BACKGROUND: Recent data from genome-wide chromosome conformation capture 
analysis indicate that the human genome is divided into conserved megabase-sized 
self-interacting regions called topological domains. These topological domains 
form the regulatory backbone of the genome and are separated by regulatory 
boundary elements or barriers. Copy-number variations can potentially alter the 
topological domain architecture by deleting or duplicating the barriers and 
thereby allowing enhancers from neighboring domains to ectopically activate 
genes causing misexpression and disease, a mutational mechanism that has 
recently been termed enhancer adoption.
RESULTS: We use the Human Phenotype Ontology database to relate the phenotypes 
of 922 deletion cases recorded in the DECIPHER database to monogenic diseases 
associated with genes in or adjacent to the deletions. We identify combinations 
of tissue-specific enhancers and genes adjacent to the deletion and associated 
with phenotypes in the corresponding tissue, whereby the phenotype matched that 
observed in the deletion. We compare this computationally with a gene-dosage 
pathomechanism that attempts to explain the deletion phenotype based on 
haploinsufficiency of genes located within the deletions. Up to 11.8% of the 
deletions could be best explained by enhancer adoption or a combination of 
enhancer adoption and gene-dosage effects.
CONCLUSIONS: Our results suggest that enhancer adoption caused by deletions of 
regulatory boundaries may contribute to a substantial minority of copy-number 
variation phenotypes and should thus be taken into account in their medical 
interpretation.