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

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

doi:10.1590/s0004-27302010000800009

Cited by 14 publications

(15 citation statements)

References 29 publications

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“…Co-occurring variants in different RAS/MAPK pathway-related genes have already been described in NCFCS patients. 32,33 However, it is not known whether these co-occurring variants lead to more severe or atypical phenotypes. In fact, to predict the disease causality of the novel variants, either alone or in cooccurrence, remains challenging.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive massive parallel DNA sequencing strategy for the genetic diagnosis of the neuro-cardio-facio-cutaneous syndromes

et al. 2014

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Variants in 11 genes of the RAS/MAPK signaling pathway have been causally linked to the neuro-cardio-facio-cutaneous syndromes group (NCFCS). Recently, A2ML1 and RIT1 were also associated with these syndromes. Because of the genetic and clinical heterogeneity of NCFCS, it is challenging to define strategies for their molecular diagnosis. The aim of this study was to develop and validate a massive parallel sequencing (MPS)-based strategy for the molecular diagnosis of NCFCS. A multiplex PCR-based strategy for the enrichment of the 13 genes and a variant prioritization pipeline was established. Two sets of genomic DNA samples were studied using the Ion PGM System: (1) training set (n ¼ 15) to optimize the strategy and (2) validation set (n ¼ 20) to validate and evaluate the power of the new methodology. Sanger sequencing was performed to confirm all variants and low covered regions. All variants identified by Sanger sequencing were detected with our MPS approach. The methodology resulted in an experimental approach with a specificity of 99.0% and a maximum analytical sensitivity of Z98.2% with a confidence of 99%. Importantly, two patients (out of 20) harbored described disease-causing variants in genes that are not routinely tested (RIT1 and SHOC2). The addition of less frequently altered genes increased in E10% the diagnostic yield of the strategy currently used. The presented workflow provides a comprehensive genetic screening strategy for patients with NCFCS in a fast and cost-efficient manner. This approach demonstrates the potential of a combined MPS-Sanger sequencing-based strategy as an effective diagnostic tool for heterogeneous diseases.

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Section: Discussionmentioning

confidence: 99%

Comprehensive massive parallel DNA sequencing strategy for the genetic diagnosis of the neuro-cardio-facio-cutaneous syndromes

et al. 2014

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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.

157

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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“…Likewise, PTPN11 mutations have been found in combination with mutations in SOS2 (Brasil et al, 2010a), KRAS (Brasil et al, 2010b), and NF1 (Thiel et al, 2009) in Noonan-like syndromes. Clinically defined variants of NS include NS with multiple lentigines (also known as LEOPARD), caused by mutations in PTPN11 , CRAF , or BRAF , and NS-like disorder caused by mutations in CBL (Aoki et al, 2016).…”

Section: Ras and Human Diseasementioning

confidence: 99%

RAS Proteins and Their Regulators in Human Disease

Simanshu

Nissley

McCormick

2017

Cell

1,382

1,350

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RAS proteins are binary switches, cycling between ON and OFF states during signal transduction. These switches are normally tightly controlled, but in RAS-related diseases, such as cancer, RASopathies, and many psychiatric disorders, mutations in the RAS genes or their regulators render RAS proteins persistently active. The structural basis of the switch and many of the pathways that RAS controls are well known, but the precise mechanisms by which RAS proteins function are less clear. All RAS biology occurs in membranes: a precise understanding of RAS’ interaction with membranes is essential to understand RAS action and to intervene in RAS-driven diseases.

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

Cited by 14 publications

References 29 publications

Comprehensive massive parallel DNA sequencing strategy for the genetic diagnosis of the neuro-cardio-facio-cutaneous syndromes

Comprehensive massive parallel DNA sequencing strategy for the genetic diagnosis of the neuro-cardio-facio-cutaneous syndromes

Next-generation sequencing identifies rare variants associated with Noonan syndrome

RAS Proteins and Their Regulators in Human Disease

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