<i>PTPN11</i> and <i>KRAS</i> Gene Analysis in Patients with Noonan and Noonan-Like Syndromes

Brasil, Amanda Salem; Pereira, Alexandre C.; Wanderley, Luciana Turolla; Kim, Chong; Malaquias, Alexsandra C.; Jorge, Alexander A L; Krieger, José Eduardo; Bertola, Débora Romeo

doi:10.1089/gtmb.2009.0192

Cited by 29 publications

(30 citation statements)

References 48 publications

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“…Two previous studies (14,15), including one from our group, showed the presence of one known pathogenic mutation and another gene alteration that probably functions as a modifier. We described a NS patient presenting the pathogenic p.N308D mutation in the PTPN11 gene and also the p.N85S mutation in the KRAS gene (14). The patient presented typical features of NS and learning disabilities, which is not common, but far from an exception, in individuals with the p.N308D mutation in the PTPN11 gene.…”

Section: Discussionmentioning

confidence: 69%

“…In our group we identified five other NS patients with p.N308S mutation in the PTPN11 gene and one patient with p.R552G mutation in the SOS1 gene (14,27). The phenotype of these patients did not significantly differ from the patient harboring both mutations (Table 3).…”

Section: Phenotype Analysismentioning

confidence: 79%

“…No mutation was identified in the KRAS and RAF1 genes. One previously described mutation in PTPN11 was identified in the heterozygous state [p.N308S (14)]. Direct sequencing of SOS1 revealed two heterozygous allelic variants: one previously described mutation [p.R552G (9)] and a new variant p.A708T.…”

Section: Molecular Resultsmentioning

confidence: 99%

“…Recently, two groups described NS patients presenting two mutations in different RAS/MAPK pathway-related genes (14,15). In both studies, one of the mutations predicted to affect the protein function (pathogenic mutation), while the other mutation predicted to be benign (uncertain pathogenicity).…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 69%

Section: Phenotype Analysismentioning

confidence: 79%

Section: Molecular Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…As discussed above, both of these variants cause increased ERK activation in transfected heterologous cells. Co-occurring mutations in NS-causing genes have been reported in a few patients with NS (38)(39)(40). Additive or modifying effects were observed in a NS patient carrying SHOC2 and PTPN11 mutations and in another individual harboring PTPN11 and KRAS mutations.…”

Section: Significancementioning

confidence: 95%

Next-generation sequencing identifies rare variants associated with Noonan syndrome

Chen

Yin

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

165

148

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Noonan syndrome (NS) is a relatively common genetic disorder, characterized by typical facies, short stature, developmental delay, and cardiac abnormalities. Known causative genes account for 70-80% of clinically diagnosed NS patients, but the genetic basis for the remaining 20-30% of cases is unknown. We performed nextgeneration sequencing on germ-line DNA from 27 NS patients lacking a mutation in the known NS genes. We identified gainof-function alleles in Ras-like without CAAX 1 (RIT1) and mitogenactivated protein kinase kinase 1 (MAP2K1) and previously unseen loss-of-function variants in RAS p21 protein activator 2 (RASA2) that are likely to cause NS in these patients. Expression of the mutant RASA2, MAP2K1, or RIT1 alleles in heterologous cells increased RAS-ERK pathway activation, supporting a causative role in NS pathogenesis. Two patients had more than one disease-associated variant. Moreover, the diagnosis of an individual initially thought to have NS was revised to neurofibromatosis type 1 based on an NF1 nonsense mutation detected in this patient. Another patient harbored a missense mutation in NF1 that resulted in decreased protein stability and impaired ability to suppress RAS-ERK activation; however, this patient continues to exhibit a NS-like phenotype. In addition, a nonsense mutation in RPS6KA3 was found in one patient initially diagnosed with NS whose diagnosis was later revised to Coffin-Lowry syndrome. Finally, we identified other potential candidates for new NS genes, as well as potential carrier alleles for unrelated syndromes. Taken together, our data suggest that nextgeneration sequencing can provide a useful adjunct to RASopathy diagnosis and emphasize that the standard clinical categories for RASopathies might not be adequate to describe all patients.human genetics | developmental diseases | whole exome sequencing | PTPN11 | RAS

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Co‐occurring SHOC2 and PTPN11 mutations in a patient with severe/complex Noonan syndrome‐like phenotype

Ekvall

Hagenäs

Allanson

et al. 2011

American J of Med Genetics Pt A

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Noonan syndrome (NS) is a heterogeneous disorder caused by activating mutations in the RAS‐MAPK signaling pathway. It is associated with variable clinical expression including short stature, congenital heart defect, unusual pectus deformity, and typical facial features and the inheritance is autosomal dominant. Here, we present a clinical and molecular characterization of a patient with Noonan‐like syndrome with loose anagen hair phenotype and additional features including mild psychomotor developmental delay, osteoporosis, gingival hyperplasia, spinal neuroblastoma, intrathoracic extramedullary hematopoiesis, and liver hemangioma. Mutation analysis of PTPN11, SOS1, RAF1, KRAS, BRAF, MEK1, MEK2, NRAS, and SHOC2 was conducted, revealing a co‐occurrence of two heterozygous previously identified mutations in the index patient. The mutation SHOC2 c.4A > G; p.Ser2Gly represents a de novo mutation, whereas, PTPN11 c.1226G > C; p.Gly409Ala was inherited from the mother and also identified in the brother. The mother and the brother present with some NS manifestations, such as short stature, delayed puberty, keratosis pilaris, café‐au‐lait spots, refraction error (mother), and undescended testis (brother), but no NS facial features, supporting the notion that the PTPN11 p.Gly409Ala mutation leads to a relatively mild phenotype. We propose that, the atypical phenotype of the young woman with NS reported here is an additive effect, where the PTPN11 mutation acts as a modifier. Interestingly, co‐occurrence of RAS‐MAPK mutations has been previously identified in a few patients with variable NS or neurofibromatosis‐NS phenotypes. Taken together, the results suggest that co‐occurrence of mutations or modifying loci in the RAS‐MAPK pathway may contribute to the clinical variability observed among NS patients. © 2011 Wiley‐Liss, Inc.

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PTPN11 and KRAS Gene Analysis in Patients with Noonan and Noonan-Like Syndromes

Cited by 29 publications

References 48 publications

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

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

Next-generation sequencing identifies rare variants associated with Noonan syndrome

Co‐occurring SHOC2 and PTPN11 mutations in a patient with severe/complex Noonan syndrome‐like phenotype

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