{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T20:24:36Z","timestamp":1790627076753,"version":"4.1.0"},"reference-count":38,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2017,9,29]],"date-time":"2017-09-29T00:00:00Z","timestamp":1506643200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Neurofibromatosis type I, a genetic disorder due to mutations in the NF1 gene, is characterized by a high mutation rate (about 50% of the cases are de novo) but, with the exception of whole gene deletions associated with a more severe phenotype, no specific hotspots and few solid genotype\/phenotype correlations. After retrospectively re-evaluating all NF1 gene variants found in the diagnostic activity, we studied 108 patients affected by neurofibromatosis type I who harbored mutations that had not been previously reported in the international databases, with the aim of analyzing their type and distribution along the gene and of correlating them with the phenotypic features of the affected patients. Out of the 108 previously unreported variants, 14 were inherited by one of the affected parents and 94 were de novo. Twenty-nine (26.9%) mutations were of uncertain significance, whereas 79 (73.2%) were predicted as pathogenic or probably pathogenic. No differential distribution in the exons or in the protein domains was observed and no statistically significant genotype\/phenotype correlation was found, confirming previous evidences.<\/jats:p>","DOI":"10.3390\/ijms18102071","type":"journal-article","created":{"date-parts":[[2017,9,29]],"date-time":"2017-09-29T12:24:04Z","timestamp":1506687844000},"page":"2071","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Patterns of Novel Alleles and Genotype\/Phenotype Correlations Resulting from the Analysis of 108 Previously Undetected Mutations in Patients Affected by Neurofibromatosis Type I"],"prefix":"10.3390","volume":"18","author":[{"given":"Francesco","family":"Bonatti","sequence":"first","affiliation":[{"name":"Medical Genetics, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Adorni","sequence":"additional","affiliation":[{"name":"Medical Genetics, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annalisa","family":"Matichecchia","sequence":"additional","affiliation":[{"name":"Medical Genetics, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Mozzoni","sequence":"additional","affiliation":[{"name":"Medical Genetics, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vera","family":"Uliana","sequence":"additional","affiliation":[{"name":"Medical Genetics, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Pisani","sequence":"additional","affiliation":[{"name":"Children\u2019s Neuropsycological Services, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Livia","family":"Garavelli","sequence":"additional","affiliation":[{"name":"Clinical Genetics, IRCCS S. Maria Nuova Hospital, Reggio 42123 Emilia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Graziano","sequence":"additional","affiliation":[{"name":"Medical Genetics, S. Orsola-Malpighi University Hospital, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Gnoli","sequence":"additional","affiliation":[{"name":"Medical Genetics and Skeletal Rare Diseases, Istituto Ortopedico Rizzoli, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5690-6504","authenticated-orcid":false,"given":"Diana","family":"Carli","sequence":"additional","affiliation":[{"name":"Medical Genetics, Citt\u00e0 della Salute e della Scienza University Hospital, 10126 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Bigoni","sequence":"additional","affiliation":[{"name":"UOL Medical Genetics, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Boschi","sequence":"additional","affiliation":[{"name":"Plastic Surgery, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Martorana","sequence":"additional","affiliation":[{"name":"Medical Genetics, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Percesepe","sequence":"additional","affiliation":[{"name":"Medical Genetics, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,9,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1038\/nature13127","article-title":"Guidelines for investigating causality of sequence variants in human disease","volume":"508","author":"MacArthur","year":"2014","journal-title":"Nature"},{"key":"ref_3","unstructured":"(2017, August 28). Clinvar, Available online: https:\/\/www.ncbi.nlm.nih.gov\/clinvar\/."},{"key":"ref_4","unstructured":"Palgrave, M. (2016). BioSocieties, Springer."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/ng.2854","article-title":"Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database","volume":"46","author":"Thompson","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1932","DOI":"10.1016\/j.ajpath.2010.12.056","article-title":"The pathoetiology of neurofibromatosis 1","volume":"178","author":"Jouhilahti","year":"2011","journal-title":"Am. J. Pathol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"17004","DOI":"10.1038\/nrdp.2017.4","article-title":"Neurofibromatosis type 1","volume":"3","author":"Gutmann","year":"2017","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1517\/17530059.2010.494660","article-title":"Neurofibromatosis type 1: Diagnosis and recent advances","volume":"4","author":"Upadhyaya","year":"2010","journal-title":"Expert. Opin. Med. Diagn."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1506","DOI":"10.1002\/humu.21271","article-title":"NF1 microdeletions in Neurofibromatosis type 1: From genotype to phenotype","volume":"31","author":"Pasmant","year":"2010","journal-title":"Hum. Mutat."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1007\/s00439-017-1766-y","article-title":"Emerging genotype-phenotype relationships in patients with large NF1 deletions","volume":"136","author":"Mautner","year":"2017","journal-title":"Hum. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1002\/(SICI)1098-1004(1997)9:5<458::AID-HUMU13>3.0.CO;2-1","article-title":"Deletions spanning the Neurofibromatosis type 1 gene: Implications for genotype-phenotype correlations in Neurofibromatosis type 1?","volume":"9","author":"Cnossen","year":"1997","journal-title":"Hum. Mutat."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1038\/nrc3911","article-title":"A RASopathy gene commonly mutated in cancer: The Neurofibromatosis type 1 tumour suppressor","volume":"15","author":"Ratner","year":"2015","journal-title":"Nat. Rev. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1002\/humu.9245","article-title":"Novel and recurrent mutations in the NF1 gene in Italian patients with Neurofibromatosis type 1","volume":"23","author":"Schirinzi","year":"2004","journal-title":"Hum. Mutat."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"11291","DOI":"10.1038\/srep11291","article-title":"Molecular characterization of NF1 and Neurofibromatosis type 1 genotype-phenotype correlations in a Chinese population","volume":"5","author":"Zhang","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1038\/ejhg.2014.145","article-title":"Neurofibromatosis type 1 molecular diagnosis: What can NGS do for you when you have a large gene with loss of function mutations?","volume":"23","author":"Pasmant","year":"2015","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1086\/515504","article-title":"Confirmation of a double-hit model for the NF1 gene in benign Neurofibromas","volume":"61","author":"Serra","year":"1997","journal-title":"Am. J. Hum. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1002\/mgg3.161","article-title":"126 novel mutations in Italian patients with Neurofibromatosis type 1","volume":"3","author":"Bianchessi","year":"2015","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1159\/000327557","article-title":"Neurofibromatosis without Neurofibromas: Confirmation of a genotype-phenotype correlation and implications for genetic testing","volume":"3","author":"Pardo","year":"2011","journal-title":"Case. Rep. Neurol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1086\/510781","article-title":"An absence of cutaneous neurofibromas associated with a 3-bp inframe deletion in exon 17 of the NF1 gene (c.2970-2972 delAAT): Evidence of a clinically significant NF1 genotype-phenotype correlation","volume":"80","author":"Upadhyaya","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1038\/ejhg.2014.243","article-title":"p.Arg1809Cys substitution in neurofibromin is associated with a distinctive NF1 phenotype without neurofibromas","volume":"23","author":"Pinna","year":"2015","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1002\/humu.22832","article-title":"High Incidence of Noonan syndrome features including short stature and pulmonic stenosis in patients carrying NF1 missense mutations affecting p.Arg1809: Genotype-phenotype correlation","volume":"36","author":"Rojnueangnit","year":"2015","journal-title":"Hum. Mutat."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/1479-7364-6-12","article-title":"Genotype-phenotype associations in Neurofibromatosis type 1 (NF1): An increased risk of tumor complications in patients with NF1 splice-site mutations?","volume":"6","author":"Alkindy","year":"2012","journal-title":"Hum. Genom."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1136\/jmg.40.10.e109","article-title":"Evaluation of genotype-phenotype correlations in Neurofibromatosis type 1","volume":"40","author":"Castle","year":"2003","journal-title":"J. Med. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1510","DOI":"10.1002\/humu.22392","article-title":"NF1 molecular characterization and Neurofibromatosis type I genotype-phenotype correlation: The French experience","volume":"34","author":"Sabbagh","year":"2013","journal-title":"Hum. Mutat."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1038\/ejhg.2012.221","article-title":"Increased rate of missense\/in-frame mutations in individuals with NF1-related pulmonary stenosis: A novel genotype-phenotype correlation","volume":"21","author":"Constantini","year":"2013","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1097\/GIM.0b013e318176fabb","article-title":"Statement on guidance for genetic counseling in advanced paternal age","volume":"10","author":"Toriello","year":"2008","journal-title":"Genet. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1038\/ng.3292","article-title":"Genome-wide patterns and properties of de novo mutations in humans","volume":"47","author":"Francioli","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/nrg3241","article-title":"De novo mutations in human genetic disease","volume":"13","author":"Veltman","year":"2012","journal-title":"Nat. Rev. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1001\/jama.1997.03550010065042","article-title":"The diagnostic evaluation and multidisciplinary management of Neurofibromatosis 1 and Neurofibromatosis 2","volume":"278","author":"Gutmann","year":"1997","journal-title":"JAMA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1002\/humu.9111","article-title":"NF1 gene analysis based on DHPLC","volume":"21","author":"Buccino","year":"2003","journal-title":"Hum. Mutat."},{"key":"ref_31","unstructured":"(2017, August 28). Mutalyzer. Available online: https:\/\/mutalyzer.nl\/."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1016\/j.ajhg.2016.08.016","article-title":"REVEL: An ensemble method for predicting the pathogenicity of rare missense variants","volume":"99","author":"Ioannidis","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"ref_33","unstructured":"(2017, August 14). The Human Gene Mutation Database, HGMD. Available online: http:\/\/www.hgmd.cf.ac.uk\/ac\/all.php."},{"key":"ref_34","unstructured":"(2017, August 28). Leiden Open Variation Database 3.0, LOVD. Available online: http:\/\/www.lovd.nl\/3.0\/home."},{"key":"ref_35","unstructured":"(2017, August 28). Ensembl. Available online: http:\/\/www.ensembl.org\/index.html."},{"key":"ref_36","unstructured":"(2017, August 28). ExAC Browser. Available online: http:\/\/exac.broadinstitute.org\/."},{"key":"ref_37","unstructured":"(2017, July 28). Human Phenotype Ontology (HPO). Available online: http:\/\/human-phenotype-ontology.github.io\/."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1111\/j.1523-1739.2005.00269.x","article-title":"Judicious use of multiple hypotesis test","volume":"19","author":"Roback","year":"2005","journal-title":"Conserv. Biol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/10\/2071\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:46:13Z","timestamp":1760208373000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/10\/2071"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,9,29]]},"references-count":38,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2017,10]]}},"alternative-id":["ijms18102071"],"URL":"https:\/\/doi.org\/10.3390\/ijms18102071","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,9,29]]}}}