Inverted duplications deletions: underdiagnosed rearrangements??

Abstract

Molecular techniques led to the discovery that several chromosome rearrangements interpreted as terminal duplications were in fact inverted duplications contiguous to terminal deletions. Inv dup del rearrangements originate through a symmetric dicentric chromosome that, after asymmetric breakage, generates an inv dup del and a deleted chromosome. In recurrent inverted duplications the dicentric chromosome is formed at meiosis through non‐allelic homologous recombination. In non‐recurrent inv dup del cases, dicentric intermediates are formed by non‐homologous end joining or intrastrand annealing. Some authors hypothesized that in these cases the dicentric may have been formed directly in the zygote. Healing of the broken dicentric chromosomes can occur not only in a telomerase‐dependent way but also through telomere capture and circularization thus creating translocated or ring inv dup del chromosomes. In all the cases reported up to now, the duplicated region was always longer than the deleted one, but we can safely assume that there is another group of rearrangements where the deleted region is longer than the duplicated portion. In general, in these cases, the cytogeneticist will suspect the presence of a deletion and confirm it by FISH with a subtelomeric probe, but he/she will almost certainly miss the duplication. It is likely that the conventional analysis techniques used until now have led to a substantial underestimate of the frequency of inv dup del rearrangements and that the widespread use of array‐CGH in routine analysis will allow a more realistic estimate. Obviously, the concomitant presence of deletion and duplication has important consequences in genotype/phenotype correlations.

Low-copy repeats at the human VIPR2 gene predispose to recurrent and nonrecurrent rearrangements

“…The final interpretation was: 46,XX,der(7)t(7;D or G)(7q36; p11.2).arr 7q35 q36.3(144 063 347 Â 2, 144 093 894-158 612 902 Â 3, 158 747 771-158 811 268 Â 1; hg18). These data suggest that the derivative chromosome was the product of an inverted duplication associated with a distal contiguous deletion (inv-dup-del) 12 Figure 1d, Supplementary Figure 1a). These LCRs are annotated in the GRCh37/h19 assembly of the human genome.…”

“…The same mechanism, NAHR between two large complex LCRs, generates the recurrent inverted duplication/deletion of 8p, inv dup(8p). 12,13 We also documented rare NAHR-mediated rearrangements at a pair of small inverted LCRs close to the MYOM gene on 8p. 7 Most nonrecurrent inverted duplications/terminal deletions seem to be generated by NHEJ or intra-strand annealing (reviewed in Zuffardi et al 12 ).…”

The Human Cleavage Stage Embryo Is a Cradle of Chromosomal Rearrangements

“…This model also predicts the formation of inv dup del chromosomes in the cleavage stage embryo. Many non-recurrent inv dup del rearrangements, which result from an asymmetric breakage of a symmetric dicentric chromosome in a pre-meiotic, meiotic or postzygotic anaphase, have been detected during pre-and postnatal genetic diagnoses [Zuffardi et al, 2009]. Also, ring and translocation chromosomes have been found to contain inv dup scars at the fusion or the break point [Rossi et al, 2007].…”

“…However, if pulled towards opposite spindle poles, inv dup del chromosomes are generated because the dicentric will most likely break distal from the fusion point. Both pure terminal deletion and inv dup del chromosomes are a frequent anomaly in human chromosomal disorders [Schinzel, 2001;Ballif et al, 2003;Zuffardi et al, 2009]. Amplified terminal segments are explained by a randomly segregating inv dup segment ( A ) or a second BFB cycle ( B ).…”

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

“…[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).…”