De novo ALX4 variant detected in child with non-syndromic craniosynostosis

Abstract

Current understanding of the genetic factors contributing to the etiology of non-syndromic craniosynostosis (NSC) remains scarce. The present work investigated the presence of variants in ALX4, EFNA4, and TWIST1 genes in children with NSC to verify if variants within these genes may contribute to the occurrence of these abnormal phenotypes. A total of 101 children (aged 45.07 ± 40.94 months) with NSC participated in this cross-sectional study. Parents and siblings of the probands were invited to participate. Medical and family history of craniosynostosis were documented. Biological samples were collected to obtain genomic DNA. Coding exons of human TWIST1, ALX4, and EFNA4 genes were amplified by polymerase chain reaction and Sanger sequenced. Five missense variants were identified in ALX4 in children with bilateral coronal, sagittal, and metopic synostosis. A de novo ALX4 variant, c.799G4A: p.Ala267Thr, was identified in a proband with sagittal synostosis. Three missense variants were identified in the EFNA4 gene in children with metopic and sagittal synostosis. A TWIST1 variant occurred in a child with unilateral coronal synostosis. Variants were predicted to be among the 0.

TBX3 and EFNA4 Variant in a Family with Ulnar-Mammary Syndrome and Sagittal Craniosynostosis

“…This variant was found in one patient with unilateral coronal suture synostosis, and segregation analysis showed an incompletely penetrant phenotype in the parents of the proband [ 22 ]. Subsequent studies identified the EFNA4 variant (c.178C > T, p.His60Tyr) in three additional patients with nonsyndromic, single suture synostosis ( Supplementary Figure S2 ) [ 23 , 24 ]. Functional analysis by Merill et al demonstrated that this variant results in a 65% loss of the binding of ephrin-A4 proteins to EphA7, the partner receptor, by disrupting the formation of the ligand–receptor heterotetramer [ 22 ].…”