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Neurofibromatosis type 1 (NF1) is caused by mutations of the NF1 gene at 17q11.2. The encoded protein, termed neurofibromin, contains a Ras-GTPase activating (RasGAP) domain, which accelerates the inactivation of Ras. Homozygous inactivation of neurofibromin is associated with a dysregulation of Ras mediated signalling pathways and tumorigenesis in NF1 patients.1,2 More than 70% of the germline mutations are intragenically distributed throughout the coding region and are protein truncating.3,4 In 5–20% of all NF1 patients, however, heterozygous microdeletions at 17q11.2 have been identified.5–8 These patients with microdeletions often have a severe clinical phenotype characterised by facial dysmorphy, excessive numbers of neurofibromas, and mental deficits. In the majority of cases, the deletions at 17q11.2 span 1.4 mbp and are caused by recombination between highly homologous low copy repeats (LCR), which flank the NF1 gene at distances of ~400 kb on the proximal side and 700 kb on the distal side.9–13 The LCRs mediating intrachomosomal deletions at 17q11.2 are derived from the WI-12393 gene and contain sequences with high homology to 19p13.9,11,13,14 The structure of the NF1 gene region at 17q11.2 is further complicated by other duplicated sequences, such as the pseudogene fragments of the SMURF2 and the KIAA0160 genes located at 17q.9,14 These sequences may also represent templates for unequal recombinations and subsequent deletions of the intervening chromosomal regions at 17q11.2. Indeed, five patients with large deletions in 17q spanning more than 1.4 mbp have been described.5,9,10,15–17 Up to now, breakpoints in these patients with long range deletions have not been placed precisely within the physical map of chromosome 17q11-12, which is still uncertain for a few regions.
In this study, we determined the precise boundaries of the constitutional deletion in patient BUD …