Figure 1

Models of deletion pathomechanism. In each panel, an exemplary deletion is shown as a red bar, a TDB is indicated with a black arrow, and genes associated with the phenotypes of the CNV patient are shown in blue, other genes in gray. Phenotypic abnormalities are represented as exemplary HPO terms (HP1, HP2 and HP3). Three tissue-specific enhancers are shown in (B) as black ovals. (A) Gene-dosage effect (GDE). A deletion leads to a reduction in the dosage of haplosensitive genes located within the CNV. The individual with the deletion has two phenotypic abnormalities (HP1, HP2) resulting from deletion of two haplosensitive genes. A Mendelian disease related to mutations in the first gene is associated with HP1, and a Mendelian disease related to mutations in the second gene is associated with HP2. (B) Topological domain boundary disruption (TDBD). Removal of the topological domain boundary allows the tissue-specific enhancer inappropriately to activate a phenotypically relevant gene located adjacent to the deletion, a phenomenon that we refer to as enhancer adoption. In this case, the individual with the deletion has a phenotypic abnormality (HP3) that is also seen in individuals with a Mendelian disease related to a mutation in the gene adjacent to the deletion.