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.

• Authors: Anshuman Sewda, Sierra R White, Monica Erazo, Ke Hao, Gemma García-Fructuoso, Ivette Fernández-Rodriguez, Yann Heuzé, Joan T Richtsmeier, Paul A Romitti, Boris Reva, Ethylin Wang Jabs, Inga Peter
• Journal: Pediatric research (Pediatr Res) Vol. 85 Issue 4 Pg. 463-468 (03 2019) ISSN: 1530-0447 [Electronic] United States
• PMID: 30651579 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Nuclear Proteins
• TWIST1 protein, human
• Twist-Related Protein 1

Topics

• Craniosynostoses (genetics)
• Female
• High-Throughput Nucleotide Sequencing
• Humans
• Male
• Nuclear Proteins (genetics)
• Syndrome
• Twist-Related Protein 1 (genetics)