Craniosynostosis, the premature fusion of 1 or more cranial sutures is a common malformation occurring in 3 to 5 per 10,000 live births. Most often craniosynostosis occurs as an isolated (i.e. nonsyndromic) anomaly. Nonsyndromic craniosynostosis (NSC) is a heterogeneous condition of multifactorial etiology with evidence of genetic factors. Significant progress has been made in understanding the clinical and molecular aspects of monogenic syndromic craniosynostosis. However, the phenotype characterization of NSC and the variability within diagnostic subgroups is incomplete and the causes of NSC remain unknown. Analysis of the clinical features and the craniofacial anthropometric profiles of a large group of prospectively recruited patients with sagittal and coronal NSC evaluated under a standardized protocol will further characterize these phenotypes. The clinically homogeneous group of patients with isolated nonsyndromic sagittal craniosynostosis will be used to identify causative genes by candidate gene association analysis. We have already enrolled and characterized 100 sagittal and 39 coronal NSC families and our existing recruitment system will ensure at least 250 additional sagittal and coronal NSC families by year 4 of this study. We will use advanced imaging technologies and quantitative morphological tools to characterize and evaluate 3D phenotypic variation within and between the diagnostic categories of sagittal and coronal NSC. The genotyping of the first 47 case-parent trios with isolated sagittal NSC was initiated and the results indicate associations with a region on chromosome 3q and with several of the tested candidate genes. Our efforts will be dedicated to reproducing and validating these associations and to identifying variants within these genes that predispose to NSC. We will also continue SNP-based genotyping and the association analysis of additional candidate genes. In summary, this application proposes a multicenter phenotype and genotype study aimed at determining the clinical, anthropometric, and molecular characteristics of NSC.
Our aims are to accrue well-characterized sagittal and coronal patient populations, to identify areas for improved clinical care, and to establish a sample repository available to the scientific community. In addition, we will also identify genes associated with sagittal NSC. The resources that we have amassed and the collaborative and integrated approaches that we will utilize put us in a unique position to accomplish these aims. ? ? ?

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
Project #
Application #
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Harris, Emily L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Davis
Schools of Medicine
United States
Zip Code
Lattanzi, Wanda; Barba, Marta; Di Pietro, Lorena et al. (2017) Genetic advances in craniosynostosis. Am J Med Genet A 173:1406-1429
Justice, Cristina M; Kim, Jinoh; Kim, Sun-Don et al. (2017) A variant associated with sagittal nonsyndromic craniosynostosis alters the regulatory function of a non-coding element. Am J Med Genet A 173:2893-2897
Weaver, K Nicole; El Hallek, Moussa; Hopkin, Robert J et al. (2014) Keutel syndrome: report of two novel MGP mutations and discussion of clinical overlap with arylsulfatase E deficiency and relapsing polychondritis. Am J Med Genet A 164A:1062-8
Reutter, Heiko; Draaken, Markus; Pennimpede, Tracie et al. (2014) Genome-wide association study and mouse expression data identify a highly conserved 32 kb intergenic region between WNT3 and WNT9b as possible susceptibility locus for isolated classic exstrophy of the bladder. Hum Mol Genet 23:5536-44
Heuzé, Yann; Balzeau, Antoine (2014) Asymmetry of the midfacial skeleton of eastern lowland gorillas (Gorilla beringei graueri) and potential association with frontal lobe asymmetries. J Hum Evol 74:123-129
Greenwood, Jaclyn; Flodman, Pamela; Osann, Kathryn et al. (2014) Familial incidence and associated symptoms in a population of individuals with nonsyndromic craniosynostosis. Genet Med 16:302-10
Kim, Sun-Don; Yagnik, Garima; Cunningham, Michael L et al. (2014) MAPK/ERK Signaling Pathway Analysis in Primary Osteoblasts From Patients With Nonsyndromic Sagittal Craniosynostosis. Cleft Palate Craniofac J 51:115-9
Heuzé, Yann; Martínez-Abadías, Neus; Stella, Jennifer M et al. (2014) Quantification of facial skeletal shape variation in fibroblast growth factor receptor-related craniosynostosis syndromes. Birth Defects Res A Clin Mol Teratol 100:250-9
Draaken, Markus; Baudisch, Friederike; Timmermann, Bernd et al. (2014) Classic bladder exstrophy: Frequent 22q11.21 duplications and definition of a 414 kb phenocritical region. Birth Defects Res A Clin Mol Teratol 100:512-7
Kim, Sun-Don; Pahuja, Kanika Bajaj; Ravazzola, Mariella et al. (2012) SEC23-SEC31 the interface plays critical role for export of procollagen from the endoplasmic reticulum. J Biol Chem 287:10134-44

Showing the most recent 10 out of 31 publications