Introduction: Craniofrontonasal Dysplasia (CFND) is an X-linked disorder characterized by hypertelorism, broad nasal root, bifid nasal tip, craniosynostosis, and cleft lip and palate. CFND was mapped to a 6.97 Mb region in Xp22. Another locus was mapped to the pericentromeric region of the X chromosome, suggesting locus heterogeneity. Recently, mutations in the Ephrin-B1 gene, which maps to Xq12, were found in individuals with CFND.
Objectives: the goal was to confirm the map location of CFND to exclude genetic heterogeneity. A mutation screen of the Ephrin-B1 gene was performed to determine if there is a genotype-phenotype correlation.
Methods: Seven individuals of a three-generation family with CFND were genotyped with polymorphic markers between DXS1223 and DXS6789 (Xp22.31-Xq21.33). Five additional individuals with CFND and two individuals with a similar disorder, Frontonasal Dysplasia (FND), were screened for Ephrin-B1 mutations.
Results: The linkage analysis of the three-generation family identified a shared haplotype only in affected females. An unaffected family member had recombination events between markers DXS8022-DXS987 and GATA160B08-DXS6800. Six of the eight individuals affected with CFND were found to have mutations in Ephrin-B1. All mutations changed conserved amino acids of Ephrin-B1. None of these nucleotide substitutions are reported to be single nucleotide polymorphisms by dbSNP. Mutations in Ephrin-B1 were not detected in the individuals diagnosed with FND.
Conclusions: The identification of six mutations in eight patients, including the proband from the three-generation family, indicates that Ephrin-B1 is the major gene for CFND. The absence of mutations in two individuals does not exclude genetic heterogeneity, but it is more likely that mutations in regulatory elements of Ephrin-B1 are the explanation. The limited number of patients with FND precludes conclusive evidence that FND and CFND are allelic.
IADR/AADR/CADR General Session
2005 IADR/AADR/CADR General Session (Baltimore, Maryland) Baltimore, Maryland
2005 1278 Craniofacial Biology
Van Westen, Luciana Miranda
( University of Iowa, Iowa City, IA, USA
)
Mccarrier, Julie
( Hackensack University Medical Center, Hackensack, NJ, USA
)
Miller, Marvin
( Children's Medical Center, Dayton, OH, USA
)
Nino, Michell
( John Hopkins Hospital, Baltimore, MD, USA
)
Slavotinek, Anne
( University of California, San Francisco, San Francisco, CA, USA
)
Lidral, Andrew C.
( University of Iowa, Iowa, IA, USA
)
Krahn, Katherine
( University of Iowa, Iowa City, IA, USA
)
Mach, Amy
( University of Iowa, Iowa City, IA, USA
)
Bullard, Steve
( University of Iowa, Iowa City, IA, USA
)
Bader, Patricia
( Northeast Indiana Genetic Counseling Center, Fort Wayne, IN, USA
)
Beck, Anita
( Children's Hospital at Stanford, Stanford, CA, USA
)
Braddock, Stephen
( University of Missouri, Columbia, MO, USA
)
Clark, Robin
( Loma Linda University, Loma Linda, CA, USA
)
Cunningham, Michael L.
( University of Washington, Seattle, WA, USA
)
Poster Session
Craniofacial Biology--Sarnat Award Finalists, Poster Session II
03/10/2005
