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.

Figure 1.

REL distributions measured in 14 patients with WBS and in 14 control skin fibroblasts. REL boxplots are shown for control genes (IFNGR2 [A] and USP18 [B]), for hemizygous genes that map to the commonly deleted WBS interval (LIMK1 [C] and BAZ1B [D]), for nonhemizygous genes that map to the flank of the commonly deleted WBS interval (HIP1 [E], NM_017994 [F], and POR [G]), and for LCR genes that map to the repeats flanking the WBS deletion (WBSCR20 [H]). Asterisks indicate P<.04 and double asterisks indicate P<.005, at both t and Mann-Whitney tests.

Figure 2.

Differences of expression levels in patients with WBS and in controls. Ratio of ARELs from 14 patients with WBS and from 14 controls, measured in skin fibroblasts. Left to right, Two HSA7 short-arm genes, HSA7 long-arm genes from the centromere to the telomere, followed by the control genes (squares) and the mean (disks) of each tested gene category. Nonhemizygous WBS HSA7 genes (blue) map centromerically (cen) or telomerically (tel) of the deletion. LCR = Gene mapping to the repeats flanking the WBS deletion (green). hemizygous = Hemizygous WBS HSA7 genes (red). controls = Control genes mapping outside HSA7 (yellow). A schematic representation (not to scale) of the HSA7 cytogenetic bands in which the assessed genes map is presented in the lower part of the graph. Asterisks indicate P<.05 and double asterisks indicate P<.001, at both t and Mann-Whitney tests for individual genes and also at pairwise t test for categories. A double number sign (##) indicates that the t and Mann-Whitney tests are significant at P<.001 and P<.005, respectively (see table 4 for details).

Figure 3.

Schematic partial transcript map of the 7q11.23 region in normal chromosome (top) and in chromosomes bearing the classical WBS 1.55-Mb (center) and 1.84-Mb (bottom) deletions. The different centromeric (c), middle (m), and telomeric (t) duplicons within the LCRs are represented by specific arrows that specify their relative orientation and type. Gray arrow indicates BLOCK-A (A); striped arrow indicates BLOCK-B (B); and white arrow indicates BLOCK-C (C). Genes are depicted by black rectangles, with their names given above.