Nonsyndromic sagittal craniosynostosis represents the most common cause of cranial vault deformity, with an estimated incidence of 0.4-1/1000. The premature sagittal suture fusion can lead to increased intracranial pressure and impairment in the neurocognitive development. The cost associated with the management of the condition is substantial. Despite an obvious strong genetic base, the etiology of non-syndromic sagittal craniosynostosis remains obscure, therefore only symptomatic treatment modalities currently exist. Recently it has been shown that an important fraction of de-novo mutations presumed to be germline in fact occurred either post-zygotically in the offspring or were inherited as a consequence of low-level mosaicism in one of the parents. We put forth the hypothesis that a loss-of-heterozygosity, two-hit, recessive model is responsible for the development of nonsyndromic sagittal craniosynostosis. One genetic mutation is germline transmitted and the other occurs in somatically, in mosaic fashion, very early in development at the level of the tissues that form the sagittal suture.
The first aim of the proposal is design to identify the de-novo mutations in genes regulating bone fusion at the level of the sagittal suture that are responsible for the premature suture closure. Exome sequencing of paired blood and bony tissue from the fused sagittal suture of affected individuals will be done to identify such mutations. Data analysis and directed sequencing of samples from multiple additional individuals for validation of findings will be performed.
The second aim will address the genetic germline contribution to the development of sagittal synostosis. Taking advantage by the unique resource represented by the Utah Population Database, multiplex families from our clinical practice that show aggregation of nonsyndromic sagittal synostosis will be expanded. Whole genome sequencing of blood samples and data analysis will be performed in affected and unaffected individuals from these high-risk expanded pedigrees. Success in identification of genetic variation in patients with sagittal synostosis will create the opportunity for understanding the pathophysiology of the disease process. This significance of the study is that understanding the genetic etiology of craniosynostosis will allow personalized genetic counseling and implementation of therapies specific to the mechanism of disease.
/ RELEVANCE TO PUBLIC HEALTH Non-syndromic sagittal synostosis is one of the most common congenital disorders. Despite a significant genetic base, its etiology remains unclear. Success in the identification of the genetic variation in patients with sagittal synostosis will create the opportunity for understanding the pathophysiology of the disease process. The clinical impact of understanding the genetic etiology of craniosynostosis is that it will allow personalized genetic counseling and implementation of therapies specific to the mechanism of the disease.