Abstract
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 language | English |
|---|---|
| Pages (from-to) | 1092-1101 |
| Number of pages | 10 |
| Journal | American Journal of Human Genetics |
| Volume | 77 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Dec 2005 |
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ASJC Scopus subject areas
- Genetics
Cite this
NF1 gene mutations represent the major molecular event underlying neurofibromatosis-Noonan syndrome. / De Luca, Alessandro; Bottillo, Irene; Sarkozy, Anna; Carta, Claudio; Neri, Cinzia; Bellacchio, Emanuele; Schirinzi, Annalisa; Conti, Emanuela; Zampino, Giuseppe; Battaglia, Agatino; Majore, Silvia; Rinaldi, Maria M.; Carella, Massimo; Marino, Bruno; Pizzuti, Antonio; Digilio, Maria Cristina; Tartaglia, Marco; Dallapiccola, Bruno.
In: American Journal of Human Genetics, Vol. 77, No. 6, 12.2005, p. 1092-1101.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - NF1 gene mutations represent the major molecular event underlying neurofibromatosis-Noonan syndrome
AU - De Luca, Alessandro
AU - Bottillo, Irene
AU - Sarkozy, Anna
AU - Carta, Claudio
AU - Neri, Cinzia
AU - Bellacchio, Emanuele
AU - Schirinzi, Annalisa
AU - Conti, Emanuela
AU - Zampino, Giuseppe
AU - Battaglia, Agatino
AU - Majore, Silvia
AU - Rinaldi, Maria M.
AU - Carella, Massimo
AU - Marino, Bruno
AU - Pizzuti, Antonio
AU - Digilio, Maria Cristina
AU - Tartaglia, Marco
AU - Dallapiccola, Bruno
PY - 2005/12
Y1 - 2005/12
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=28144437387&partnerID=8YFLogxK
U2 - 10.1086/498454
DO - 10.1086/498454
M3 - Article
VL - 77
SP - 1092
EP - 1101
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 6
ER -