Published

Peer review status:: Peer reviewed

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APA Style

Tooze, R. S., Miller, K. A., Swagemakers, S. M. A., Calpena, E., McGowan, S. J., Boute, O., Collet, C., Johnson, D., Laffargue, F., de Leeuw, N., Morton, J. V., Noons, P., Ockeloen, C. W., Phipps, J. M., Tan, T. Y., Timberlake, A. T., Vanlerberghe, C., Wall, S. A., Weber, A., … Wilkie, A. O. M. (2023). Pathogenic variants in the paired-related homeobox 1 gene (PRRX1) cause craniosynostosis with incomplete penetrance. Genetics in Medicine, 25(9).

MLA Style

Tooze, R. S., et al. “Pathogenic Variants in the Paired-Related Homeobox 1 Gene (PRRX1) Cause Craniosynostosis with Incomplete Penetrance.” Genetics in Medicine, vol. 25, no. 9, Elsevier, 2023.

Chicago Style

Tooze, RS, KA Miller, SMA Swagemakers, E Calpena, SJ McGowan, O Boute, C Collet, et al. 2023. “Pathogenic Variants in the Paired-Related Homeobox 1 Gene (PRRX1) Cause Craniosynostosis with Incomplete Penetrance.” Genetics in Medicine 25 (9).
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