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

Kehrer‐Sawatzki, Hildegard; Tinschert, Sigrid; Jenne, Dieter E.

doi:10.1136/jmg.40.10.e116

Cited by 23 publications

(23 citation statements)

References 35 publications

(36 reference statements)

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“…2; Kayes et al 1992Kayes et al , 1994Cnossen et al 1997;Upadhyaya et al 1996Upadhyaya et al , 1998Dorschner et al 2000;Jenne et al 2003;Kehrer-Sawatzki et al 2003;Venturin et al 2004aVenturin et al , 2004b. Although the breakpoints of many of these atypical deletions have not been identified at the base-pair level, the confinement of the respective regions indicates that the breakpoints are not recurrent.…”

Section: Discussionmentioning

confidence: 88%

“…A few cases of unusually sized NF1 deletions have been described, ranging from 1-Mb to more than 7-Mb in size (Kayes et al 1992(Kayes et al , 1994Cnossen et al 1997;Upadhyaya et al 1998;Dorschner et al 2000;Riva et al 2000;Jenne et al 2003;Kehrer-Sawatzki et al 2003;Venturin et al 2004aVenturin et al , 2004b. Although the breakpoints of many of these atypical deletions have not been determined precisely, it can be deduced that they deviate from those of the common NF1 microdeletions.…”

Section: Introductionmentioning

confidence: 92%

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Extensively high load of internal tumors determined by whole body MRI scanning in a patient with neurofibromatosis type 1 and a non-LCR-mediated 2-Mb deletion in 17q11.2

2005

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Deletions in 17q11.2 affecting the NF1 gene and surrounding regions occur in 5% of patients with NF1. The two major types of NF1 deletions encompass 1.4-Mb and 1.2-Mb, respectively, and have breakpoints in the NF1 low-copy repeats or in the JJAZ gene and its pseudogene. Deletions larger than 1.4-Mb are rare, and only seven cases have been reported so far. Here, we describe a 26-year-old NF1 patient with an "atypical" NF1 deletion of 2-Mb. In contrast to the 1.4-Mb deletions, which preferentially occur by interchromosomal recombination during maternal meiosis, the deletion described here occurred intrachromosomally on the paternal chromosome. The centromeric deletion breakpoint lies in an L1-element located 1.3-Mb proximal to the NF1 gene. The telomeric deletion boundary is located in a single copy segment between an AT-rich segment and an AluSx-element in intron 15 of the JJAZ1 gene. Structural analysis implies that non-B DNA conformations at the breakpoints destabilized the duplex DNA and caused double-strand breaks. Although the breakpoints of this 2-Mb deletion are not recurrent, it is conspicuous that one breakpoint is located in the JJAZ1 gene. Paralogous recombination between the JJAZ1 gene and its pseudogene causes the recurrent 1.2 Mb deletions. The genomic architecture of the NF1 gene region, influenced by paralogous sequences such as the JJAZ1 gene and its pseudogene, seems also to stimulate the occurrence of non-recurrent deletions mediated by non-homologous end joining. Patient 442 described here suffers from a very high burden of subdermal neurofibromas. Magnetic resonance imaging of the whole body revealed numerous internal tumors, mainly plexiform neurofibromas and spinal tumors. This demonstrates the value of whole-body MRI scanning in determining the total tumor load, which is an important aspect in genotype/phenotype correlations with regard to large NF1 deletions.

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Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 92%

Extensively high load of internal tumors determined by whole body MRI scanning in a patient with neurofibromatosis type 1 and a non-LCR-mediated 2-Mb deletion in 17q11.2

2005

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“…The typical type-2 microdeletion is smaller (1.2 Mb) and has breakpoints located in the SUZ12 gene (suppressor of zeste 12 homolog; NM_015355) and its pseudogene SUZ12P (Petek et al, 2003;KehrerSawatzki et al, 2004;Steinmann et al, 2007;Roehl et al, 2010). Even less frequent, atypical NF1 microdeletions with non-recurring breakpoints have also been reported (Riva et al, 2000;Kehrer-Sawatzki et al, 2003Venturin et al, 2004a;Mantripragada et al, 2006;Pasmant et al, 2008).…”

Section: Introductionmentioning

confidence: 94%

“…The array comprised a total of 14,207 oligonucleotide probes spanning the whole of chromosome 17, including 12 314 probes spanning a ~8 Mb interval surrounding the NF1 locus (~300 kb). This 8-Mb interval spanned the NF1 gene region and included the largest NF1 atypical microdeletions described in the literature (Riva P et al, 2000;Kehrer-Sawatzki et al, 2003;Venturin et al, 2004a;Pasmant et al, 2008). Details of the microarray design, including the 14,207 oligonucleotide probe chromosome locations, has been deposited in NCBI's GEO (Edgar et al, 2002) and are accessible through the GEO accession number GSE19730.…”

Section: Characterization Of Nf1 Microdeletionsmentioning

confidence: 99%

NF1 microdeletions in neurofibromatosis type 1: from genotype to phenotype

et al. 2010

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ABSTRACT:In 5-10% of patients, neurofibromatosis type 1 (NF1) results from microdeletions that encompass the entire NF1 gene and a variable number of flanking genes. Two recurrent microdeletion types are found in most cases, with microdeletion breakpoints located in paralogous regions flanking NF1 (proximal NF1-REP-a and distal NF1-REP-c for the 1.4 Mb type-1 microdeletion, and SUZ12 and SUZ12P for the 1.2 Mb type-2 microdeletion). A more severe phenotype is usually associated with NF1 microdeletion patients than in those with intragenic mutations. We characterized NF1 microdeletions in 70 unrelated NF1 microdeleted patients using a high-resolution NF1 custom array comparative genomic hybridization (CGH). Genotypephenotype correlations were studied in 58 of these microdeletion patients and compared to 389 patients with intragenic truncating NF1 mutations and phenotyped in the same standardized way. Our results confirmed in an unbiased manner the existence of a contiguous gene syndrome with a OFFICIAL JOURNAL www.hgvs.orgGenotype-phenotype Correlation in NF1 Microdeletion Patients E1507 significantly higher incidence of learning disabilities and facial dysmorphism in microdeleted patients compared to patients with intragenic NF1 mutations. Microdeleted NF1 patients also showed a trend toward significance for childhood overgrowth. High-resolution array-CGH identified a new recurrent ~1.0 Mb microdeletion type, designated as type-3, with breakpoints in the paralogous regions middle NF1-REP-b and distal NF1-REP-c.

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“…Most of the NF1 deletion breakpoints are localised within REPs, but NF1 gross deletions delimited by variant endpoints have also been reported (Dorschner et al 2000;Jenne et al 2001;Kehrer-Sawatzki et al 2003;Petek et al 2003;present study). More general chromosome-specific rearrangements mediated by regions different from the ones usually involved have been reported in a number of genomic disorders (Thomas et al 1999;Shaikh et al 2000;Shaw et al 2002).…”

Section: Mapping Of Unusual Deletion Breakpointsmentioning

confidence: 99%

Evidence for non-homologous end joining and non-allelic homologous recombination in atypical NF1 microdeletions

et al. 2004

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NF1 microdeletion syndrome is caused by haploinsufficiency of the NF1 gene and of gene(s) located in adjacent flanking regions. Most of the NF1 deletions originate by non-allelic homologous recombination between repeated sequences (REP-P and -M) mapped to 17q11.2, while the remaining deletions show unusual breakpoints. We performed high-resolution FISH analysis of 18 NF1 microdeleted patients with the aims of mapping non-recurrent deletion breakpoints and verifying the presence of additional recombination-prone architectural motifs. This approach allowed us to obtain the sequence of the first junction fragment of an atypical deletion. By conventional FISH, we identified 16 patients with REP-mediated common deletions, and two patients carrying atypical deletions of 1.3 Mb and 3 Mb. Following fibre-FISH, we identified breakpoint regions of 100 kb, which led to the generation of several locus-specific probes restricting the atypical deletion endpoint intervals to a few kilobases. Sequence analysis provided evidence of small blocks of REPs, clustered around the 1.3-Mb deletion breakpoints, probably involved in intrachromatid non-allelic homologous recombination (NAHR), while isolation and sequencing of the 3-Mb deletion junction fragment indicated that a non-homologous end joining (NHEJ) mechanism is implicated.

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

Cited by 23 publications

References 35 publications

Extensively high load of internal tumors determined by whole body MRI scanning in a patient with neurofibromatosis type 1 and a non-LCR-mediated 2-Mb deletion in 17q11.2

Extensively high load of internal tumors determined by whole body MRI scanning in a patient with neurofibromatosis type 1 and a non-LCR-mediated 2-Mb deletion in 17q11.2

NF1 microdeletions in neurofibromatosis type 1: from genotype to phenotype

Evidence for non-homologous end joining and non-allelic homologous recombination in atypical NF1 microdeletions

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