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.

Regulation of epithelial cell polarity by PAR-3 depends on Girdin transcription and Girdin–Gαi3 signaling

“…2E). To further validate AP-2α control of Girdin transcription, point mutations frequently observed in patients with branchio-oculo-facial syndrome (Milunsky et al, 2011), which are known to result in loss of AP-2α DNA binding (Garcia et al, 2000), were introduced into the basic region of human AP-2α expression plasmids. A reporter assay clearly indicated that these AP-2α point mutants failed to activate the Girdin promoter (Fig.…”

Syndrome branchio-oculo-facial

“…Il correspond à une anomalie du développement embryonnaire qui se traduit par des lésions cutanées caractéristiques associées à des atteintes oculaires et du massif cranio-facial. Les critères diagnostiques proposés par Milunski et al en 2010 [4] sont présentés dans le Tableau 1.…”

“…Lésion cutanée cervicale Anomalie oculaire Anomalie faciale Présence de deux critères majeurs associés à au moins un critère mineur parmi Un parent atteint au premier degré Présence dans le derme de cellules thymiques ectopiques D'après Milunski et al, 2010 [4].…”

Neurocristopathies

“…The cutaneous defects range from thin skin or a patch of hair to erythematous lesions. The majority of individuals diagnosed with BOFS carry a mutation in transcription factor TFAP2A [85]. TFAP2A is expressed during multiple stages of NCC development, including formation and migration, and has been shown to have roles in NCC specification [86].…”