Copyright © 2008 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 82, Issue 5, 1171-1177, 17 April 2008
doi:10.1016/j.ajhg.2008.03.005
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TFAP2A Mutations Result in Branchio-Oculo-Facial Syndrome
Jeff M. Milunsky1, 2, 3, 
, 
, Tom A. Maher1, Geping Zhao1, Amy E. Roberts4, Heather J. Stalker5, Roberto T. Zori5, Michelle N. Burch5, Michele Clemens6, John B. Mulliken7, Rosemarie Smith8 and Angela E. Lin9
1 Center for Human Genetics, Boston University School of Medicine, Boston, MA 02118-2526, USA
2 Department of Pediatrics, Boston University School of Medicine, Boston, MA 02118-2526, USA
3 Department of Genetics and Genomics, Boston University School of Medicine, Boston, MA 02118-2526, USA
4 Department of Cardiology, Children's Hospital, Boston, MA 02114, USA
5 Division of Genetics, Raymond C. Philips Unit, Department of Pediatrics, University of Florida, Gainesville, FL 32610, USA
6 Department of Genetics, Magee-Womens Hospital of UPMC, Pittsburgh, PA, USA
7 Department of Plastic Surgery, Children's Hospital, Boston, MA 02118-2526, USA
8 Division of Genetics, The Barbara Bush Children's Hospital, Maine Medical Center, Portland, ME, USA
9 Genetics Unit, MassGeneral Hospital for Children, Simches Research Building 2222, 185 Cambridge Avenue, Boston, MA 02114, USA
Corresponding authorAbstract
Branchio-oculo-facial syndrome (BOFS) is a rare autosomal-dominant cleft palate-craniofacial disorder with variable expressivity. The major features include cutaneous anomalies (cervical, infra- and/or supra-auricular defects, often with dermal thymus), ocular anomalies, characteristic facial appearance (malformed pinnae, oral clefts), and, less commonly, renal and ectodermal (dental and hair) anomalies. The molecular basis for this disorder is heretofore unknown. We detected a 3.2 Mb deletion by 500K SNP microarray in an affected mother and son with BOFS at chromosome 6p24.3. Candidate genes in this region were selected for sequencing on the basis of their expression patterns and involvement in developmental pathways associated with the clinical findings of BOFS. Four additional BOFS patients were found to have de novo missense mutations in the highly conserved exons 4 and 5 (basic region of the DNA binding domain) of the TFAP2A gene in the candidate deleted region. We conclude BOFS is caused by mutations involving TFAP2A. More patients need to be studied to determine possible genetic heterogeneity and to establish whether there are genotype-phenotype correlations.
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