Abstract
Lambdoid craniosynostosis (CS) is a congenital anomaly resulting from premature fusion of the cranial suture between the parietal and occipital bones. Predominantly sporadic, it is the rarest form of CS and its genetic etiology is largely unexplored. Exome sequencing of 25 kindreds, including 18 parent–offspring trios with sporadic lambdoid CS, revealed a marked excess of damaging (predominantly missense) de novo mutations that account for ~ 40% of sporadic cases. These mutations clustered in the BMP signaling cascade (P = 1.6 × 10–7), including mutations in genes encoding BMP receptors (ACVRL1 and ACVR2A), transcription factors (SOX11, FOXO1) and a transcriptional co-repressor (IFRD1), none of which have been implicated in other forms of CS. These missense mutations are at residues critical for substrate or target sequence recognition and many are inferred to cause genetic gain-of-function. Additionally, mutations in transcription factor NFIX were implicated in syndromic craniosynostosis affecting diverse sutures. Single cell RNA sequencing analysis of the mouse lambdoid suture identified enrichment of mutations in osteoblast precursors (P = 1.6 × 10−6), implicating perturbations in the balance between proliferation and differentiation of osteoprogenitor cells in lambdoid CS. The results contribute to the growing knowledge of the genetics of CS, have implications for genetic counseling, and further elucidate the molecular etiology of premature suture fusion.
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Data availability
The sequences for case-parent trios reported in the paper have been deposited in the NCBI database of Genotypes and Phenotypes (dbGaP) under accession phs000744.
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Acknowledgements
This project was supported by the Yale Center for Mendelian Genomics (NIH Grant M#UM1HG006504-05). This study makes use of data generated by the DECIPHER community. A full list of centres who contributed to the generation of the data is available from https://decipher.sanger.ac.uk and via email from decipher@sanger.ac.uk. Funding for the DECIPHER project was provided by Wellcome.
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ATT; conceptualization, formal analysis, investigation, writing—original draft, writing—review and editing, EK; investigation; SCJ; investigation, CNW; project administration, investigation, EL; project administration, investigation, Yale Center for Genome Analysis; project administration, AA; visualization, AA; visualization, SB; investigation, HS.; investigation, MRPB; investigation, RR; investigation, SRR; investigation, ET; investigation, ALS; investigation, TJB; investigation, MA, investigation; DS; investigation, DAS; investigation; RLF; investigation, JAP; investigation, KTK, investigation, writing; RPL, conceptualization, project administration, funding acquisition, writing—original draft, writing—review and editing.
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Timberlake, A.T., Kiziltug, E., Jin, S.C. et al. De novo mutations in the BMP signaling pathway in lambdoid craniosynostosis. Hum Genet 142, 21–32 (2023). https://doi.org/10.1007/s00439-022-02477-2
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DOI: https://doi.org/10.1007/s00439-022-02477-2