6p.24 microdeletion involving TFAP2A without classic features of branchio‐oculo‐facial syndrome

Abstract

CP. 2013. 6p.24 Microdeletion involving TFAP2A without classic features of branchio-oculo-facial syndrome. Am J Med Genet Part A 161A:901-904.

Modeling the Pathological Long-Range Regulatory Effects of Human Structural Variation with Patient-Specific hiPSCs

“…These abnormalities are likely to be caused by neural crest (NC) developmental defects, indicating that BOFS is a human neurocristopathy (Trainor, 2015). In agreement with this, all BOFS patients reported to date carry heterozygous mutations or deletions within TFAP2A that are predicted to result in either antimorphic, hypomorphic, or null alleles for this NC master regulator (Brewer et al, 2004;LeBlanc et al, 2013;Li et al, 2013;Milunsky et al, 2008Milunsky et al, , 2011. Furthermore, although Tfap2a-null mice display a BOFS-like phenotype, Tfap2a +/À animals appear morphologically normal and, thus, are not haploinsufficient (Brewer et al, 2004;Schorle et al, 1996;Zhang et al, 1996), highlighting the need to ideally investigate BOFS in a human embryonic context.…”

Rare or Overlooked? Structural Disruption of Regulatory Domains in Human Neurocristopathies

“…However, there are important differences between mice and humans (Mestas and Hughes, 2004), for example, in gene dosage sensitivity: For many developmental genes implicated in human congenital disorders (including NCP), humans, but not mice, are haploinsufficient. This is well illustrated by BOFS: In humans this NCP is caused by heterozygous mutations/deletions in TFAP2A, and Tfap2a +/− mice appear as morphologically normal (note that Tfap2a −/− display a severe BOFS-like phenotype) (Schorle et al, 1996;Zhang et al, 1996;Brewer et al, 2004;Milunsky et al, 2011Milunsky et al, , 2008Leblanc et al, 2013;Li et al, 2013). Therefore, when these differences in gene dosage sensitivity are encountered, the pathological mechanisms of congenital disorders should be ideally investigated in human cellular models.…”