Branchio-Oculo-Facial Syndrome (BOFS) via the TFAP2A Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
8529 TFAP2A 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8529TFAP2A81479 81479 $890 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.

A 25% additional charge will be applied to STAT orders. View STAT turnaround times here.

For Reflex to PGxome pricing click here.

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

Turnaround Time

18 days on average


Genetic Counselors


Clinical Features and Genetics

Clinical Features

Branchio-Oculo-Facial Syndrome (BOFS) is a rare autosomal dominant congenital disorder with highly variable expression. BOFS is characterized by Branchial defects, which include erythematous cutaneous defects in the cervical region. Ocular anomalies are more diverse and include microphthalmia, anophthalmia, lacrimal duct obstruction, coloboma, cataract and ptosis. Facial defects include cleft lip and/or palate (CL/P), pseudocleft or abnormal philtrum (Al-Dosari et al. 2010; Aliferis et al. 2011; Günes et al. 2014). Other common findings are malformed and prominent pinnae and conductive hearing loss from inner ear and/or petrous bone anomalies. Less frequent findings are premature hair graying, ectopic thymus, renal anomalies and mild developmental delay (Lin and Milunsky 2011; Li et al. 2013). BOFS patients with predominant ocular phenotypes may go undiagnosed. Upper lip examination would be helpful in such cases. TFAP2A gene testing can be useful in confirming the diagnosis and also for better genetic counseling (Lin et al. 1991; Aliferis et al. 2011).


Autosomal dominant BOFS is caused by mutations in the TFAP2A (transcription factor AP-2α) gene. TFAP2A encoded AP-2α is a member of the AP2 transcription factor family, which is an essential regulator of mammalian cranial neural-tube closure and craniofacial development (Schorle et al. 1996; Zhang et al. 1996). The retinoic acid-inducible AP-2 family members (AP-2α, AP-2β, AP-2δ, AP-2γ, and AP-2ε) are shown to be expressed in several embryonic areas such as the forebrain, face and limb buds during mouse embryogenesis (Chazaud et al. 1996). Specifically, AP-2α is expressed in several eye tissues, including the developing lens, and is required in early ocular morphogenesis (West-Mays et al. 1999). AP-2α knockout mice studies have shown that loss of AP-2α in multiple tissues in the craniofacial region leads to severe optic cup patterning defects and failure of optic stalk morphogenesis. Tissue-specific deletion of AP-2α in the surface ectoderm, neural crest or retina did not recapitulate the phenotype, which indicates that tissue–tissue interactions are required for ocular morphogenesis (Bassett et al. 2010). To date, genetic heterogeneity has not been reported in BOFS. The majority of the TFAP2A causative mutations are missense (~90%) and act in a dominant-negative manner, which affect the DNA-binding domain activity of AP-2α. An analysis done in 30 families identified TFAP2A mutations in ~90% (27/30) of the families (Milunsky et al. 2011). Several mutations were recurrent and all mutations occurred in exons 4 and 5, which have been reported as hotspot regions for missense mutations (Milunsky et al. 2011). De novo mutations have also been reported in this region (Milunsky et al. 2008). A clear correlation between genotype and phenotype has not been seen in the cases analyzed to date (less than 100 cases). Complete penetrance, variable expressivity and marked clinical variability have been reported within the affected family members (Li et al. 2013). So far, about 35 total mutations (missense, small and gross deletion and insertions/duplications) have been reported in TFAP2A that are associated with BOFS (Human Gene Mutation Database).

Testing Strategy

This test provides full coverage of all coding exons of the TFAP2A gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Clinical Sensitivity - Sequencing with CNV PGxome

A genotype-phenotype analysis done in 30 families (41 affected individuals) identified TFAP2A mutations in 90% of the families (Milunsky et al. 2011).

Indications for Test

All patients with symptoms suggestive of Branchio-Oculo-Facial Syndrome (BOFS) are candidates.


Official Gene Symbol OMIM ID
TFAP2A 107580
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Branchiooculofacial Syndrome AD 113620


  • Al-Dosari MS, Almazyad M, Al-Ebdi L, Mohamed JY, Al-Dahmash S, Al-Dhibi H, Al-Kahtani E, Al-Turkmani S, Alkuraya H, Hall BD, others. 2010. Ocular manifestations of branchio-oculo-facial syndrome: report of a novel mutation and review of the literature. Molecular vision 16: 813. PubMed ID: 20461149
  • Aliferis K, Stoetzel C, Pelletier V, Hellé S, Angioï-Duprez K, Vigneron J, Leheup B, Marion V, Dollfus H. 2011. A novel TFAP2A mutation in familial Branchio-Oculo-Facial Syndrome with predominant ocular phenotype. Ophthalmic Genet. 32: 250–255. PubMed ID: 21728810
  • Bassett EA, Williams T, Zacharias AL, Gage PJ, Fuhrmann S, West-Mays JA. 2010. AP-2 knockout mice exhibit optic cup patterning defects and failure of optic stalk morphogenesis. Human Molecular Genetics 19: 1791–1804. PubMed ID: 20150232
  • Chazaud C, Oulad-Abdelghani M, Bouillet P, Décimo D, Chambon P, Dollé P. 1996. AP-2.2, a novel gene related to AP-2, is expressed in the forebrain, limbs and face during mouse embryogenesis. Mechanisms of development 54: 83–94. PubMed ID: 8808408
  • Günes N, Cengiz FB, Duman D, Dervişoğlu S, Tekin M, Tüysüz B. 2014. Branchio-oculo-facial syndrome in a newborn caused by a novel TFAP2A mutation. Genet. Couns. 25: 41–47. PubMed ID: 24783654
  • Human Gene Mutation Database (Bio-base).
  • Li H, Sheridan R, Williams T. 2013. Analysis of TFAP2A mutations in Branchio-Oculo-Facial Syndrome indicates functional complexity within the AP-2 DNA-binding domain. Human Molecular Genetics 22: 3195–3206. PubMed ID: 23578821
  • Lin AE, Milunsky JM. 2011. Branchiooculofacial Syndrome. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 21634087
  • Milunsky JM, Maher TA, Zhao G, Roberts AE, Stalker HJ, Zori RT, Burch MN, Clemens M, Mulliken JB, Smith R, Lin AE. 2008. TFAP2A Mutations Result in Branchio-Oculo-Facial Syndrome. The American Journal of Human Genetics 82: 1171–1177. PubMed ID: 18423521
  • Milunsky JM, Maher TM, Zhao G, Wang Z, Mulliken JB, Chitayat D, Clemens M, Stalker HJ, Bauer M, Burch M, Chénier S, Cunningham ML, et al. 2011. Genotype-phenotype analysis of the branchio-oculo-facial syndrome. Am. J. Med. Genet. A 155A: 22–32. PubMed ID: 21204207
  • Schorle H, Meier P, Buchert M, Jaenisch R, Mitchell PJ. 1996. Transcription factor AP-2 essential for cranial closure and craniofacial development. Nature 381: 235–238. PubMed ID: 8622765
  • West-Mays JA, Zhang J, Nottoli T, Hagopian-Donaldson S, Libby D, Strissel KJ, Williams T. 1999. AP-2alpha transcription factor is required for early morphogenesis of the lens vesicle. Dev. Biol. 206: 46–62. PubMed ID: 9918694
  • Zhang J, Hagopian-Donaldson S, Serbedzija G, Elsemore J, Plehn-Dujowich D, McMahon AP, Flavell RA, Williams T. 1996. Neural tube, skeletal and body wall defects in mice lacking transcription factor AP-2. Nature 381: 238–241. PubMed ID: 8622766


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