title: Deletions of chromosomal regulatory boundaries are associated with congenital disease.
abstract: 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.
authors.forename: Jonas
authors.initials: J
authors.lastname: Ibn-Salem
authors.forename: Sebastian
authors.initials: S
authors.lastname: Köhler
authors.forename: Michael I
authors.initials: MI
authors.lastname: Love
authors.forename: Ho-Ryun
authors.initials: HR
authors.lastname: Chung
authors.forename: Ni
authors.initials: N
authors.lastname: Huang
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Hurles
authors.forename: Melissa
authors.initials: M
authors.lastname: Haendel
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Washington
authors.forename: Damian
authors.initials: D
authors.lastname: Smedley
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Mungall
authors.forename: Suzanna E
authors.initials: SE
authors.lastname: Lewis
authors.forename: Claus-Eric
authors.initials: CE
authors.lastname: Ott
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bauer
authors.forename: Paul N
authors.initials: PN
authors.lastname: Schofield
authors.forename: Stefan
authors.initials: S
authors.lastname: Mundlos
authors.forename: Malte
authors.initials: M
authors.lastname: Spielmann
authors.forename: Peter N
authors.initials: PN
authors.lastname: Robinson
mesh_terms: D002877:Chromosomes, Human / Q000235:genetics*; D056915:DNA Copy Number Variations; D030541:Databases, Genetic; D018628:Gene Dosage; D063990:Gene Ontology; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D015894:Genome, Human; D023281:Genomics; D057895:Haploinsufficiency; D006801:Humans; D008957:Models, Genetic; D058977:Molecular Sequence Annotation; D010641:Phenotype; D017384:Sequence Deletion