Clinical Research Article | Published:

Nonsyndromic craniosynostosis: novel coding variants

Subjects

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  1. 1.

    Flaherty, K., Singh, N. & Richtsmeier, J. T. Understanding craniosynostosis as a growth disorder. Wiley Interdiscip. Rev. Dev. Biol. 5, 429–459 (2016).

  2. 2.

    Cornelissen, M. et al. Increase of prevalence of craniosynostosis. J. Craniomaxillofac. Surg. 44, 1273–1279 (2016).

  3. 3.

    Greenwood, J., Flodman, P., Osann, K., Boyadjiev, S. A. & Kimonis, V. Familial incidence and associated symptoms in a population of individuals with nonsyndromic craniosynostosis. Genet. Med. 16, 302–310 (2014).

  4. 4.

    Cohen M. M. & MacLean R. E. Craniosynostosis: Diagnosis, Evaluation, and Management. 2nd edn. (Oxford University Press, New York, 2000).

  5. 5.

    Wilkie, A. O. M., Johnson, D. & Wall, S. A. Clinical genetics of craniosynostosis. Curr. Opin. Pediatr. 29, 622–628 (2017).

  6. 6.

    Hunter, A. G. & Rudd, N. L. Craniosynostosis. II. Coronal synostosis: its familial characteristics and associated clinical findings in 109 patients lacking bilateral polysyndactyly or syndactyly. Teratology 15, 301–309 (1977).

  7. 7.

    Lajeunie, E., Le Merrer, M., Bonaiti-Pellie, C., Marchac, D. & Renier, D. Genetic study of nonsyndromic coronal craniosynostosis. Am. J. Med. Genet. 55, 500–504 (1995).

  8. 8.

    Selber, J. et al. The changing epidemiologic spectrum of single-suture synostoses. Plast. Reconstr. Surg. 122, 527–533 (2008).

  9. 9.

    Lajeunie, E., Le Merrer, M., Bonaiti-Pellie, C., Marchac, D. & Renier, D. Genetic study of scaphocephaly. Am. J. Med. Genet. 62, 282–285 (1996).

  10. 10.

    Lajeunie, E., Crimmins, D. W., Arnaud, E. & Renier, D. Genetic considerations in nonsyndromic midline craniosynostoses: a study of twins and their families. J. Neurosurg. 103, 353–356 (2005).

  11. 11.

    Justice, C. M. et al. A genome-wide association study identifies susceptibility loci for nonsyndromic sagittal craniosynostosis near BMP2 and within BBS9. Nat. Genet. 44, 1360–1364 (2012).

  12. 12.

    Lee, E., et al. A craniosynostosis massively parallel sequencing panel study in 309 Australian and New Zealand patients: findings and recommendations. Genet. Med. 20, 1061–1068 (2018).

  13. 13.

    Apostolopoulou, D., et al. Genetic analysis of syndromic and nonsyndromic patients with craniosynostosis identifies novel mutations in the TWIST1 and EFNB1 genes. Cleft Palate Craniofac J. 55, 1092–1102 (2018).

  14. 14.

    Clarke, C. M. et al. Single suture craniosynostosis: Identification of rare variants in genes associated with syndromic forms. Am. J. Med. Genet. A 176, 290–300 (2018).

  15. 15.

    Ye, X. et al. Mutation screening of candidate genes in patients with nonsyndromic sagittal craniosynostosis. Plast. Reconstr. Surg. 137, 952–961 (2016).

  16. 16.

    Cingolani, P. et al. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strainw1118; iso-2; iso-3. Fly. (Austin) 6, 80–92 (2012).

  17. 17.

    Sim, N. L. et al. SIFT web server: predicting effects of amino acid substitutions on proteins. Nucleic Acids Res. 40, W452–W457 (2012).

  18. 18.

    Adzhubei, I. A. et al. A method and server for predicting damaging missense mutations. Nat. Methods 7, 248–249 (2010).

  19. 19.

    Kircher, M. et al. A general framework for estimating the relative pathogenicity of human genetic variants. Nat. Genet. 46, 310–315 (2014).

  20. 20.

    Reva, B., Antipin, Y. & Sander, C. Predicting the functional impact of protein mutations: application to cancer genomics. Nucleic Acids Res. 39, e118 (2011).

  21. 21.

    Veleri, S. et al. Knockdown of Bardet-Biedl syndrome gene BBS9/PTHB1 leads to cilia defects. PLoS ONE 7, e34389 (2012).

  22. 22.

    Katsianou, M. A., Adamopoulos, C., Vastardis, H. & Basdra, E. K. Signaling mechanisms implicated in cranial sutures pathophysiology: Craniosynostosis. BBA Clin. 6, 165–176 (2016).

  23. 23.

    Lattanzi, W., Barba, M., Di Pietro, L. & Boyadjiev, S. A. Genetic advances in craniosynostosis. Am. J. Med. Genet. A. 173, 1406–1429 (2017).

  24. 24.

    Heuze, Y., Holmes, G., Peter, I., Richtsmeier, J. T. & Jabs, E. W. Closing the Gap: genetic and genomic continuum from syndromic to nonsyndromic craniosynostoses. Curr. Genet. Med. Rep. 2, 135–145 (2014).

  25. 25.

    Compagni, A., Logan, M., Klein, R. & Adams, R. H. Control of skeletal patterning by ephrinB1-EphB interactions. Dev. Cell 5, 217–230 (2003).

  26. 26.

    Merrill, A. E. et al. Cell mixing at a neural crest-mesoderm boundary and deficient ephrin-Eph signaling in the pathogenesis of craniosynostosis. Hum. Mol. Genet. 15, 1319–1328 (2006).

  27. 27.

    Ting, M. C. et al. EphA4 as an effector of Twist1 in the guidance of osteogenic precursor cells during calvarial bone growth and in craniosynostosis. Development 136, 855–864 (2009).

  28. 28.

    Howard, T. D. et al. Mutations in TWIST, a basic helix-loop-helix transcription factor, in Saethre-Chotzen syndrome. Nat. Genet. 15, 36–41 (1997).

  29. 29.

    Seto, M. L. et al. Isolated sagittal and coronal craniosynostosis associated with TWIST box mutations. Am. J. Med. Genet. A 143A, 678–686 (2007).

  30. 30.

    Bertola, D. R., Rodrigues, M. G., Quaio, C. R., Kim, C. A. & Passos-Bueno, M. R. Vertical transmission of a frontonasal phenotype caused by a novel ALX4 mutation. Am. J. Med. Genet. A 161A, 600–604 (2013).

  31. 31.

    Wu, Y. Q. et al. Haploinsufficiency of ALX4 as a potential cause of parietal foramina in the 11p11.2 contiguous gene-deletion syndrome. Am. J. Hum. Genet. 67, 1327–1332 (2000).

  32. 32.

    Vona, B. et al. Targeted next-generation sequencing of deafness genes in hearing-impaired individuals uncovers informative mutations. Genet. Med. 16, 945–953 (2014).

  33. 33.

    Wang, Y. et al. p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice. J. Clin. Invest. 122, 2153–2164 (2012).

  34. 34.

    Shukla, V., Coumoul, X., Wang, R. H., Kim, H. S. & Deng, C. X. RNA interference and inhibition of MEK-ERK signaling prevent abnormal skeletal phenotypes in a mouse model of craniosynostosis. Nat. Genet. 39, 1145–1150 (2007).

  35. 35.

    Melville, H., Wang, Y., Taub, P. J. & Jabs, E. W. Genetic basis of potential therapeutic strategies for craniosynostosis. Am. J. Med. Genet. A 152A, 3007–3015 (2010).

  36. 36.

    Yin, L. et al. A Pro253Arg mutation in fibroblast growth factor receptor 2 (Fgfr2) causes skeleton malformation mimicking human Apert syndrome by affecting both chondrogenesis and osteogenesis. Bone 42, 631–643 (2008).

  37. 37.

    Perlyn, C. A., Morriss-Kay, G., Darvann, T., Tenenbaum, M. & Ornitz, D. M. A model for the pharmacological treatment of crouzon syndrome. Neurosurgery 59, 210–215 (2006). discussion-5.

  38. 38.

    Eswarakumar, V. P. et al. Attenuation of signaling pathways stimulated by pathologically activated FGF-receptor 2 mutants prevents craniosynostosis. Proc. Natl Acad. Sci. USA 103, 18603–18608 (2006).

  39. 39.

    Goriely, A. et al. Germline and somatic mosaicism for FGFR2 mutation in the mother of a child with Crouzon syndrome: Implications for genetic testing in “paternal age-effect” syndromes. Am. J. Med. Genet. A 152A, 2067–2073 (2010).

  40. 40.

    Robin, N. H., Scott, J. A., Cohen, A. R. & Goldstein, J. A. Nonpenetrance in FGFR3-associated coronal synostosis syndrome. Am. J. Med. Genet. 80, 296–297 (1998).

Download references

Acknowledgements

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.

Supplementary information

  1. Supplementary Information

Rights and permissions

To obtain permission to re-use content from this article visit RightsLink.

About this article

Fig. 1