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.

Figure 1.

Functional consequences of novel mutations: (a) TWIST1 p.(Lys145Asn) acts as a transcriptional regulator for cranial suture patterning and fusion. The mutation affects the evolutionarily conserved residue and one of the key binding site residues. Functional impact predicted by Mutation Assessor is ‘Medium’. (b) TWIST1 p.(Asp141His) mutation affects one of the high-scoring specificity residues, i.e. residues conserved within protein subfamilies. Functional impact predicted by Mutation Assessor is ‘Medium’. (c) BBS9 p.(Leu737Val) is required for proper BBSome complex assembly which is required for ciliogenesis. The mutation affects the evolutionarily conserved residue. Functional impact predicted by Mutation Assessor is ‘High’. (d) ALX4 p.(Lys42Asn) encodes a paired-like homeodomain transcription factor expressed in the mesenchyme of developing bones. The mutation affects the evolutionarily conserved residue.