Ten novel mutations in the human neurofibromatosis type 1 (NF1) gene in Italian patients

Origone, Paola; Luca, Alessandro De; Bellini, Carlo; Buccino, Anna; Mingarelli, Rita; Costabel, Simona; Rosa, Carmen La; Garrè, Cecilia; Coviello, Domenico; Ajmar, Franco; Dallapiccola, Bruno; Bonioli, E

doi:10.1002/humu.9039

Cited by 17 publications

(19 citation statements)

References 16 publications

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“…Thus far, no national NF1 register has been instituted in Italy, and few papers have described Italian genetic records (Origone et al. 2002; De Luca et al. 2004, 2007), although the findings of an Italian mortality study were consistent with those performed in other industrialized countries (Zöller et al.…”

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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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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“…One hundred-ten unrelated subjects (53 men; 57 women) were analysed in this study, including also 58 NF1 patients previously reported (Origone et al, 2002;De Luca et al, 2003). Clinical data confirming NF1 diagnostic criteria were available in 73 (66%) patients, while in the remaining cases either no clinical data were provided or patients fulfilled only one diagnostic criterion.…”

Section: Patientsmentioning

confidence: 99%

Novel and recurrent mutations in theNF1 gene in Italian patients with neurofibromatosis type 1

et al. 2004

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Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant disorders in humans, affecting 1 in 3500 individuals. NF1 is a fully penetrant exhibiting a mutation rate some 10-fold higher compared to most other disease genes. As a consequence, a high number of cases (up to 50%) are sporadic. Mutation detection is complex due to the large size of NF1 gene, the presence of pseudogenes and the great variety of lesions. In the present study we attempted to delineate the NF1 mutational spectrum in the Italian population reporting four-year experience with the direct analysis of the whole NF1 coding region in 110 unrelated subjects affected by NF1. For each patient, the whole coding sequence and all splice sites were studied for mutations, either by the protein truncation test (PTT), or, most often, by denaturing high performance liquid chromatography (DHPLC). Mutations were identified in 75 (68%) patients. Twenty-two mutations were found to be novel. The detection rate for the different methods was 7/18 (39%) for PTT, and 68/103 (66%) for DHPLC. The mutations were evenly distributed along the NF1 coding sequence. Thirty-two of the 75 unrelated NF1 patients in which germline mutations were identified (32/75, 43%) harbour 23 different recurrent mutations. Fifteen sequence variants likely to represent nonpathogenic polymorphisms were observed at the NF1 locus. Genotype-phenotype analysis was unable to detect any obvious correlation.

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“…Analysis of the NF1 gene by the PCR-SSCP technique and DNA sequencing in this case revealed a mutation in exon 29 (R1748X), which affects a CpG dinucleotide (5242C -1 T). This alteration, also reported in other 9 patients by Valero et al [14] , Boulandet et al [15] , Fahsold et al [16] and Origone et al [17] , is expected to generate a truncated protein with 1,747 amino acids. CpG dinucleotides show a high mutation rate due to spontaneous deamination of methylated cytosine.…”

Section: Figmentioning

confidence: 58%

Presence of the R1748X Mutation in the <i>NF1</i> Gene in a Brazilian Patient with Ectropion uveae

et al. 2004

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Congenital ectropion uveae is a rare, nonprogressive anomaly characterized by the presence of iris pigment epithelium on the anterior surface of the iris stroma and is occasionally associated with Rieger’s anomaly, Prader-Willi syndrome and neurofibromatosis type 1 (NF1). The most important complication of ectropion uveae is congenital or juvenile glaucoma. We described a patient with ectropion and the mutation R1748X in the NF1 gene. This is the third report in the literature describing ectropion associated with neurofibromatosis. If this association is confirmed by other authors, the NF1 patients should be examined for the presence of ectropion and, consequently, for the development of glaucoma.

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Ten novel mutations in the human neurofibromatosis type 1 (NF1) gene in Italian patients

Cited by 17 publications

References 16 publications

126 novel mutations in Italian patients with neurofibromatosis type 1

126 novel mutations in Italian patients with neurofibromatosis type 1

Novel and recurrent mutations in theNF1 gene in Italian patients with neurofibromatosis type 1

Presence of the R1748X Mutation in the <i>NF1</i> Gene in a Brazilian Patient with Ectropion uveae

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