Localization of Jacobsen syndrome breakpoints on a 40-Mb physical map of distal chromosome 11q

Jacobsen syndrome is a haploinsufficiency disorder caused, mon frequently b y terminal deletion of part of the long arm of chromosome ii, with breakpoi nts in 11q23.3-11q24.2. Inheritance of an expanded p(CCG)(n) trinucleotide repeat at the folate-sensitive fragile site FRA11B has been implicated in t he generation of the chromosome breakpoint in several Jacobsen syndrome pat ients. The majority of such breakpoints, however, map distal to this fragil e site and are not linked with its expression. To characterize these distal breakpoints and ultimately to further investigate the mechanisms of chromo some breakage, a 40-Mb YAC contig covering the distal long arm of chromosom e II was assembled. The utility of the YAC contig was demonstrated in three ways: (1) by rapidly mapping the breakpoints from two new Jacobsen syndrom e patients using FISH; (2) by demonstrating conversion to high resolution P AC contigs after direct screening of PAC library filters with a YAC clone c ontaining a Jacobsen syndrome breakpoint; and (3) by placing 23 Jacobsen sy ndrome breakpoints on the physical map. This analysis has suggested the exi stence of at least two new Jacobsen syndrome breakpoint cluster regions in distal chromosome 11.