• Richtsmeier, Joan Therese (PI)
  • Beatty, Terri (PI)
  • Jabs, Ethylin Wang (PI)
  • Jabs, Ethylin (PI)
  • Semenza, Gregg (PI)
  • vander Kolk, Craig (PI)
  • Scott, Alan (PI)
  • Richtsmeier, Joan Therese (PI)
  • Beatty, Terri (PI)
  • Jabs, Ethylin (PI)
  • Semenza, Gregg (PI)
  • vander Kolk, Craig (PI)
  • Scott, Alan (PI)
  • Beatty, Terri (PI)
  • Semenza, Gregg (PI)
  • vander Kolk, Craig (PI)
  • Scott, Alan (PI)

Project: Research project

Project Details


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.
Effective start/end date1/1/019/29/99


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