Submicroscopic Deletion in Patients with Williams-Beuren Syndrome Influences Expression Levels of the Nonhemizygous Flanking Genes

Abstract

Genomic imbalance is a common cause of phenotypic abnormalities. We measured the relative expression level of genes that map within the microdeletion that causes Williams-Beuren syndrome and within its flanking regions. We found, unexpectedly, that not only hemizygous genes but also normal-copy neighboring genes show decreased relative levels of expression. Our results suggest that not only the aneuploid genes but also the flanking genes that map several megabases away from a genomic rearrangement should be considered possible contributors to the phenotypic variation in genomic disorders.

Novel H3K4me3 marks are enriched at human- and chimpanzee-specific cytogenetic structures

“…Our findings suggest that evolutionary novelties and neighboring sequences should be investigated not only for gene expression differences and as fertile ground for the emergence of novel genes and transcripts, but also in the quest for lineage-specific epigenetic and regulatory changes. Our results also indicate how the duplicated regions that border copy number variants could play a role in the modification of the expression of normal copy number flanking genes (Merla et al 2006;Reymond et al 2007;Henrichsen et al 2009a,b), an effect that can extend over the entire length of the affected chromosome (Ricard et al 2010). …”

The genomic basis of the Williams – Beuren syndrome

“…In addition, a remarkable decrease in relative expression was also detected in non-hemizygous genes outside the WBS deletion region (ASL, KCTD7, HIP1, POR, MDH2), though the expression decrease was not as large as that observed for hemizygous genes. These findings suggest that genes that map close to the deletion region may be regulated by genes located within the WBS region via cis-regulatory elements and are jointly responsible for features of WBS phenotype [186]. An altered expression of genes within the WBS region was also found in patients with duplications in this region.…”

Recurrent copy number changes in mentally retarded children harbour genes involved in cellular localization and the glutamate receptor complex

“…55,56 Hence, CNCs may affect the phenotype by complex mechanisms in addition to and possibly different from altered gene dosage. Therefore, CNCs shared among unrelated patients with related phenotypes remain pathogenically relevant and merit further scrutiny.…”