Identification and analysis of the genetic causes in nine unrelated probands with syndromic craniosynostosis

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.