Craniosynostosis, the premature closure of sutures between the bones in the skull, is an easily recognized birth defect but little is known about its etiology. There are several forms of craniosynostosis, depending on which of the five sutures of the skull are involved. Both genetic and environmental factors are likely contribute to the etiology of this malformation. Familial forms of craniosynostosis have been reported, and several Mendelian syndromes include premature closure of sutures. Here we propose a clinic-based study of patients diagnosed with craniosynostosis to test candidate genes and identify risk factors for various subtypes of this malformation. We expect to ascertain approximately 70 new cases of non-syndromic craniosynostosis per year treated at Johns Hopkins and the Univ. of Maryland, and evaluate these cases for familial history of craniofacial abnormalities and other congenital malformations. We project that a total of approximately 315 cases of non-syndromic craniosynostosis will be identified.
The specific aims of this study are: (1) To screen this cohort of cases for mutations in the MSX2 locus to establish what proportion of craniosynostosis may be attributed to this locus. Jabs et al. (1993) recently reported a mutation in the MSX2 locus on chromosome 5 (which contains a human homeobox domain) was responsible for an autosomal dominant form of craniosynostosis in a single extended kindred. Both allele specific oligonucleotide methods and direct sequencing of the MSX2 locus will be done to establish if this newly described mutation accounts for a major fraction of this malformation. (2) To conduct linkage analysis on multiplex families ascertained through a proband with craniosynostosis and test for heterogeneity in genetic control of this malformation. Both families identified through these two clinics and families obtained through collaboration with other investigators will be used to test for linkage to a number of candidate genes. (3) To use questionnaire and DNA from blood samples obtained from these non-syndromic cases (and their parents) in an epidemiologic study of environmental risk factors and other candidate genes, particularly MSX1 and transforming growth factor Beta. Markers in or near candidates genes will be tested for association with this malformation using a case-control design. Controls will be normal infants (and their parents) recruited as part of an ongoing study of oral clefts. By taking advantage of resources available at this institution and co-ordinating this study with others now being carried out by this group, we can accomplish the goals of this study in a very cost efficient manner.
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