{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T10:07:41Z","timestamp":1788430061564,"version":"build-2803163510"},"reference-count":44,"publisher":"Journal of Neurosurgery Publishing Group (JNSPG)","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,1,1]]},"abstract":"<jats:sec>\n<jats:title>OBJECTIVE<\/jats:title>\n<jats:p> 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.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>METHODS<\/jats:title>\n<jats:p> 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.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>RESULTS<\/jats:title>\n<jats:p> 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\u2013mutated 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.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>CONCLUSIONS<\/jats:title>\n<jats:p> These data implicate a concurrent impact of nsCS-associated de novo mutations on cranial morphogenesis and cortical development via cell- and non\u2013cell-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.<\/jats:p>\n<\/jats:sec>","DOI":"10.3171\/2023.8.peds23155","type":"journal-article","created":{"date-parts":[[2023,10,28]],"date-time":"2023-10-28T02:34:31Z","timestamp":1698460471000},"page":"59-72","source":"Crossref","is-referenced-by-count":7,"title":["Concurrent impact of de novo mutations on cranial and cortical development in nonsyndromic craniosynostosis"],"prefix":"10.3171","volume":"33","author":[{"given":"Emre","family":"Kiziltug","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phan Q.","family":"Duy","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, University of Virginia School of Medicine, Charlottesville, Virginia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Garrett","family":"Allington","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew T.","family":"Timberlake","sequence":"additional","affiliation":[{"name":"Hansj\u00f6rg Wyss Department of Plastic Surgery, New York University Langone Medical Center, New York, New York;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riki","family":"Kawaguchi","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron S.","family":"Long","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Plastic Surgery, Yale University School of Medicine, New Haven, Connecticut;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana N.","family":"Almeida","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Plastic Surgery, Yale University School of Medicine, New Haven, Connecticut;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael L.","family":"DiLuna","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seth L.","family":"Alper","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Nephrology and Vascular Biology Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Alperovich","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Plastic Surgery, Yale University School of Medicine, New Haven, Connecticut;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel H.","family":"Geschwind","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristopher T.","family":"Kahle","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts;"},{"name":"Broad Institute of MIT and Harvard, Cambridge, Massachusetts; and"},{"name":"Harvard Center for Developmental Brain Disorders, Massachusetts General Hospital, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1754","reference":[{"issue":"4","key":"b1","series-title":"Acta Neuropathol","first-page":"469","article-title":"Hand in glove: brain and skull in development and dysmorphogenesis","volume":"125","author":"Richtsmeier JT","year":"2013","unstructured":"Richtsmeier JT, Flaherty K. 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