Heterogeneity of breakpoints in non-LCR-mediated large constitutional deletions of the 17q11.2 NF1 tumour suppressor region

Key points * Deletions of the entire neurofibromatosis type 1 (NF1) region at 17q11.2 most often span the same 1.4 mbp interval and are caused by meiotic recombinations between low copy repeats (LCR) which flank the deleted interval. Several NF1 patients with even larger deletions at 17q have been reported, but the position of their breakpoints within a contiguous BAC/PAC contig has not been determined. * The molecular characterisation of a deletion spanning more than 1.4 mbp in NF1 patient BUD is described and compared with that in four patients who have previously been characterised by marker analysis and Southern hybridisation using short genomic probes (D17S117, D17S120, D17S57, D17S73, D17S115). Both the proximal and distal breakpoints of all five patients clearly fall at different locations and are not bordered by LCRs. The centromeric break in patient BUD was mapped to BAC 271K11 at 17q11.2 between a partial SMS repeat and the WI-12393 derived LCR, whereas the distal break was located between the two SCHLAFEN (SLFN) genes, SLFN1 and SLFN3, at 17q12. * Comparisons between the otherwise conserved human and mouse segments showed major differences in the number and orientation of SLFN genes. Thus the distal breakpoint of patient BUD lies in a region containing multiple evolutionary breakpoints. The deletion was shown to be paternally inherited and to occur through an intrachromosomal mechanism. As three of four previously analysed NF1 deletions that were not bordered by LCRs were also found to be of paternal origin, non-LCR-triggered deletions are most probably mitotic events during spermatogenesis. * Patient BUD as well as patient UWA106-3, who also has a large deletion extending beyond the distal NF1 LCR at 17q11.2, suffer from multiple spinal neurofibromas. Their deletions may include a modifier locus which predisposes these patients to the development of these tumours