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Seattle, WA, United States

Park S.S.,Seattle Childrens Research Institute | Beyer R.P.,University of Washington | Smyth M.D.,University of Washington | Clarke C.M.,Seattle Childrens Research Institute | And 7 more authors.
Bone | Year: 2015

Single suture craniosynostosis (SSC) is the premature fusion of one calvarial suture and occurs in 1-1700-2500 live births. Congenital fusion of either the sagittal, metopic, or coronal sutures represents 95% of all cases of SSC. Sagittal and metopic synostosis have a male preponderance (3:1) while premature fusion of the coronal suture has a female preponderance (2:1). Although environmental and genetic factors contribute to SSC, the etiology of the majority of SSC cases remains unclear. In this study, 227 primary calvarial osteoblast cell lines from patients with coronal, metopic, or sagittal synostosis and unaffected controls were established and assayed for ALP activity and BrdU incorporation (n. = 226) as respective measures of early stage osteoblast differentiation and proliferation. Primary osteoblast cell lines from individuals with sagittal synostosis demonstrated higher levels of ALP activity and reduced proliferation when compared to control lines. In order to address the sex differences in SSC types, the data was further stratified by sex. Osteoblasts from males and females with sagittal synostosis as well as males with metopic synostosis demonstrated higher levels of ALP activity when compared to sex matched controls, and males with sagittal or metopic synostosis demonstrated reduced levels of proliferation. In order to elucidate genes and pathways involved in these observed phenotypes, correlation analyses comparing ALP activity and proliferation to global gene expression was performed. Transcripts related to osteoblast differentiation were identified both differentially up and downregulated, correlated with ALP activity when compared to controls, and demonstrated a striking sex specific gene expression pattern. These data support that the dysregulation of osteoblast differentiation plays a role in the development of SSC and that genetic factors contribute to the observed sex related differences. © 2015 Elsevier Inc. Source

Stamper B.D.,Seattle Childrens Research Institute | Park S.S.,Seattle Childrens Research Institute | Beyer R.P.,University of Washington | Bammler T.K.,University of Washington | And 2 more authors.
Gene Regulation and Systems Biology | Year: 2012

Background: The premature fusion of one cranial suture, also referred to as non-syndromic craniosynostosis, most commonly involves premature fusion of the sagittal, coronal, or metopic sutures, in that order. Population-based epidemiological studies have found that the birth prevalence of single-suture craniosynostosis is both suture- and sex-dependent. Methods: Transcriptomic data from 199 individuals with isolated sagittal (n = 100), unilateral coronal (n = 50), and metopic (n = 49) synostosis were compared against a control population (n = 50) to identify transcripts accounting for the different sex-based frequencies observed in this disease. Results: Differential sex-based gene expression was classified as either gained (divergent) or lost (convergent) in affected individuals to identify transcripts related to disease predilection. Divergent expression was dependent on synostosis sub-type, and was extensive in metopic craniosynostosis specifically. Convergent microarray-based expression was independent of synostosis sub-type, with convergent expression of FBN2, IGF2BP3, PDE1C and TINAGL1 being the most robust across all synostosis sub-types. Conclusions: Analysis of sex-based gene expression followed by validation by qRT-PCR identified that concurrent upregulation of FBN2 and IGF2BP3, and downregulation of TINAGL1 in craniosynostosis cases were all associated with increased RUNX2 expression and may represent a transcriptomic signature that can be used to characterize a subset of single-suture craniosynostosis cases. © the author(s), publisher and licensee Libertas Academica Ltd. Source

Brinkley J.F.,University of Washington | Borromeo C.,University of Pittsburgh | Cox T.C.,Seattle University | Cunningham M.J.,University of Washington | And 3 more authors.
American Journal of Medical Genetics, Part C: Seminars in Medical Genetics | Year: 2013

We introduce the Ontology of Craniofacial Development and Malformation (OCDM) as a mechanism for representing knowledge about craniofacial development and malformation, and for using that knowledge to facilitate integrating craniofacial data obtained via multiple techniques from multiple labs and at multiple levels of granularity. The OCDM is a project of the NIDCR-sponsored FaceBase Consortium, whose goal is to promote and enable research into the genetic and epigenetic causes of specific craniofacial abnormalities through the provision of publicly accessible, integrated craniofacial data. However, the OCDM should be usable for integrating any web-accessible craniofacial data, not just those data available through FaceBase. The OCDM is based on the Foundational Model of Anatomy (FMA), our comprehensive ontology of canonical human adult anatomy, and includes modules to represent adult and developmental craniofacial anatomy in both human and mouse, mappings between homologous structures in human and mouse, and associated malformations. We describe these modules, as well as prototype uses of the OCDM for integrating craniofacial data. By using the terms from the OCDM to annotate data, and by combining queries over the ontology with those over annotated data, it becomes possible to create "intelligent" queries that can, for example, find gene expression data obtained from mouse structures that are precursors to homologous human structures involved in malformations such as cleft lip. We suggest that the OCDM can be useful not only for integrating craniofacial data, but also for expressing new knowledge gained from analyzing the integrated data. © 2013 Wiley Periodicals, Inc. Source

Collett B.R.,University of Washington | Collett B.R.,Seattle Childrens Research Institute | Aylward E.H.,Seattle Childrens Research Institute | Berg J.,Seattle Childrens Research Institute | And 6 more authors.
Child's Nervous System | Year: 2012

Purpose: Infants with deformational plagiocephaly (DP) have been shown to exhibit developmental delays relative to unaffected infants. Although the mechanisms accounting for these delays are unknown, one hypothesis focuses on underlying differences in brain development. In this study, we used MRI to examine brain volume and shape in infants with and without DP. Methods: Participants included 20 infants with DP (mean age= 7.9 months, SD=1.2; n=12 male) and 21 controls (mean age= 7.9 months, SD=1.3; n=11 male). Measures included volumes of the total brain and cerebellum; midsagittal areas of the corpus callosum and cerebellar vermis; and linear distance measures used to quantify the shape of selected brain structures. We also evaluated the association between shape measures and developmental scores on the Bayley Scales of Infant and Toddler Development-III (BSID-III). Results: Brain volume did not distinguish cases and controls (p=.214-.976). However, cases exhibited greater asymmetry and flattening of the posterior brain (p<.001-.002) and cerebellar vermis (p=.035), shortening of the corpus callosum (p=.012), and differences in the orientation of the corpus callosum (p=.005). Asymmetry and flattening of brain structures were associated with worse developmental outcomes on the BSID-III. Conclusions: Infants with DP show differences in brain shape, consistent with the skull deformity characteristic of this condition, and shape measures were associated with infant development. Longitudinal studies, beginning in the neonatal period, are needed to clarify whether developmental effects precede or follow brain deformation. © Springer-Verlag 2012. Source

Wang K.H.,Seattle Childrens Research Institute | Heike C.L.,Clinical Translational Science Institute | Heike C.L.,Seattle Childrens Craniofacial Center | Heike C.L.,University of Washington | And 10 more authors.
Frontiers in Physiology | Year: 2014

Orofacial clefting is a common birth defect with wide phenotypic variability. Many systems have been developed to classify cleft patterns to facilitate diagnosis, management, surgical treatment, and research. In this review, we examine the rationale for different existing classification schemes and determine their inter-relationships, as well as strengths and deficiencies for subclassification of clefts of the lip. The various systems differ in how they describe and define attributes of cleft lip (CL) phenotypes. Application and analysis of the CL classifications reveal discrepancies that may result in errors when comparing studies that use different systems. These inconsistencies in terminology, variable levels of subclassification, and ambiguity in some descriptions may confound analyses and impede further research aimed at understanding the genetics and etiology of clefts, development of effective treatment options for patients, as well as cross-institutional comparisons of outcome measures. Identification and reconciliation of discrepancies among existing systems is the first step toward creating a common standard to allow for a more explicit interpretation that will ultimately lead to a better understanding of the causes and manifestations of phenotypic variations in clefting. © 2014 Wang, Heike, Clarkson, Mejino, Brinkley, Tse, Birgfeld, Fitzsimons and Cox. Source

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