NF1 gene mutations represent the major molecular event underlying neurofibromatosis-Noonan syndrome

Alessandro De Luca, Irene Bottillo, Anna Sarkozy, Claudio Carta, Cinzia Neri, Emanuele Bellacchio, Annalisa Schirinzi, Emanuela Conti, Giuseppe Zampino, Agatino Battaglia, Silvia Majore, Maria M. Rinaldi, Massimo Carella, Bruno Marino, Antonio Pizzuti, Maria Cristina Digilio, Marco Tartaglia, Bruno Dallapiccola

Research output: Contribution to journalArticlepeer-review


Neurofibromatosis type 1 (NF1) demonstrates phenotypic overlap with Noonan syndrome (NS) in some patients, which results in the so-called neurofibromatosis-Noonan syndrome (NFNS). From a genetic point of view, NFNS is a poorly understood condition, and controversy remains as to whether it represents a variable manifestation of either NF1 or NS or is a distinct clinical entity. To answer this question, we screened a cohort with clinically well-characterized NFNS for mutations in the entire coding sequence of the NF1 and PTPN11 genes. Heterozygous NF1 defects were identified in 16 of the 17 unrelated subjects included in the study, which provides evidence that mutations in NF1 represent the major molecular event underlying this condition. Lesions included nonsense mutations, out-of-frame deletions, missense changes, small inframe deletions, and one large multiexon deletion. Remarkably, a high prevalence of inframe defects affecting exons 24 and 25, which encode a portion of the GAP-related domain of the protein, was observed. On the other hand, no defect in PTPN11 was observed, and no lesion affecting exons 11-27 of the NF1 gene was identified in 100 PTPN11 mutation-negative subjects with NS, which provides further evidence that NFNS and NS are genetically distinct disorders. These results support the view that NFNS represents a variant of NF1 and is caused by mutations of the NF1 gene, some of which have been demonstrated to cause classic NF1 in other individuals.

Original languageEnglish
Pages (from-to)1092-1101
Number of pages10
JournalAmerican Journal of Human Genetics
Issue number6
Publication statusPublished - Dec 2005

ASJC Scopus subject areas

  • Genetics


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