Defining the critical region for intellectual disability and brain malformations in 6q27 microdeletions

Abstract

Terminal microdeletions of the long arm of chromosome 6 are associated with a phenotype that includes multiple brain malformations, intellectual disability, and epilepsy. A 1.7-Mb region has been proposed to contain a gene responsible for the brain anomalies. Here, we present the case of a 12-year-old girl with multiple brain alterations and moderate intellectual disability with a 18-kb deletion in chromosome 6q27, which is smaller than the microdeletions previously described by microarray analysis. We refined the smallest region of overlap possibly associated with the phenotype of brain malformations and intellectual disability to a segment of 325 kb, comprising the DLL1, PSMB1, TBP, and PDCD2 genes since these genes were structurally and/or functionally lost in the smaller deletions described to date. We hypothesize that DLL1 is responsible for brain malformations and possibly interacts with other adjacent genes. The TBP gene encodes a transcription factor which is potentially related to cognitive development. TBP is linked to PSMB1 and PDCD2 in a conserved manner among mammals, suggesting a potential interaction between these genes. In conclusion, the 6q27 microdeletion is a complex syndrome with variable expressivity of brain malformations and intellectual disability phenotypes which are possibly triggered by the 4 genes described and adjacent genes susceptible to gene regulation changes.