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

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