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Nonsyndromic craniosynostosis: novel coding variants




Craniosynostosis (CS), the premature fusion of one or more neurocranial sutures, is associated with approximately 200 syndromes; however, about 65–85% of patients present with no additional major birth defects.


We conducted targeted next-generation sequencing of 60 known syndromic and other candidate genes in patients with sagittal nonsyndromic CS (sNCS, n = 40) and coronal nonsyndromic CS (cNCS, n = 19).


We identified 18 previously published and 5 novel pathogenic variants, including three de novo variants. Novel variants included a paternally inherited c.2209C>G:p.(Leu737Val) variant in BBS9 of a patient with cNCS. Common variants in BBS9, a gene required for ciliogenesis during cranial suture development, have been associated with sNCS risk in a previous genome-wide association study. We also identified c.313G>T:p.(Glu105*) variant in EFNB1 and c.435G>C:p.(Lys145Asn) variant in TWIST1, both in patients with cNCS. Mutations in EFNB1 and TWIST1 have been linked to craniofrontonasal and Saethre–Chotzen syndrome, respectively; both present with coronal CS.


We provide additional evidence that variants in genes implicated in syndromic CS play a role in isolated CS, supporting their inclusion in genetic panels for screening patients with NCS. We also identified a novel BBS9 variant that further shows the potential involvement of BBS9 in the pathogenesis of CS.

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This work was supported by Eunice Kennedy Shriver National Institute of Child Health and Human Development [P01HD078233], and the Centers for Disease Control and Prevention [R01DD000350 and U01DD001035].

Author information

Authors made substantial contributions to conception and design (A.S., I.P., E.W.J., G.G., J.T.R., P.R., M.E.), acquisition of data (A.S., I.P., E.W.J., G.G., J.T.R., P.R., M.E., Y.H., I.F.), or analysis and interpretation of data (A.S., I.P., S.R.W., B.R., K.H.); all authors contributed in drafting the article and revising it critically for important intellectual content, and all contributing authors have approved the final version for publication.

Competing interests

The authors declare no competing interests.

Correspondence to Anshuman Sewda.

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