AI Article Synopsis

  • Nonsyndromic craniosynostosis (nsCS) affects brain growth due to premature skull suture fusion, potentially leading to ongoing neurocognitive issues in affected children despite surgery.
  • The study combined genetic sequencing from 291 families with single-cell data to explore when and where nsCS-related genes impact development.
  • Findings revealed that nsCS genes interact mainly in cranial cells involved in skull formation and brain development, indicating that mutations may play a larger role in neurodevelopmental outcomes than the surgical repair itself.

Article Abstract

Objective: Nonsyndromic craniosynostosis (nsCS), characterized by premature cranial suture fusion, is considered a primary skull disorder in which impact on neurodevelopment, if present, results from the mechanical hindrance of brain growth. Despite surgical repair of the cranial defect, neurocognitive deficits persist in nearly half of affected children. Therefore, the authors performed a functional genomics analysis of nsCS to determine when, where, and in what cell types nsCS-associated genes converge during development.

Methods: The authors integrated whole-exome sequencing data from 291 nsCS proband-parent trios with 29,803 single-cell transcriptomes of the prenatal and postnatal neurocranial complex to inform when, where, and in what cell types nsCS-mutated genes might exert their pathophysiological effects.

Results: The authors found that nsCS-mutated genes converged in cranial osteoprogenitors and pial fibroblasts and their transcriptional networks that regulate both skull ossification and cerebral neurogenesis. Nonsyndromic CS-mutated genes also converged in inhibitory neurons and gene coexpression modules that overlapped with autism and other developmental disorders. Ligand-receptor cell-cell communication analysis uncovered crosstalk between suture osteoblasts and neurons via the nsCS-associated BMP, FGF, and noncanonical WNT signaling pathways.

Conclusions: These data implicate a concurrent impact of nsCS-associated de novo mutations on cranial morphogenesis and cortical development via cell- and non-cell-autonomous mechanisms in a developmental nexus of fetal osteoblasts, pial fibroblasts, and neurons. These results suggest that neurodevelopmental outcomes in nsCS patients may be driven more by mutational status than surgical technique.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10783441PMC
http://dx.doi.org/10.3171/2023.8.PEDS23155DOI Listing

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