High level of unequal meiotic crossovers at the origin of the 22q11. 2 and 7q11.23 deletions

Abstract

Interstitial chromosomal deletions at 22q11.2 and 7q11.23 are detected in the vast majority of patients affected by CATCH 22 syndromes and the Williams-Beuren syndrome, respectively. In a group of 15 Williams-Beuren patients, we have shown previously that a large number of 7q11.23 deletions occur in association with an interchromosomal rearrangement, indicative of an unequal crossing-over event between the two homologous chromosomes 7. In this study, we show that a similar mechanism also underlies the formation of the 22q11.2 deletions associated with CATCH 22. In eight out of 10 families with a proband affected by CATCH 22, we were able to show that a meiotic recombination had occurred at the critical deleted region based on segregation analysis of grandparental haplotypes. The incidences of crossovers observed between the closest informative markers, proximal and distal to the deletion, were compared with the expected recombination frequencies between the markers. A significant number of recombination events occur at the breakpoint of deletions in CATCH 22 patients (P = 2.99x10(-7)). The segregation analysis of haplotypes in three-generation families was also performed on an extended number of Williams-Beuren cases (22 cases in all). The statistically significant occurrence of meiotic crossovers (P = 4.45x10(-9)) further supports the previous findings. Thus, unequal meiotic crossover events appear to play a relevant role in the formation of the two interstitial deletions. The recurrence risk for healthy parents in cases where such meiotic recombinations can be demonstrated is probably negligible. Such a finding is in agreement with the predominantly sporadic occurrence of the 22q11.2 and 7q11. 23 deletions. No parent-of-origin bias was observed in the two groups of patients with regard to the origin of the deletion and to the occurrence of inter- versus intrachromosomal rearrangements.

A new diagnostic workflow for patients with mental retardation and/or multiple congenital abnormalities: test arrays first

“…Deletions in Williams and DiGeorge syndrome were equally of paternal and maternal origin equally. 37 Deletions in neurofibromatosis type 1 and in 1p36 syndrome were predominant on the maternally derived chromosome. 38,39 By contrast, duplications in Charcot-Marie-Tooth disease type I and deletions in Wolf -Hirschhorn and Cri Du Chat syndromes occur more frequently in the paternally derived chromosome.…”

The genomic basis of the Williams – Beuren syndrome

“…Usually, WBS occurs sporadically with only a slight increased risk in the range of 1-2 % of recurrences for siblings of affected children. Nevertheless, the possibility of a gonadal mosaicism for the deletion has to be considered [79,80]. Inversion carriers at 7q11.23 will have an increased risk of meiotic recombination leading to gametes with unbalanced rearrangements.…”

“…It is assumed that the highest rates of NAHR occur at repeats with a close distance and high similarity [101][102][103]. Haplotype analyses in families with an affected child with WBS revealed that twothirds of the cases the chromosomal misalignment seems to result from interchromosomal reshuffling between homologous chromosomes 7 and in one-third of cases from an intrachromosomal (inter-or intrachromatid) rearrangement between sister chromatids [79,80,82]. Breakpoint-specific sequencing of the WBS region in sperm revealed that interchromatid recombination is much less frequent than intrachromatid or interchromosomal recombination.…”

Functional and genetic characterization of two extremely rare cases of Williams–Beuren Syndrome associated with chronic granulomatous disease

“…1 The microdeletion arise through non-allelic homologous recombination between low-copy repeats (LCRs) flanking this region. 4 However, implication of genes other than ELN in the deletion or flanking regions on the pathogenesis of this disease is still uncertain.…”