Mutation spectrum of NF1 gene in Italian patients with neurofibromatosis type 1 using Ion Torrent PGM™ platform

Calı̀, Francesco; Chiavetta, Valeria; Ruggeri, Giuseppa; Piccione, Maria; Selicorni, Angelo; Palazzo, Daniela; Bonsignore, Maria R.; Cereda, Anna; Elia, Maurizio; Failla, Pinella; Figura, M.; Fiumara, Agata; Maitz, Silvia; Mandarà, Giuseppa Maria Luana; Mattina, Teresa; Ragalmuto, Alda; Romano, Corrado; Ruggieri, Martino; Salluzzo, Roberto; Saporoso, Antonino; Schepis, Carmelo; Sorge, Giovanni; Spanò, Maria; Tortorella, Gaetano; Romano, Valentino

doi:10.1016/j.ejmg.2016.11.001

Cited by 33 publications

(26 citation statements)

References 39 publications

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“…A total of 309 NF1 patients were selected on the basis of the inclusion and exclusion criteria and included in the study; 255 were recruited from the authors' institutions (92 with OPG and 163 without OPG) and 54 were retrieved from the recent literature (40 with OPG and 14 without OPG) [33][34][35][36][37][38][39][40][41]. One hundred and thirty-two patients were included in the NF1 OPG group (61 females, 57 males; the sex of 14 patients retrieved from the literature was not reported) and 177 in the NF1 non-OPG group (91 females, 76 males; 10 unknown).…”

Section: Resultsmentioning

confidence: 99%

“…The literature review allowed us to select 54 patients; there were more patients in the OPG group (40) than in the non-OPG group (14) [33][34][35][36][37][38][39][40][41].…”

Section: Literature Reviewmentioning

confidence: 99%

“…Constitutional intragenic NF1 mutations were determined by means of standard techniques using gDNA and, more recently, cDNA; that is, Sanger sequencing and NGS to test for point mutations, and MLPA to test for intragenic deletion/duplication [11,38].…”

Section: Molecular Testing and Analysis Of Nf1 Mutationsmentioning

confidence: 99%

See 2 more Smart Citations

Risk of Optic Pathway Glioma in Neurofibromatosis Type 1: No Evidence of Genotype–Phenotype Correlations in a Large Independent Cohort

Melloni

Eoli

Cesaretti

et al. 2019

Cancers

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The occurrence of optic pathway gliomas (OPGs) in children with neurofibromatosis type 1 (NF1) still raises many questions regarding screening and surveillance because of the lack of robust prognostic factors. Recent studies of an overall cohort of 381 patients have suggested that the genotype may be the main determinant of the development of OPG, with the risk being higher in patients harbouring NF1 mutations in the 5’ tertile and the cysteine/serine-rich domain. In an attempt to confirm this hypothesis, we used strict criteria to select a large independent cohort of 309 NF1 patients with defined constitutional NF1 mutations and appropriate brain images (255 directly enrolled and 54 as a result of a literature search). One hundred and thirty-two patients had OPG and 177 did not. The association of the position (tertiles and functional domains) and type of NF1 mutation with the development of OPG was analysed using the χ2 test and Fisher’s exact probability test; odds ratios (ORs) with 95% confidence intervals were calculated, and Bonferroni’s correction for multiple comparisons was applied; multiple logistic regression was also used to study genotype–phenotype associations further. Our findings show no significant correlation between the site/type of NF1 mutation and the risk of OPG, and thus do not support the hypothesis that certain constitutional mutations provide prognostic information in this regard. In addition, we combined our cohort with a previously described cohort of 381 patients for a total of 690 patients and statistically re-analysed the results. The re-analysis confirmed that there were no correlations between the site (tertile and domain) and the risk of OPG, thus further strengthening our conclusions.

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Section: Resultsmentioning

confidence: 99%

“…The literature review allowed us to select 54 patients; there were more patients in the OPG group (40) than in the non-OPG group (14) [33][34][35][36][37][38][39][40][41].…”

Section: Literature Reviewmentioning

confidence: 99%

See 1 more Smart Citation

Risk of Optic Pathway Glioma in Neurofibromatosis Type 1: No Evidence of Genotype–Phenotype Correlations in a Large Independent Cohort

Melloni

Eoli

Cesaretti

et al. 2019

Cancers

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“…Of note, there was no correlation between the incidence of recurrence∖malignant degeneration and the clinical∖histological type of neurofibroma in our cohort. These observations might tentatively be linked to peculiar aspects of the maturation and differentiation of Schwann cells in neurofibromas, which might translate into different concentrations of the cytoplasmatic content of neurofibromin, arising from differences in the morphological expression of genetic alterations of the NF1 gene (monoallelic or biallelic) [ 2 – 6 ] and the neural microenvironment [ 7 ]. Of course this is just speculation at present, and further immunohistochemical studies will need to demonstrate the possible link between neurofibromin content, fluorescence, and neurofibroma behavior.…”

Section: Discussionmentioning

confidence: 99%

Confocal Microscopy Predicts the Risk of Recurrence and Malignant Transformation of Mucocutaneous Neurofibromas in NF-1: An Observational Study

Giudice

Favia

Tempesta

et al. 2018

Dermatology Research and Practice

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From 2005 to 2010, 20 consecutive patients with fully manifested neurofibromatosis type 1 (NF1) underwent elective neurofibroma resection at our institution (Departments of Plastic Surgery and of Odontostomatology). Specimens were photographed under optical microscope and confocal laser scanning microscopy (CLSM) with ultra-high accuracy of detail, including depth of field. Patients were followed up for a minimum of 4 years and up to a maximum of 12 years, postsurgery. While all nonrecurring lesions showed intense fluorescence, six of the seven lesions with absence of fluorescence under CLSM recurred at a mean of 5.5 years after surgical excision. Among the re-excised lesions, 3 were diagnosed as malignant at the subsequent removal. Despite the limitation of a small cohort, CLSM appears to be a simple and low-cost technique to differentiate forms of neurofibromas with low and high risk of recurrence and malignant degeneration.

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“…Although some previous studies had evaluated the use of NGS technology to investigate mutations in the NF1 gene [3,7,16,17,18,19,20,21], only exons and conserved splice sites were sequenced, which is the approach commonly used by other investigators based on Sanger methodology.…”

Section: Discussionmentioning

confidence: 99%

Hybridization Capture-Based Next-Generation Sequencing to Evaluate Coding Sequence and Deep Intronic Mutations in the NF1 Gene

Cunha

Oliveira

Silva

et al. 2016

Genes

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Neurofibromatosis 1 (NF1) is one of the most common genetic disorders and is caused by mutations in the NF1 gene. NF1 gene mutational analysis presents a considerable challenge because of its large size, existence of highly homologous pseudogenes located throughout the human genome, absence of mutational hotspots, and diversity of mutations types, including deep intronic splicing mutations. We aimed to evaluate the use of hybridization capture-based next-generation sequencing to screen coding and noncoding NF1 regions. Hybridization capture-based next-generation sequencing, with genomic DNA as starting material, was used to sequence the whole NF1 gene (exons and introns) from 11 unrelated individuals and 1 relative, who all had NF1. All of them met the NF1 clinical diagnostic criteria. We showed a mutation detection rate of 91% (10 out of 11). We identified eight recurrent and two novel mutations, which were all confirmed by Sanger methodology. In the Sanger sequencing confirmation, we also included another three relatives with NF1. Splicing alterations accounted for 50% of the mutations. One of them was caused by a deep intronic mutation (c.1260 + 1604A > G). Frameshift truncation and missense mutations corresponded to 30% and 20% of the pathogenic variants, respectively. In conclusion, we show the use of a simple and fast approach to screen, at once, the entire NF1 gene (exons and introns) for different types of pathogenic variations, including the deep intronic splicing mutations.

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Mutation spectrum of NF1 gene in Italian patients with neurofibromatosis type 1 using Ion Torrent PGM™ platform

Cited by 33 publications

References 39 publications

Risk of Optic Pathway Glioma in Neurofibromatosis Type 1: No Evidence of Genotype–Phenotype Correlations in a Large Independent Cohort

Risk of Optic Pathway Glioma in Neurofibromatosis Type 1: No Evidence of Genotype–Phenotype Correlations in a Large Independent Cohort

Confocal Microscopy Predicts the Risk of Recurrence and Malignant Transformation of Mucocutaneous Neurofibromas in NF-1: An Observational Study

Hybridization Capture-Based Next-Generation Sequencing to Evaluate Coding Sequence and Deep Intronic Mutations in the NF1 Gene

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