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Genomic analysis of 1000 craniosynostosis trios defines molecular mechanisms of disease
Andrew T. Timberlake1, Garrett Allington2, Emre Kiziltug2, Alexandra Junn3, David A Staffenberg1, Roberto Flores1, Michael Alperovich3, Sheng Chih Jin4, John A. Persing3, Kristopher T. Kahle5
1 Hansjörg Wyss Department of Plastic and Reconstructive Surgery, NYU Langone Medical Center, New York, NY, USA2 Department of Pathology, Yale University School of Medicine, New Haven, CT, USA3 Section of Plastic and Reconstructive Surgery, Yale University School of Medicine, New Haven, CT, USA 4 Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA5 Department

Background: Next generation sequencing technologies have resulted in genetic diagnoses for many forms of craniosynostosis (CS), however the molecular mechanisms of disease remain largely unexplored. In the largest cohort of CS patients studied to date, we sought to characterize how mutations identified in craniosynostosis probands might concomitantly impact suture fusion and neurodevelopment.
Methods: We analyzed exome sequencing data from 1000 trios with craniosynostosis to identify novel genes and pathways implicated in the pathoetiology of CS. Bulk RNA-sequence data were used to build a spatiotemporal expression map of the developing brain, and scRNA sequence data was used to identify cell types expressing genes of interest at critical neurodevelopmental timepoints in both syndromic and nonsyndromic forms of CS.
Results: We replicate a previous association of damaging de novo mutations in Wnt, BMP, and FGF/MAPK signaling to NSC, and identify mutations in >20 novel genes in syndromic CS that cause epigenetic and transcriptional dysregulation. We also describe a novel CS syndrome caused by a recurrent de novo missense mutation impacting retinoic acid signaling. Transcriptomic analyses suggest that depletion of mid-fetal (post conception weeks 8-21) stem cell populations affecting osteoblast differentiation, neural differentiation, and meningeal fibroblast proliferation underlie premature suture fusion and aberrant neurodevelopment.
Conclusions: Craniosynostosis is a neurodevelopmental disorder in which genetic perturbations dysregulate both neurogenesis and suture homeostasis. The results provide a framework for further large scale investigation of genetic and neurodevelopmental anomalies in CS.


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