Seattle Children's Research Institute, together with an international team of scientists and clinicians from 22 other institutions, have identified two genetic risk factors for the most common form of non-syndromic craniosynostosis, a birth defect in which the bony plates of an infant's skull prematurely fuse. The condition is known as sagittal craniosynostosis and often results in an abnormal head shape and facial features.
The study identified two genes (BMP2 and BBS9) associated with sagittal craniosynostosis that are known to be involved in broader skeletal development.
Results of the research project, "A genome-wide association study identifies susceptibility loci for non-syndromic sagittal craniosynostosis near BMP2 and within BBS9," are published online today in the journal Nature Genetics.
"Seattle Children's treats hundreds of children with different types of craniosynostosis each year, many whose families are looking for answers to what causes the condition and many of whom participated in this study. This discovery brings us one step closer to unraveling the mysteries of craniosynostosis, which will lead to improved counseling of our patients and their families," said Michael Cunningham, MD, PhD, a principal investigator at Seattle Children's Research Institute who studies the genetics and developmental biology of craniosynostosis.
Dr. Cunningham is the medical director of the Craniofacial Center at Seattle Children's Hospital, Professor of Pediatrics at the University of Washington and a founding member of the International Craniosynostosis Consortium (ICC), the organization that enrolled and evaluated all study participants.
In this study – believed to be the first genome-wide association study of non-syndromic sagittal craniosynostosis – investigators scanned the whole genome of a group of children and adults with the condition and compared them to a control group without it. Researchers identified single nucleotide polymorphisms (SNPs) that were associated with the condition. SNPs are changes in DNA in which a nucleotide differs from the one normally in that position and can be used to identify genes linked to the disease.
The research team evaluated DNA, taken from blood or oral samples, of 214 cases and both of their parents, who did not have the condition. The final analysis came from a group of 130 children and their families.
During normal development, the bony plates of the skull are separate during fetal development and early infancy, which allows for growth of the skull. The borders where these bony plates intersect are known as sutures. The sagittal suture usually does not fuse until adulthood. If the midline suture at the top of the head closes too early, a child will develop sagittal craniosynostosis. Without surgical treatment, this can cause increased pressure within the skull, visual problems and learning disabilities.
Sagittal craniosynostosis affects about one in 5,000 newborns and boys are three to four times more likely than girls to have the condition. Prior research has suggested that the condition can recur in families, but the exact genetic causes have not been well understood.
"Our participation in this collaborative effort and our ongoing research into the biology of craniosynostosis will result in tangible changes in how we diagnose and treat craniosynostosis," Dr. Cunningham said.
Simon Boyadjiev, Professor of Pediatrics and Genetics at UC Davis, is the founder of the ICC and principal investigator of this study. Other study authors include:; Cristina M. Justice, Yoonhee Kim and Alexander F. Wilson of the U.S. National Human Genome Research Institute; Garima Yagnik, Craig Senders, James Boggan, Marike Zwienenberg-Lee, and Jinoh Kim of UC Davis School of Medicine; Inga Peter, Ethylin Wang Jabs, Monica Erazo, Xiaoqian Ye, Edmond Ainehsazan, Lisong Shi and Peter J. Taub of Mount Sinai School of Medicine; Virginia Kimonis of UC Irvine School of Medicine; Tony Roscioli of University of New South Wales, Australia; Steven A. Wall and Andrew O.M. Wilkie, John Radcliffe Hospital, United Kingdom; Joan Stoler of Children's Hospital Boston; Joan T. Richtsmeier and Yann Heuzé of Pennsylvania State University; Pedro A. Sanchez-Lara of University of Southern California; Michael F. Buckley of SEALS, Australia; Charlotte M. Druschel, Michele Caggana and Denise M. Kay of New York State Department of Health; James L. Mills of Eunice Kennedy Shriver National Institute of Child Health and Human Development; Paul A. Romitti of University of Iowa; Ophir D. Klein of UC San Francisco School of Medicine and Cyrill Naydenov of the Medical University, Sofia, Bulgaria.
The research was supported by grants to the various authors from the National Institute of Dental and Craniofacial Research (National Institutes of Health ,NIH) and National Center for Research Resources (NIH); the U.S. Centers for Disease Control and Prevention; the Intramural Research Program of the U.S. National Institutes of Health (NIH); the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NIH); the Robert Wood Johnson Foundation; the University of Southern California Child Health Research Career Development Program and the UCLA Child Health Research Career Development Program; the American Recovery and Reinvestment Act; the National Center for Advancing Translational Sciences; the National Human Genome Research Institute (NIH) and a contract from the NIH to the Johns Hopkins University.
About Seattle Children's Research Institute
Located in downtown Seattle's biotech corridor, Seattle Children's Research Institute is pushing the boundaries of medical research to find cures for pediatric diseases and improve outcomes for children all over the world. Internationally recognized investigators and staff at the research institute are advancing new discoveries in cancer, genetics, immunology, pathology, infectious disease, injury prevention and bioethics, among others. As part of Seattle Children's Hospital, the research institute brings together leading minds in pediatric research to provide patients with the best care possible. Seattle Children's serves as the primary teaching, clinical and research site for the Department of Pediatrics at the University of Washington School of Medicine, which consistently ranks as one of the best pediatric departments in the country. For more information, visit http://www.seattlechildrens.org/research.
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