Molecular characterization of inv dup del(8p): Analysis of five cases

Abstract

We analyzed five patients with inverted duplication deletion of 8p [inv dup del(8p)] using fluorescence in situ hybridization (FISH) and short tandem repeat polymorphism (STRP) analysis. In all patients, inv dup del(8p) consisted of a deleted distal segment, an intact in-between segment, and a duplicated proximal segment. In all of them, the proximal breakpoint of the deletion and one of the breakpoints of the duplication were identical, each located at one of the two olfactory receptor gene clusters at 8p23. FISH analysis showed all their mothers to be heterozygous carriers of an 8p23 inversion [inv(8)(p23)]. STRP analysis indicated that the deletions occurred in maternally derived chromosomes. The duplicated segments had two copies of maternal, either heterozygous or homozygous alleles. These findings support and reinforce those in 16 patients with inv dup del(8p) and their parents by Floridia et al. [1996: Am J Hum Genet 58:785-796] and subsequent additional studies of 10 of them by Giglio et al. [2001: Am J Hum Genet 68:874-883]. Based on these findings, we propose a model for the inv dup del(8p) formation. The inverted segment and its normal counterpart in inv(8)(p23) heterozygous carrier mothers form a loop at the pachytene period of meiosis I. Inv dup del(8p) with heterozygous duplication is formed through at least one meiotic recombination within the loop. Inv dup del(8p) with the homozygous duplication arises through two meiotic recombinations on the inv(8)(p23) chromosome (one within the loop and the other between the loop and centromere). Subsequent rescue by eliminating a part of the duplicated segment and a centromere enables formation of viable inv dup del(8p). The frequency of the inv(8)(p23) allele is 39% in a normal Japanese population, comparable to 26% in Europeans Giglio et al. [2001: Am J Hum Genet 68:874-883]. The proposed mechanism of formation of inv dup del(8p) requires two independent events (a recombination within the loop and subsequent rescue), which may explain its rarity.

Ring chromosome formation as a novel escape mechanism in patients with inverted duplication and terminal deletion

“…9 A mechanism for the formation of inverted duplications associated with terminal deletions has been described both for intrachromosomal duplications, based on normal parental chromosomes 18 and for intra-and interchromosomal duplications based on a parental inversion carrier. 19 These proposed mechanisms assume that an intrachromosomal U-type recombination during meiosis I, or a loop formation combined with one or two recombination events between homologous alleles, has occurred. The consequential recombinant dicentric chromosome would be deleted beyond the distal recombination site.…”

DNA sequence and analysis of human chromosome 8

“…Among 247 sequence-based genetic markers (Supplementary Table S4) there are six discrepancies. One discrepancy consists of eight markers and spans a region in 8p23 known to be the site of a polymorphic inversion in the human population 15,16 (see below). Five discrepancies each consist of single markers out of order by one position; all occur in small regions where the genetic map shows no recombination in one of the two sexes (Supplementary Table S4).…”

Genomic profile of copy number variants on the short arm of human chromosome 8

“…27,51 Although no annotated repeat sequences occur around the breakpoints of this SMC (8) in patient 10, the 8p breakpoint (38.94 Mb) of this SMC(8) is adjacent to the proximal breakpoint (B39.72 Mb) of the inverted duplicated regions in five reported cases with inv dup del(8p). 10 This region appears to be extremely unstable because 72% (847 of 915) of the benign CNVs in this study carry proximal and/or distal breakpoints within the region (Figure 2; Table 2). On the basis of these rare genomic abnormalities on 8p, we may conclude that the regions with nucleotide coordinates at B10.…”

“…[2][3][4][5][6] These REPD-and/or REPP-related 8p genomic rearrangements include (1) the 8p23.1 deletion or duplication between REPD and REPP, [6][7][8][9] (2) the 8p23.1 paracentric inversion between REPD and REPP, 8,10 (3) the pericentric inversion (inv(8)(p23.1q22.1)) and recombinant chromosome 8 (rec (8)dup(8q)inv(8)(p23.1q22.1)), 11 (4) the 8p interstitial inverted duplication with associated terminal deletion (inv dup del(8p)), 5,6,8,10,[12][13][14][15][16][17][18][19][20][21][22][23][24] (5) the 8p translocations involving the 8p23.1, 25,26 and (6) different types of supernumerary chromosome 8 (SMC (8)) involving the breakpoints within 8p23.1. 4,27 In addition to these defined 8p genomic abnormalities, other pathogenic genomic changes have been identified, [28][29][30] whereas numerous genomic imbalances on 8p are still described as copy number variants (CNVs) of unknown clinical significance or CNVs without apparent clinical significance (benign CNVs) (http://projects.tcag.ca/variation).…”