Clinical characterisation of 29 neurofibromatosis type-1 patients with molecularly ascertained 1.4 Mb type-1 NF1 deletions

Mautner, Victor; Kluwe, Lan; Friedrich, Reinhard E; Roehl, Angelika C.; Bammert, S.; Högel, Josef; Spori, H.; Cooper, David Neil; Kehrer‐Sawatzki, Hildegard

doi:10.1136/jmg.2009.075937

Cited by 152 publications

(185 citation statements)

References 55 publications

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“…Among them, 5-10% are large 17q11.2 deletions encompassing the entire NF1 locus and neighbouring genes. 12 These large NF1 locus deletions have been associated with a more severe phenotype including an elevated risk for MPNSTs. [13][14] For patients with intragenic NF1 mutations (more than 90% of all NF1 cases), no clear-cut allele-phenotype correlations have been established so far [15][16][17][18] with the exception of a 3-bp inframe deletion (c.2970_2972delAAT) in exon 22 of the NF1 gene that has been associated with the absence of cutaneous neurofibromas.…”

Section: Introductionmentioning

confidence: 99%

Neurofibromatosis type 1 molecular diagnosis: what can NGS do for you when you have a large gene with loss of function mutations?

et al. 2014

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Molecular diagnosis of neurofibromatosis type 1 (NF1) is challenging owing to the large size of the tumour suppressor gene NF1, and the lack of mutation hotspots. A somatic alteration of the wild-type NF1 allele is observed in NF1-associated tumours. Genetic heterogeneity in NF1 was confirmed in patients with SPRED1 mutations. Here, we present a targeted next-generation sequencing (NGS) of NF1 and SPRED1 using a multiplex PCR approach (230 amplicons of B150 bp) on a PGM sequencer. The chip capacity allowed mixing 48 bar-coded samples in a 4-day workflow. We validated the NGS approach by retrospectively testing 30 NF1-mutated samples, and then prospectively analysed 279 patients in routine diagnosis. On average, 98.5% of all targeted bases were covered by at least 20X and 96% by at least 100X. An NF1 or SPRED1 alteration was found in 246/279 (88%) and 10/279 (4%) patients, respectively. Genotyping throughput was increased over 10 times, as compared with Sanger, with B90h for consumables per sample. Interestingly, our targeted NGS approach also provided quantitative information based on sequencing depth allowing identification of multiexons deletion or duplication. We then addressed the NF1 somatic mutation detection sensitivity in mosaic NF1 patients and tumours.

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Section: Introductionmentioning

confidence: 99%

Neurofibromatosis type 1 molecular diagnosis: what can NGS do for you when you have a large gene with loss of function mutations?

et al. 2014

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“…Consequently, MLPA could not differentiate between a 1.4-Mb deletion and a larger, atypical deletion. Likewise, the currently available MLPA-kit (P122, version C1) cannot provide the degree of resolution required to distinguish between type-1 NF1 deletions (with breakpoints in the NF1-REPs) and atypical deletions with breakpoints located close to, but Deleted: whose Deleted: -F o r P e e r R e v i e w 5 outside of, the NF1-REPs A and C as outlined previously [Mautner et al, 2010]. Such atypical deletions could also encompass the GOSR1, TBC1D29, RHOT1, RHBDL3 and C17orf75 genes in addition to the 14 genes present within the type-1 deletion interval ( Figure 1A).…”

Section: Introductionmentioning

confidence: 99%

“…NF1 microdeletions are often associated with severe disease manifestations including a high tumour load, facial dysmorphism and mental retardation [Mensink et al, 2006;Venturin et al, 2006;Mautner et al, 2010;Pasmant et al, 2010].…”

Section: Introductionmentioning

confidence: 99%

Mosaic type-1 NF1 microdeletions as a cause of both generalized and segmental neurofibromatosis type-1 (NF1)

et al. 2011

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International audienceMosaicism is an important feature of type-1 neurofibromatosis (NF1) on account of its impact upon both clinical manifestations and transmission risk. Using FISH and MLPA to screen 3500 NF1 patients, we identified 146 individuals harbouring gross NF1 deletions, 14 of whom (9.6%) displayed somatic mosaicism. The high rate of mosaicism in patients with NF1 deletions supports the postulated idea of a direct relationship between the high new mutation rate in this cancer predisposition syndrome and the frequency of mosaicism. Seven of the 14 mosaic NF1 deletions were type-2, whereas 4 were putatively type-1, and three were atypical. Two of the 4 probable type-1 deletions were confirmed as such by breakpoint-spanning PCR or SNP analysis. Both deletions were associated with a generalized manifestation of NF1. Independently, we identified a third patient with a mosaic type-1 NF1 deletion who exhibited segmental NF1. Together, these three cases constitute the first proven mosaic type-1 deletions so far reported. In two of these three mosaic type-1 deletions, the breakpoints were located within PRS1 and PRS2, previously identified as hotspots for non-allelic homologous recombination (NAHR) during meiosis. Hence, NAHR within PRS1 and PRS2 is not confined to meiosis but may also occur during postzygotic mitotic cell cycles

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“…The deletions are usually associated with a more consistently severe phenotype, including facial dysmorphism, marked learning problems and increased neurofibroma burden. 8 More recently, a specific mutation has been found to be associated with a much milder NF1 phenotype with a lack of dermal neurofibromas, and increased rate of pulmonary stenosis (PS)-the NF1 exon 17 3-bp in-frame deletion (c.2970_2972delAAT). 9 In addition, heterozygous loss-offunction mutations in another gene, SPRED1, have been described to cause NF1-like disease associated with CALS and inguinal/axillary freckles but no neurofibromas or Lisch nodules (Legius syndrome (MIM# #611431)).…”

Section: Introductionmentioning

confidence: 99%

“…The first group of patients with a specific genotype-phenotype correlation identified were those with large deletions involving the NF1 gene. 8 These patients have deletions of both the NF1 and a variable number of flanking genes. The deletions are usually associated with a more consistently severe phenotype, including facial dysmorphism, marked learning problems and increased neurofibroma burden.…”

Section: Introductionmentioning

confidence: 99%

Increased rate of missense/in-frame mutations in individuals with NF1-related pulmonary stenosis: a novel genotype–phenotype correlation

et al. 2012

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Neurofibromatosis type 1 (NF1) and its related disorders (NF1-Noonan syndrome (NFNS) and Watson syndrome (WS)) are caused by heterozygous mutations in the NF1 gene. Pulmonary stenosis (PS) occurs more commonly in NF1 and its related disorders than in the general population. This study investigated whether PS is associated with specific types of NF1 gene mutations in NF1, NFNS and WS. The frequency of different NF1 mutation types in a cohort of published and unpublished cases with NF1/NFNS/WS and PS was examined. Compared with NF1 in general, NFNS patients had higher rates of PS (9/35 ¼ 26% vs 25/2322 ¼ 1.1%, P valueo0.001). Stratification according to mutation type showed that the increased PS rate appears to be driven by the NFNS group with non-truncating mutations. Eight of twelve (66.7%) NFNS cases with non-truncating mutations had PS compared with a 1.1% PS frequency in NF1 in general (Po0.001); there was no increase in the frequency of PS in NFNS patients with truncating mutations. Eight out of eleven (73%) individuals with NF1 and PS, were found to have non-truncating mutations, a much higher frequency than the 19% reported in NF1 cohorts (Po0.015). Only three cases of WS have been published with intragenic mutations, two of three had non-truncating mutations. Therefore, PS in NF1 and its related disorders is clearly associated with non-truncating mutations in the NF1 gene providing a new genotype-phenotype correlation. The data indicate a specific role of non-truncating mutations on the NF1 cardiac phenotype.

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Clinical characterisation of 29 neurofibromatosis type-1 patients with molecularly ascertained 1.4 Mb type-1 NF1 deletions

Abstract: These findings emphasise the importance of deletion analysis in NF1 since frequent monitoring of tumour presence and growth could potentiate early surgical intervention thereby improving patient survival.

Cited by 152 publications

References 55 publications

Neurofibromatosis type 1 molecular diagnosis: what can NGS do for you when you have a large gene with loss of function mutations?

Neurofibromatosis type 1 molecular diagnosis: what can NGS do for you when you have a large gene with loss of function mutations?

Mosaic type-1 NF1 microdeletions as a cause of both generalized and segmental neurofibromatosis type-1 (NF1)

Increased rate of missense/in-frame mutations in individuals with NF1-related pulmonary stenosis: a novel genotype–phenotype correlation

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