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. 2023 Mar 10;24(6):5353.
doi: 10.3390/ijms24065353.

Transcriptomic Signatures of Single-Suture Craniosynostosis Phenotypes

Samantha Lapehn  1 , Jonas A Gustafson  1 , Andrew E Timms  1 , Michael L Cunningham  1   2 , Alison G Paquette  1   2
Affiliations

Transcriptomic Signatures of Single-Suture Craniosynostosis Phenotypes

Samantha Lapehn et al. Int J Mol Sci. .

Abstract

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.

Keywords: RNA sequencing; craniosynostosis; homeobox; transcriptome.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Differentially expressed genes (DEGs) (FDR < 0.05) for the primary model. DEGs are represented as blue (decreased) or orange (increased) points. The top 10 DEGs, based on log fold change, are labeled by gene ID. (A) Coronal phenotype, (B) sagittal phenotype, (C) metopic phenotype, (D) lambdoid phenotype, (E) number and direction of DEGs for each phenotype, (F) overlap of DEGs across phenotypes.
Figure 2
Figure 2
Comparison of differentially expressed genes (DEGs) for each phenotype model. (A) Comparison of DEG number across combined-sex, male-stratified, and female-stratified phenotype models. (B) Overlap of DEGs across models in coronal phenotype. (C) Overlap of DEGs across models in sagittal phenotype. (D) Overlap of DEGs across models in lambdoid phenotype. (E) Overlap of DEGs across models in metopic phenotype.
Figure 3
Figure 3
Homeobox DEGs for combined-sex and male-stratified phenotype models, shaded by log fold change. No homeobox genes were identified as DEGs in the female-stratified model.
Figure 4
Figure 4
Transcription factor enrichment analysis with Enrichr. (A) Significant transcription factors (TFs) (FDR < 0.05) for the combined-sex and male-stratified phenotype models identified through enrichment analysis with Enrichr. Red genes are homeobox genes. (B) Differentially expressed downstream genes of EZH2, shaded by log fold change (C) Differentially expressed downstream genes of SUZ12, shaded by log fold change.
See this image and copyright information in PMC

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