Neurofibromatosis-Noonan syndrome: Molecular evidence of the concurrence of both disorders in a patient

Bertola, Débora Romeo; Pereira, Alexandre C.; Passetti, Fábio; Oliveira, Paulo Sérgio Lopes de; Messiaen, Ludwine; Gelb, Bruce D.; Kim, Chong; Krieger, José Eduardo

doi:10.1002/ajmg.a.30813

Cited by 76 publications

(78 citation statements)

References 28 publications

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“…12 It is likely that the athypical symptoms observed in this patient resulted from the additive effect of two mutations affecting different genes, as reported in some subjects with neurofibromatosis-Noonan syndrome (MIM #601321). 15,16 These observations are in line with the present findings pointing to an association between c.5425C4T change and facial features of NS, including ptosis, low-set posteriorly rotated ears, hypertelorism, short neck and triangular face. Although none of the patients exhibited PVS, accurate cardiac screening on larger cohorts might be considered to assess whether the c.5425C4T substitution results in a higher risk of developing PVS or other congenital heart diseases.…”

Section: Discussionsupporting

confidence: 92%

p.Arg1809Cys substitution in neurofibromin is associated with a distinctive NF1 phenotype without neurofibromas

et al. 2014

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Analysis of 786 NF1 mutation-positive subjects with clinical diagnosis of neurofibromatosis type 1 (NF1) allowed to identify the heterozygous c.5425C4T missense variant (p.Arg1809Cys) in six (0.7%) unrelated probands (three familial and three sporadic cases), all exhibiting a mild form of disease. Detailed clinical characterization of these subjects and other eight affected relatives showed that all individuals had multiple cafè-au-lait spots, frequently associated with skinfold freckling, but absence of discrete cutaneous or plexiform neurofibromas, Lisch nodules, typical NF1 osseous lesions or symptomatic optic gliomas. Facial features in half of the individuals were suggestive of Noonan syndrome. Our finding and revision of the literature consistently indicate that the c.5425C4T change is associated with a distinctive, mild form of NF1, providing new data with direct impact on genetic counseling and patient management.

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Section: Discussionsupporting

confidence: 92%

p.Arg1809Cys substitution in neurofibromin is associated with a distinctive NF1 phenotype without neurofibromas

et al. 2014

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“…The authors concluded that the p.G409A mutation in the PTPN11 gene represents a mild partial mutation, acting as a modifier. On the other hand, the report of two pathogenic mutations in patients presenting neurofibromatosis-Noonan syndrome (NFNS) have been previously described (31,32) but in both cases one of the parents had one of the mutations, which increases the chance of this occurrence.…”

Section: Discussionmentioning

confidence: 99%

Co-occurring PTPN11 and SOS1 gene mutations in Noonan syndrome: does this predict a more severe phenotype?

Brasil

Malaquias²,

Wanderley

et al. 2010

Arq Bras Endocrinol Metab

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Noonan syndrome (NS) is an autosomal dominant disorder, with variable phenotypic expression, characterized by short stature, facial dysmorphisms and heart disease. Different genes of the RAS/MAPK signaling pathway are responsible for the syndrome, the most common are: PTPN11, SOS1, RAF1, and KRAS. The objective of this study was to report a patient with Noonan syndrome presenting mutations in two genes of RAS/MAPK pathway in order to establish whether these mutations lead to a more severe expression of the phenotype. We used direct sequencing of the PTPN11, SOS1, RAF1, and KRAS genes. We have identified two described mutations in heterozygosity: p.N308D and p.R552G in the genes PTPN11 and SOS1, respectively. The patient has typical clinical features similar to the ones with NS and mutation in only one gene, even those with the same mutation identified in this patient. A more severe or atypical phenotype was not observed, suggesting that these mutations do not exhibit an additive effect.

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“…In addition, NF1 and NS have previously been found to coexist in the same patient. 19 No PTPN11, KRAS, RAF1, or SOS1 codingsequence mutations were found in the reported patient. However, mutations of these four genes account for only about 80% of NS cases, meaning that we cannot formally rule out the co-occurrence of NS and NF1 in the reported patient, despite our extensive molecular studies.…”

Section: Discussionmentioning

confidence: 73%

Characterization of a 7.6-Mb germline deletion encompassing the NF1 locus and about a hundred genes in an NF1 contiguous gene syndrome patient

et al. 2008

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We describe a large germline deletion removing the NF1 locus, identified by heterozygosity mapping based on microsatellite markers, in an 8-year-old French girl with a particularly severe NF1 contiguous gene syndrome. We used gene-dose mapping with sequence-tagged site real-time PCR to locate the deletion end points, which were precisely characterized by means of long-range PCR and nucleotide sequencing. The deletion is located on chromosome arm 17q and is exactly 7 586 986 bp long. It encompasses the entire NF1 locus and about 100 other genes, including numerous chemokine genes, an attractive in silico-selected cerebrally expressed candidate gene (designated NUFIP2, for nuclear fragile X mental retardation protein interacting protein 2; NM_020772) and four microRNA genes. Interestingly, the centromeric breakpoint is located in intron 4 of the PIPOX gene (pipecolic acid oxidase; NM_016518) and the telomeric breakpoint in intron 5 of the GGNBP2 gene (gametogenetin binding protein 2; NM_024835) coding a transcription factor. As PIPOX and GGNBP2 have the same transcriptional orientation, we postulated, and then confirmed, the existence of a chimeric transcript. This transcript, and/or haploinsufficiency of one or several deleted genes, could explain the clinical severity of the syndrome in this patient.

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Neurofibromatosis-Noonan syndrome: Molecular evidence of the concurrence of both disorders in a patient

Cited by 76 publications

References 28 publications

p.Arg1809Cys substitution in neurofibromin is associated with a distinctive NF1 phenotype without neurofibromas

p.Arg1809Cys substitution in neurofibromin is associated with a distinctive NF1 phenotype without neurofibromas

Co-occurring PTPN11 and SOS1 gene mutations in Noonan syndrome: does this predict a more severe phenotype?

Characterization of a 7.6-Mb germline deletion encompassing the NF1 locus and about a hundred genes in an NF1 contiguous gene syndrome patient

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