Interplay between genomic architecture alterations and GDF6 regulation: A candidate mechanism in Nablus mask-like...

Nablus mask-like facial syndrome (NMLFS) is a very rare disorder associated with 8q22.1q22 microdeletions and characterized by a distinctive facial phenotype and variable neurological, cardiological, and genital anomalies. However, not all affected individuals with overlapping deletions present the mask-like phenotype, thus suggesting the involvement of an additional regulatory mechanism. Here, we perform a comparative analysis of previously reported affected individuals (n = 30) with deletions in the 8q21q22 region, stratified by the presence or absence of the NMLFS phenotype, and including an affected individual from Romania with an 8q21.13q22.1 microdeletion. We investigated the 3D genomic architecture, focusing on topologically associating domains (TADs) and regulatory elements, and identified a recurrent pattern of candidate TAD fusion significantly associated with NMLFS. This configuration brings a cluster of ultra-conserved non-coding elements (UCNEs) in the proximity of GDF6, a known regulator of craniofacial development. Thus, we propose a mechanism involving TAD fusion and enhancer hijacking affecting the candidate gene GDF6 that may underlie the facial anomaly and provide insight into the variable expressivity in 8q22.1 microdeletion syndrome.