Genotype-phenotype analysis of the branchio-oculo-facial syndrome.


Branchio-oculo-facial syndrome (BOFS; OMIM#113620) is a rare autosomal dominant craniofacial disorder with variable expression. Major features include cutaneous and ocular abnormalities, characteristic facies, renal, ectodermal, and temporal bone anomalies. Having determined that mutations involving TFAP2A result in BOFS, we studied a total of 30 families (41 affected individuals); 26/30 (87%) fulfilled our cardinal diagnostic criteria. The original family with the 3.2 Mb deletion including the TFAP2A gene remains the only BOFS family without the typical CL/P and the only family with a deletion. We have identified a hotspot region in the highly conserved exons 4 and 5 of TFAP2A that harbors missense mutations in 27/30 (90%) families. Several of these mutations are recurrent. Mosaicism was detected in one family. To date, genetic heterogeneity has not been observed. Although the cardinal criteria for BOFS have been based on the presence of each of the core defects, an affected family member or thymic remnant, we documented TFAP2A mutations in three (10%) probands in our series without a classic cervical cutaneous defect or ectopic thymus. Temporal bone anomalies were identified in 3/5 patients investigated. The occurrence of CL/P, premature graying, coloboma, heterochromia irides, and ectopic thymus, are evidence for BOFS as a neurocristopathy. Intrafamilial clinical variability can be marked. Although there does not appear to be mutation-specific genotype-phenotype correlations at this time, more patients need to be studied. Clinical testing for TFAP2A mutations is now available and will assist geneticists in confirming the typical cases or excluding the diagnosis in atypical cases.

DOI: 10.1002/ajmg.a.33783

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@article{Milunsky2011GenotypephenotypeAO, title={Genotype-phenotype analysis of the branchio-oculo-facial syndrome.}, author={Jeff M. Milunsky and Tom M Maher and Geping Zhao and Zhenyuan Wang and John Butler Mulliken and David A. Chitayat and Michele Clemens and Heather J. Stalker and Mislen S Bauer and Michele Burch and S{\'e}bastien Ch{\'e}nier and Michael L. Cunningham and Arlene V. Drack and Sandra Janssens and Audrey Karlea and Regan Klatt and Usha Kini and Ophir D Klein and Augusta M A Lachmeijer and Andr{\'e} M{\'e}garban{\'e} and Nancy J. Mendelsohn and Wendy S. Meschino and Geert Mortier and Sandhya Parkash and Christian R Ray and Angharad Roberts and Amy E. Roberts and Willie Reardon and Rhonda E. Schnur and Rosemarie Smith and Miranda Splitt and Kamer Tezcan and Margo Whiteford and Derek Wong and Roberto Zori and Angela Lin}, journal={American journal of medical genetics. Part A}, year={2011}, volume={155A 1}, pages={22-32} }