Transcriptomic Signatures of Single-Suture Craniosynostosis Phenotypes
Open accessAbstract
Craniosynostosis is a birth defect where calvarial sutures close prematurely, as part of a genetic syndrome or independently, with unknown cause. This study aimed to identify differences in gene expression in primary calvarial cell lines derived from patients with four phenotypes of single-suture craniosynostosis, compared to controls. Calvarial bone samples (N = 388 cases/85 controls) were collected from clinical sites during reconstructive skull surgery. Primary cell lines were then derived from the tissue and used for RNA sequencing. Linear models were fit to estimate covariate adjusted associations between gene expression and four phenotypes of single-suture craniosynostosis (lambdoid, metopic, sagittal, and coronal), compared to controls. Sex-stratified analysis was also performed for each phenotype. Differentially expressed genes (DEGs) included 72 genes associated with coronal, 90 genes associated with sagittal, 103 genes associated with metopic, and 33 genes associated with lambdoid craniosynostosis. The sex-stratified analysis revealed more DEGs in males (98) than females (4). There were 16 DEGs that were homeobox (HOX) genes. Three TFs (SUZ12, EZH2, AR) significantly regulated expression of DEGs in one or more phenotypes. Pathway analysis identified four KEGG pathways associated with at least one phenotype of craniosynostosis. Together, this work suggests unique molecular mechanisms related to craniosynostosis phenotype and fetal sex.
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The majority of studies reported an odds ratio of male occurring CS ranging from 1.46 to 4.5, with a geometric mean of ~2.7.
“The majority of the studies studied the odds ratio of male occurring CS with an OR ranging from 1.46 to 4.5 (with geometric mean of ~ 2.7) [2, 3, 15, 26, 50, 53, 74, 80, 82, 86, 96–98, 102, 103, 117].”
From Genetics versus environment in the pathophysiology of sagittal synostosis (2026) · cites this paper as [80]
The Introduction (section 1; page unavailable) reports nearly fourfold higher incidence among males for sagittal and metopic single-suture craniosynostosis, supporting a sex difference for those phenotypes. It does not report odds ratios across the majority of studies, a range of 1.46–4.5, or a geometric mean of about 2.7. It also notes that coronal cases are slightly more frequent among females. (LLM, conf=0.87)
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References 65 · Cited by 3
Research works printed but not linked: 1
- [7]Cohen M.M. MacLean R.E. Craniosynostosis: Diagnosis, Evaluation, and Management Oxford University Press New York, NY, USA 2000 464
- Authors
- Lapehn, S., Gustafson, J. A., Timms, A. E., Cunningham, M. L., & Paquette, A. G.
- Affiliations
- Seattle Children's Research Institute (US)
- University of Washington (US)
- Corresponding author
- Paquette, Alison G.
- Venue
- International Journal of Molecular Sciences
- Publisher
- MDPI AG
- Published
- 2023-03-10
- Volume
- 24
- Issue
- 6
- Pages
- 5353
- ISSN
- 1422-0067 (ISSN-L)
- PMC
- PMC10049207
- OpenAlex
- W4324059076
- Cited by
- 3
- References
- 65
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1
- FWCI
- 0.50
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- International Journal of Molecular Sciences (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- NIH NIDCR DE018227 (MLC)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Craniofacial Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › dental development and anomalies
- Health Sciences › Medicine › Surgery › Reconstructive Facial Surgery Techniques
- Keywords
- single-suture craniosynostosis, lambdoid craniosynostosis, metopic craniosynostosis, sagittal craniosynostosis, coronal craniosynostosis, sex differences, homeobox genes, SUZ12, EZH2, androgen receptor, differentially expressed genes, KEGG pathways, gene expression signatures
- MeSH terms
- Cranial Sutures, Craniosynostoses, Female, Humans, Male, Skull, Sutures, Transcriptome
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