Nonsyndromic craniosynostosis: novel coding variants

Anshuman Sewda, Sierra R. White, Monica Erazo, Ke Hao, Gemma García-Fructuoso, Ivette Fernández-Rodriguez, Yann Heuzé, Joan Therese Richtsmeier, Paul A. Romitti, Boris Reva, Ethylin Wang Jabs, Inga Peter

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Background: 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. Methods: 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). Results: 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. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)463-468
Number of pages6
JournalPediatric Research
Volume85
Issue number4
DOIs
StatePublished - Mar 1 2019

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Craniosynostoses
Cranial Sutures
Genes
Genome-Wide Association Study
Genetic Testing
Sutures
Mutation

All Science Journal Classification (ASJC) codes

  • Pediatrics, Perinatology, and Child Health

Cite this

Sewda, A., White, S. R., Erazo, M., Hao, K., García-Fructuoso, G., Fernández-Rodriguez, I., ... Peter, I. (2019). Nonsyndromic craniosynostosis: novel coding variants. Pediatric Research, 85(4), 463-468. https://doi.org/10.1038/s41390-019-0274-2
Sewda, Anshuman ; White, Sierra R. ; Erazo, Monica ; Hao, Ke ; García-Fructuoso, Gemma ; Fernández-Rodriguez, Ivette ; Heuzé, Yann ; Richtsmeier, Joan Therese ; Romitti, Paul A. ; Reva, Boris ; Jabs, Ethylin Wang ; Peter, Inga. / Nonsyndromic craniosynostosis : novel coding variants. In: Pediatric Research. 2019 ; Vol. 85, No. 4. pp. 463-468.
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title = "Nonsyndromic craniosynostosis: novel coding variants",
abstract = "Background: 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. Methods: 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). Results: 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. Conclusions: 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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Sewda, A, White, SR, Erazo, M, Hao, K, García-Fructuoso, G, Fernández-Rodriguez, I, Heuzé, Y, Richtsmeier, JT, Romitti, PA, Reva, B, Jabs, EW & Peter, I 2019, 'Nonsyndromic craniosynostosis: novel coding variants', Pediatric Research, vol. 85, no. 4, pp. 463-468. https://doi.org/10.1038/s41390-019-0274-2

Nonsyndromic craniosynostosis : novel coding variants. / Sewda, Anshuman; White, Sierra R.; Erazo, Monica; Hao, Ke; García-Fructuoso, Gemma; Fernández-Rodriguez, Ivette; Heuzé, Yann; Richtsmeier, Joan Therese; Romitti, Paul A.; Reva, Boris; Jabs, Ethylin Wang; Peter, Inga.

In: Pediatric Research, Vol. 85, No. 4, 01.03.2019, p. 463-468.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Nonsyndromic craniosynostosis

T2 - novel coding variants

AU - Sewda, Anshuman

AU - White, Sierra R.

AU - Erazo, Monica

AU - Hao, Ke

AU - García-Fructuoso, Gemma

AU - Fernández-Rodriguez, Ivette

AU - Heuzé, Yann

AU - Richtsmeier, Joan Therese

AU - Romitti, Paul A.

AU - Reva, Boris

AU - Jabs, Ethylin Wang

AU - Peter, Inga

PY - 2019/3/1

Y1 - 2019/3/1

N2 - Background: 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. Methods: 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). Results: 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. Conclusions: 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.

AB - Background: 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. Methods: 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). Results: 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. Conclusions: 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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Sewda A, White SR, Erazo M, Hao K, García-Fructuoso G, Fernández-Rodriguez I et al. Nonsyndromic craniosynostosis: novel coding variants. Pediatric Research. 2019 Mar 1;85(4):463-468. https://doi.org/10.1038/s41390-019-0274-2