Molecular diagnosis of neurofibromatosis type 1: 2 years experience

Griffiths, Siân Wyn; Thompson, Peter; Frayling, Ian Martin; Upadhyaya, Meena

doi:10.1007/s10689-006-9001-3

Cited by 78 publications

(62 citation statements)

References 51 publications

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“…This represents an 83% mutation detection rate, which is comparable to previously reported mutation rates for this gene, although it is still significantly lower than the mutation detection rate from the study by Messiaen et al (2000). [37][38][39] These heterozygous inherited lesions comprised 36 truncating mutations and 2 missense mutations, of which 13 were novel ( Table 1). All germline mutations were subsequently confirmed by identification in the corresponding tumour DNA samples.…”

Section: Resultssupporting

confidence: 74%

Exploring the somatic NF1 mutational spectrum associated with NF1 cutaneous neurofibromas

et al. 2011

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Neurofibromatosis type-1 (NF1), caused by heterozygous inactivation of the NF1 tumour suppressor gene, is associated with the development of benign and malignant peripheral nerve sheath tumours (MPNSTs). Although numerous germline NF1 mutations have been identified, relatively few somatic NF1 mutations have been described in neurofibromas. Here we have screened 109 cutaneous neurofibromas, excised from 46 unrelated NF1 patients, for somatic NF1 mutations. NF1 mutation screening (involving loss-of-heterozygosity (LOH) analysis, multiplex ligation-dependent probe amplification and DNA sequencing) identified 77 somatic NF1 point mutations, of which 53 were novel. LOH spanning the NF1 gene region was evident in 25 neurofibromas, but in contrast to previous data from MPNSTs, it was absent at the TP53, CDKN2A and RB1 gene loci. Analysis of DNA/RNA from neurofibroma-derived Schwann cell cultures revealed NF1 mutations in four tumours whose presence had been overlooked in the tumour DNA. Bioinformatics analysis suggested that four of seven novel somatic NF1 missense mutations (p.A330T, p.Q519P, p.A776T, p.S1463F) could be of functional/clinical significance. Functional analysis confirmed this prediction for p.S1463F, located within the GTPase-activating protein-related domain, as this mutation resulted in a 150-fold increase in activated GTP-bound Ras. Comparison of the relative frequencies of the different types of somatic NF1 mutation observed with those of their previously reported germline counterparts revealed significant (P¼0.001) differences. Although non-identical somatic mutations involving either the same or adjacent nucleotides were identified in three pairs of tumours from the same patients (Po0.0002), no association was noted between the type of germline and somatic NF1 lesion within the same individual.

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Section: Resultssupporting

confidence: 74%

Exploring the somatic NF1 mutational spectrum associated with NF1 cutaneous neurofibromas

et al. 2011

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“…(2007) (78%) and Van Minkelen et al. (2014) (81%), possibly due to the large size of the Dutch patient cohort screened in those studies and the diversity of the techniques used.…”

Section: Discussionmentioning

confidence: 94%

“…Splicing mutations represented the second most prominent class of mutations (27/126 – 21%), in agreement with previous reports (Griffiths et al. 2007; van Minkelen et al. 2014).…”

Section: Discussionmentioning

confidence: 99%

126 novel mutations in Italian patients with neurofibromatosis type 1

Bianchessi¹,

Morosini²,

Saletti³

et al. 2015

Molec Gen & Gen Med

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Genetic analysis of Neurofibromatosis type 1 (NF1) may facilitate the identification of patients in early phases of the disease. Here, we present an overview of our diagnostic research spanning the last 11 years, with a focus on the description of 225 NF1 mutations, 126 of which are novel, found in a series of 607 patients (513 unrelated) in Italy. Between 2003 and 2013, 443 unrelated patients were profiled by denaturing high pressure liquid chromatography (DHPLC) analysis of 60 amplicons derived from genomic NF1 DNA and subsequent sequencing of heterozygotic PCR products. In addition, a subset of patients was studied by multiplex ligation‐dependent probe amplification (MLPA) to identify any duplications, large deletions or microdeletions present at the locus. Over the last year, 70 unrelated patients were investigated by MLPA and sequencing of 22 amplicons spanning the entire NF1 cDNA. Mutations were found in 70% of the 293 patients studied by DHPLC, thereby fulfilling the NIH criterion for the clinical diagnosis of NF1 (detection rate: 70%); furthermore, 87% of the patients studied by RNA sequencing were genetically characterized. Mutations were also found in 36 of the 159 patients not fulfilling the NIH clinical criteria. We confirmed a higher incidence of intellectual disability in patients harboring microdeletion type 1 and observed a correlation between a mild phenotype and the small deletion c.2970_2972delAAT or the missense alteration in amino acid residue 1809 (p.Arg1809Cys). These data support the use of RNA‐based methods for genetic analysis and provide novel information for improving the management of symptoms in oligosymptomatic patients.

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“…We therefore looked for other missense variants affecting this position. Our cohort of genetically confirmed NF1 patients also included three related patients (Family 4) and one sporadic case (Family 5) carrying the already reported c.5426G4T p.(Arg1809Leu) substitution 8 (Supplementary Table 1). In addition, a novel c.5426G4C p.(Arg1809Pro) substitution was present in a further sporadic case (Supplementary Table 1; Family 6).…”

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confidence: 99%