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Gene expression changes between patent and fused cranial sutures in a nonsyndromic craniosynostosis population.

ABSTRACT: OBJECTIVE:Craniosynostosis is a premature fusion of 1 or more cranial sutures. It may occur with additional morphological abnormalities (syndromic) or in isolation. Studies suggest that dysregulation of normal cell proliferation, differentiation, and migration has a role in isolated or nonsyndromic craniosynostosis but the molecular mechanisms remain unknown. The aim of this research is to identify genes differentially expressed in prematurely fused human suture compared to patent suture in nonsyndromic craniosynostosis. METHODS:Bone fragments from synostosed and patent sutures of 7 infants with nonsyndromic craniosynostosis were collected during surgical release of fused sutures. RNA was isolated from the fragments (7 patent and 7 fused) and global gene expression profiled using the Illumina WGE-DASL assay and HumanRef 8.0 Beadchip. RESULTS:Comparison of mRNA expression in fused and patent suture identified 68 genes significantly differentially expressed and having fold changes ? -2.0 and ? 2.0 with a false discovery rate adjusted P value at .10 and 136 with adjusted P value of 0.15. SFRP2 (secreted frizzled-related protein 2) demonstrated the largest decrease in fused sutures. Analysis including only sagittal fused sutures revealed a set of 35 overlapping genes that may be involved in suture patency over all suture types. SPHKAP (sphingosine kinase type 1-interacting protein), a modulator of TGF? signaling, was significant in the sagittal subset. CONCLUSION:Differentially expressed genes were identified in fused suture relative to patent in a nonsyndromic craniosynostosis population. SFRP2 is likely important in suture patency. Genes having significant roles in osteoblastogenesis as negative regulators of canonical Wnt pathway were significantly downregulated.

SUBMITTER: Potter AB

PROVIDER: S-EPMC4401998 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Gene expression changes between patent and fused cranial sutures in a nonsyndromic craniosynostosis population.

Potter Amiee B AB Rhodes Jennifer L JL Vega Rafael A RA Ridder Thomas T Shiang Rita R

Eplasty 20150410

<h4>Objective</h4>Craniosynostosis is a premature fusion of 1 or more cranial sutures. It may occur with additional morphological abnormalities (syndromic) or in isolation. Studies suggest that dysregulation of normal cell proliferation, differentiation, and migration has a role in isolated or nonsyndromic craniosynostosis but the molecular mechanisms remain unknown. The aim of this research is to identify genes differentially expressed in prematurely fused human suture compared to patent suture ...[more]

PMID: 25987937

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Project description:BackgroundNonsyndromic craniosynostosis is one of the most common anomalies treated by craniofacial surgeons. Despite optimal surgical management, nearly half of affected children have subtle neurocognitive deficits. Whereas timing and type of surgical intervention have been studied, the possibility of genetic influence on neurodevelopment in nonsyndromic craniosynostosis patients remains unexplored.MethodsThe authors performed whole-exome sequencing for 404 case-parent trios with sporadic nonsyndromic craniosynostosis. Statistical analyses were performed to assess the burden of de novo mutations in cases compared to both expectation and 1789 healthy control trios. Individuals with and without each mutation class were analyzed, and the presence or absence of various types of neurodevelopmental delay were recorded alongside demographic information.ResultsThe authors identified a highly significant burden of damaging de novo mutations in mutation-intolerant [probability of loss of function intolerance (pLI) >0.9] genes in nonsyndromic craniosynostosis probands (p = 5.9 × 10-6). Children with these mutations had a two-fold higher incidence of neurodevelopmental delay (p = 0.001) and a more than 20-fold greater incidence of intellectual disability (p = 7.2 × 10-7), and were 3.6-fold more likely to have delays that persisted past 5 years of age (p = 4.4 × 10-4) in comparison with children with nonsyndromic craniosynostosis without these mutations. Transmitted loss of function mutations in high-pLI genes also conferred a 1.9-fold greater risk of neurodevelopmental delay (p = 4.5 ×10-4).ConclusionsThese findings implicate genetic lesions concurrently impacting neurodevelopment and cranial morphogenesis in the pathoetiology of nonsyndromic craniosynostosis and identify a strong genetic influence on neurodevelopmental outcomes in affected children. These findings may eventually prove useful in determining which children with nonsyndromic craniosynostosis are most likely to benefit from surgical intervention.Clinical question/level of evidenceRisk, III.

Dataset Information

Gene expression changes between patent and fused cranial sutures in a nonsyndromic craniosynostosis population.

Publications

Gene expression changes between patent and fused cranial sutures in a nonsyndromic craniosynostosis population.

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