Syndromic craniosynostosis is a group of multiple conditions with high 
heterogeneity, and many rare syndromes still remain to be characterized. To 
identify and analyze causative genetic variants in nine unrelated probands 
mainly manifested as syndromic craniosynostosis, we reviewed the relevant 
medical information of the patients and performed the whole exome sequencing, 
further verified with Sanger sequencing and parental background. Bioinformatics 
analysis was used to evaluate the potential deleterious or benign effect of each 
genetic variant through evolutionary conservation alignment, multi-lines of 
computer predication and the allele frequency in population dataset (control and 
patient). The Standards and guidelines from American College of Medical Genetics 
and Genomics was used to classify and interpret the pathogenicity for each 
genetic variant. All the nine probands were found to carry the possibly 
causative variants, among which three variants including two missense mutations 
(c.3385C>T in IFT122 gene, c.3581A>G in SMC1A gene) and a frameshift mutation 
(c.434dupA in TWIST1 gene) have never been reported in patients before. We 
suggested Cornelia de Lange syndrome caused by SMC1A variant is a neglected 
syndromic craniosynostosis. Our study not only expanded genotypic and phenotypic 
spectrum of the rare syndromes, but also confirmed that there existed an 
underlying genetic mechanism. We emphasized that deliberate selection of both 
the potential candidates and comprehensive detection methods for genetic 
analysis is important to increase the genetic diagnosis yield of syndromic 
craninosynostosis.