title: Genotype-phenotype analysis of the branchio-oculo-facial syndrome.
abstract: 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.
authors.affiliation: Center for Human Genetics, Boston University School of Medicine, Massachusetts 02118, USA. jmilunsk@bu.edu
authors.forename: Jeff M
authors.initials: JM
authors.lastname: Milunsky
authors.forename: Tom M
authors.initials: TM
authors.lastname: Maher
authors.forename: Geping
authors.initials: G
authors.lastname: Zhao
authors.forename: Zhenyuan
authors.initials: Z
authors.lastname: Wang
authors.forename: John B
authors.initials: JB
authors.lastname: Mulliken
authors.forename: David
authors.initials: D
authors.lastname: Chitayat
authors.forename: Michele
authors.initials: M
authors.lastname: Clemens
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Stalker
authors.forename: Mislen
authors.initials: M
authors.lastname: Bauer
authors.forename: Michele
authors.initials: M
authors.lastname: Burch
authors.forename: Sébastien
authors.initials: S
authors.lastname: Chénier
authors.forename: Michael L
authors.initials: ML
authors.lastname: Cunningham
authors.forename: Arlene V
authors.initials: AV
authors.lastname: Drack
authors.forename: Sandra
authors.initials: S
authors.lastname: Janssens
authors.forename: Audrey
authors.initials: A
authors.lastname: Karlea
authors.forename: Regan
authors.initials: R
authors.lastname: Klatt
authors.forename: Usha
authors.initials: U
authors.lastname: Kini
authors.forename: Ophir
authors.initials: O
authors.lastname: Klein
authors.forename: Augusta M
authors.initials: AM
authors.lastname: Lachmeijer
authors.forename: Andre
authors.initials: A
authors.lastname: Megarbane
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Mendelsohn
authors.forename: Wendy S
authors.initials: WS
authors.lastname: Meschino
authors.forename: Geert R
authors.initials: GR
authors.lastname: Mortier
authors.forename: Sandhya
authors.initials: S
authors.lastname: Parkash
authors.forename: C Renai
authors.initials: CR
authors.lastname: Ray
authors.forename: Angharad
authors.initials: A
authors.lastname: Roberts
authors.forename: Amy
authors.initials: A
authors.lastname: Roberts
authors.forename: Willie
authors.initials: W
authors.lastname: Reardon
authors.forename: Rhonda E
authors.initials: RE
authors.lastname: Schnur
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Smith
authors.forename: Miranda
authors.initials: M
authors.lastname: Splitt
authors.forename: Kamer
authors.initials: K
authors.lastname: Tezcan
authors.forename: Margo L
authors.initials: ML
authors.lastname: Whiteford
authors.forename: Derek A
authors.initials: DA
authors.lastname: Wong
authors.forename: Roberto
authors.initials: R
authors.lastname: Zori
authors.forename: Angela E
authors.initials: AE
authors.lastname: Lin
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D019280:Branchio-Oto-Renal Syndrome / Q000235:genetics* / Q000473:pathology*; D002872:Chromosome Deletion; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D010641:Phenotype; D017422:Sequence Analysis, DNA; D050656:Transcription Factor AP-2 / Q000235:genetics*
chemical_list: C493673:TFAP2A protein, human; D050656:Transcription Factor AP-2