Unique Nonlcrmediated Nf1 Microdeletions

A subset of submicroscopic NF1 microdeletions have breakpoints outside of the NF1-REP paralogs (Fig. 4) and appear to arise by a mechanism other than paralogous recombination. Among the five larger deletions, all except the BUD case (patient B in Fig. 4) have a telomeric breakpoint within the ACCN1 gene. BUD has a telomeric breakpoint in the SLFN gene cluster. At least four of these deletions also have different centromeric breakpoint intervals. Only breakpoints in case six have been mapped at the nucleotide level with the centromeric breakpoint between BLMH and CPD and the telomeric breakpoint in ACCN1 intron 1. The breakpoints were not located within LCR elements. However, there were stretches of 20-21 bp of Alu-like elements at the two breakpoints and LINE and short interspersed nuclear element (SINE) elements within several hundred bp from the breakpoints. Together, these data provide support for a mechanism of nonhomologous end-joining (NHEJ) (36). Because LCRs are not known to be located in/near the breakpoints of the other NF1 microdeletions shown in Fig. 4, they may well arise by NHEJ also. As more such deletions are identified, it will be of interest to determine if there is a preferential parent of origin effect. In these examples, UWA106-3, BUD, and 96-2 have paternally derived deletions, whereas 372A was maternally derived. In general, larger deletions tend to occur in NF1 patients with severe or additional complications, but phe-notypic information is limited and the extent of an NF1 deletion has no predictive value to date.

The smaller deletions depicted on Fig. 4 are of interest because precise breakpoint mapping and full clinical evaluation of such patients may serve to narrow the critical region between NF1-REP-P1 and NF1-REP-M that confers the phenotype of heavy tumor load and increased

Fig. 4. Nonrecurrent NF1 microdeletions. A schematic of the 5.6-Mb region from FLJ46247 to PEX12 is diagrammed in two panels. Figures are drawn to scale with the exception of the 1.5-Mb NF1-REP region, which is compressed for space considerations. Gene names and gene clusters are written above arrows indicating their direction of transcription. The three NF1-REP (open boxes) and an adjacent SMS REP (gray box) are indicated. Four markers within ACCN1 are shown that serve to differentiate the extent of deletions with breakpoints within this large gene. Below the map, the recurrent 1.4-Mb deletion is shown compared to that of10 cases (A-J) with unique breakpoints. Solid lines indicated deleted region and dashed lines indicate uncertainty in the precise endpoint (see text for details). Gene names in this figure are from a May, 2004 assembly of the human genome (http://genome.ucsc.edu/) and may differ from names on previously published maps of the region (23,25,26,36).

Fig. 4. Nonrecurrent NF1 microdeletions. A schematic of the 5.6-Mb region from FLJ46247 to PEX12 is diagrammed in two panels. Figures are drawn to scale with the exception of the 1.5-Mb NF1-REP region, which is compressed for space considerations. Gene names and gene clusters are written above arrows indicating their direction of transcription. The three NF1-REP (open boxes) and an adjacent SMS REP (gray box) are indicated. Four markers within ACCN1 are shown that serve to differentiate the extent of deletions with breakpoints within this large gene. Below the map, the recurrent 1.4-Mb deletion is shown compared to that of10 cases (A-J) with unique breakpoints. Solid lines indicated deleted region and dashed lines indicate uncertainty in the precise endpoint (see text for details). Gene names in this figure are from a May, 2004 assembly of the human genome (http://genome.ucsc.edu/) and may differ from names on previously published maps of the region (23,25,26,36).

malignancy risk to deletion patients. Patients 236, 178, 236, and 237 have at least one breakpoint within the NF1 gene, but the extent of the deletion and position of the other breakpoints are not known. Patient 96-2 is deleted for much of the NF1 gene, but whether other genes are involved in this deletion is not known.

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