Disruption of the TFAP2A Regulatory Domain Causes Banchio-Oculo-Facial Syndrome (BOFS) and Illuminates Pathomechanisms for Other Human Neurocristopathies

Abstract

BOFS is a rare congenital syndrome that arises due to defects during neural crest (NC) development. All reported BOFS cases are caused by heterozygous mutations within TFAP2A. Here we describe a unique BOFS patient carrying a de novo heterozygous inversion in which one of the breakpoints is located 40 kb downstream of TFAP2A. Using in vitro and in vivo NC developmental models, we uncovered that TFAP2A is located within a large Topologically Associating Domain (TAD) containing enhancers essential for TFAP2A expression in NC cells (NCC). Importantly, using patient-specific hiPSC, we showed that the inversion causes a loss of physical interaction between the inverted TFAP2A allele and its cognate enhancers, leading to TFAP2A monoallelic and haploinsufficient expression in human NCC. More generally, our results highlight potential etiological mechanisms for other human NC-related abnormalities and illustrate how structural variation can lead to a loss of enhancer-gene interactions and, consequently, to pathological changes in gene expression.