Deletions of chromosomal regulatory boundaries are associated with congenital disease

Jonas Ibn-Salem, Sebastian Köhler, Michael I. Love, Ho Ryun Chung, Ni Huang, Matthew E. Hurles, Melissa Haendel, Nicole L. Washington, Damian Smedley, Christopher J. Mungall, Suzanna E. Lewis, Claus Eric Ott, Sebastian Bauer, Paul N. Schofield, Stefan Mundlos, Malte Spielmann, Peter N. Robinson

Research output: Contribution to journalArticlepeer-review

95 Scopus citations


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.

Original languageEnglish (US)
Article number423
Pages (from-to)423
Number of pages1
JournalGenome biology
Issue number9
StatePublished - 2014
Externally publishedYes

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Genetics
  • Cell Biology


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