HIGH-LEVEL OF UNEQUAL MEIOTIC CROSSOVERS AT THE ORIGIN OF THE 22Q11.2AND 7Q11.23 DELETIONS

Interstitial chromosomal deletions at 22q11.2 and 7q11.23 are detected in the vast majority of patients affected by CATCH 22 syndromes and t he Williams-Beuren syndrome, respectively. In a group of 15 Williams-B euren patients, we have shown previously that a large number of 7q11.2 3 deletions occur in association with an interchromosomal rearrangemen t, indicative of an unequal crossing-over event between the two homolo gous chromosomes 7. In this study, we show that a similar mechanism al so underlies the formation of the 22q11.2 deletions associated with CA TCH 22. In eight out of 10 families with a proband affected by CATCH 2 2, we were able to show that a meiotic recombination had occurred at t he critical deleted region based on segregation analysis of grandparen tal haplotypes. The incidences of crossovers observed between the clos est informative markers, proximal and distal to the deletion, were com pared 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 a nalysis 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 = 4.45x1 0(-9)) further supports the previous findings. Thus, unequal meiotic c rossover events appear to play a relevant role in the formation of the two interstitial deletions. The recurrence risk for healthy parents i n cases where such meiotic recombinations can be demonstrated is proba bly 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 int rachromosomal rearrangements.