Clinical and molecular characterization of children with Noonan syndrome and other RASopathies in Argentina

Chinton, Josefina; Huckstadt, Victoria; Moresco, Angélica; Gravina, Luis Pablo; Obregón, María Gabriela

doi:10.5546/aap.2019.eng.330

Cited by 12 publications

(19 citation statements)

References 21 publications

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“…For the most prevalent gene associated with NS (PTPN11), three variants were responsible for almost half of the cases: p.Asn308Asp (21.4%), p.Asn308Ser (12%), and p.Met504Val (11%). Although the most prevalent variant (p.Asn308Asp) among the European descent population was not detected in our first reported analysis of PTPN11 (Bertola et al, 2006), in the present study, with a larger cohort and a molecular analysis not including HRM as a screening tool, its frequency is similar to that observed in other cohorts of Europe/the United States (40/204-19.6%) (Tartaglia et al, 2006) and Argentina (12/60-20%) (Chinton et al, 2019). Conversely, for the other two variants identified, there are differences when we compare our data with other from Europe/the United States and Argentina: 12, 6.3, and 1.7% for p.Asn308Ser, and 11, 0.1, and 13.3% for p.Met504Val, respectively.…”

Section: Genotype Analysissupporting

confidence: 80%

“…Likewise, in CFCS, we observed a high frequency (6/19-31.5%) of different variants involving the residue p.Glu501 in BRAF, the main gene associated with this disorder and considered a mutational hotspot, along with p.Gln275 and p.Gly469 (Pierpont et al, 2014). In the Argentinean cohort there was an overrepresentation of variants in residue p.Gln275 (5/10) (Chinton et al, 2019). Larger cohorts are necessary to confirm this preliminary finding.…”

Section: Genotype Analysissupporting

confidence: 59%

“…Another group that studies RASopathies in Latin America is located in a Pediatric Hospital in Buenos Aires, Argentina. They recently published the molecular analysis by Sanger sequencing of the hotspots of the main genes associated with RASopathies (Chinton, Huckstadt, Moresco, Gravina, & Obregon, 2019) and later, a more extensive analysis by NGS in those who tested negative for the hotspots (Chinton et al, 2020). Another report is from a small cohort of 18 Chilean individuals with NS studied by high resolution melting (HRM) and Sanger sequencing for variants in PTPN11 (Rodríguez, Unanue, Hernández, Heath, & Cassorla, 2014).…”

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confidence: 99%

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Phenotype–genotype analysis of 242 individuals with RASopathies: 18‐year experience of a tertiary center in Brazil

Bertola

Castro

Yamamoto

et al. 2020

American J of Med Genetics Pt C

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We report the clinical and molecular data of a large cohort comprising 242 individuals with RASopathies, from a single Tertiary Center in Brazil, the largest study from Latin America. Noonan syndrome represented 76% of the subjects, with heterozygous variants in nine different genes, mainly PTPN11, SOS1, RAF1, LZTR1, and RIT1, detected by Sanger and next-generation sequencing. The latter was applied to 126 individuals, with a positive yield of 63% in genes of the RAS/MAPK cascade. We present evidence that there are some allelic differences in PTPN11 across distinct populations. We highlight the clinical aspects that pose more medical concerns, such as the cardiac anomalies, bleeding diathesis and proliferative lesions. The genotype-phenotype analysis between the RASopathies showed statistically significant differences in some cardinal features, such as craniofacial and cardiac anomalies, the latter also statistically significant for different genes in Noonan syndrome. We present two individuals with a Noonan syndrome phenotype, one with an atypical, structural cardiac defect, harboring variants in genes mainly associated with isolated hypertrophic cardiomyopathy and discuss the role of these variants in their phenotype.

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Section: Genotype Analysissupporting

confidence: 80%

Section: Genotype Analysissupporting

confidence: 59%

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confidence: 99%

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Phenotype–genotype analysis of 242 individuals with RASopathies: 18‐year experience of a tertiary center in Brazil

Bertola

Castro

Yamamoto

et al. 2020

American J of Med Genetics Pt C

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“…The clinical and molecular characterization of Noonan syndrome patients tends to be similar between patients of different ethnic backgrounds (Kruszka et al, 2017). Few studies have aimed to examine these features in the Latin American population (Bertola et al, 2006;Chinton, Huckstadt, Moresco, Gravina, & Obregon, 2019;Rodríguez, Unanue, Hernández, Heath, & Cassorla, 2013;Bertola et al, 2020).…”

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confidence: 99%

Clinical and molecular analysis of 26 individuals with Noonan syndrome in a reference institution in Colombia

Lores

Prada

Ramírez‐Montaño

et al. 2020

American J of Med Genetics Pt C

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Our aim was to characterize the phenotype and genotype of individuals with Noonan syndrome in Colombia. There are published cohorts of Noonan individuals from several countries in Latin America including Brazil, Chile, and Argentina, but none from Colombia. We described 26 individuals with NS from a single large referral center in the South West of Colombia using an established database in the genetics department and hospital records search using ICD‐10 codes. All patients included in this study were evaluated by a medical geneticist and have molecular confirmation of NS diagnosis. The median age at referral was 3.5 years (range, 0–39), and at molecular diagnosis was 5 years (range, 0–40). Patients mostly originated from the southwest region of Colombia (19/26, 73%). Pathogenic variants in PTPN11 are the most common cause of NS in Colombian individuals followed by SHOC2 and SOS1 variants. The prevalence of cardiomyopathy was low in this population compared to other populations. Further research is needed with a larger sample size and including different regions of Colombia to correlate our findings. This study provides new information about time to diagnosis of NS in Colombia, genotypes, and provides important information to help develop guidelines for diagnosis and management of this disease in the region.

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“…Mutations in 13 genes so far, have been reported to underlie the Noonan syndrome (NS), the most genetically diverse RASopathy and the most common. Approximately 80% of individuals with NS harbor mutations in genes whose products are involved in the RAS/MAPK pathway including PTPN11 [ 8 – 12 ] in about half of all cases, SOS1 [ 8 , 9 , 11 – 14 ] in an additional 10 to 15%, RAF1 [ 8 , 9 , 11 , 12 , 14 – 17 ] and RIT1 [ 12 , 18 – 20 ] in about an additional 5%. The remaining underlying genetic causes in nearly 20% of individuals with NS includes pathogenic variants in BRAF [ 8 , 21 ], KRAS [ 8 , 12 , 14 , 22 , 23 ], LZTR1 [ 12 , 24 – 27 ], MAP2K1 [ 23 , 28 , 29 ], MRAS [ 30 – 32 ], NRAS [ 12 , 33 – 35 ], RASA2 [ 29 , 36 ], RRAS2 [ 29 , 37 , 38 ] and SOS2 [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

Integrated in silico MS-based phosphoproteomics and network enrichment analysis of RASopathy proteins

Montero-Bullón

González-Velasco

Isidoro‐García

et al. 2021

Orphanet J Rare Dis

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Background RASopathies are a group of syndromes showing clinical overlap caused by mutations in genes affecting the RAS-MAPK pathway. Consequent disruption on cellular signaling leads and is driven by phosphoproteome remodeling. However, we still lack a comprehensive picture of the different key players and altered downstream effectors. Methods An in silico interactome of RASopathy proteins was generated using pathway enrichment analysis/STRING tool, including identification of main hub proteins. We also integrated phosphoproteomic and immunoblotting studies using previous published information on RASopathy proteins and their neighbors in the context of RASopathy syndromes. Data from Phosphosite database (www.phosphosite.org) was collected in order to obtain the potential phosphosites subjected to regulation in the 27 causative RASopathy proteins. We compiled a dataset of dysregulated phosphosites in RASopathies, searched for commonalities between syndromes in harmonized data, and analyzed the role of phosphorylation in the syndromes by the identification of key players between the causative RASopathy proteins and the associated interactome. Results In this study, we provide a curated data set of 27 causative RASopathy genes, identify up to 511 protein–protein associations using pathway enrichment analysis/STRING tool, and identify 12 nodes as main hub proteins. We found that a large group of proteins contain tyrosine residues and their biological processes include but are not limited to the nervous system. Harmonizing published RASopathy phosphoproteomic and immunoblotting studies we identified a total of 147 phosphosites with increased phosphorylation, whereas 47 have reduced phosphorylation. The PKB signaling pathway is the most represented among the dysregulated phosphoproteins within the RASopathy proteins and their neighbors, followed by phosphoproteins implicated in the regulation of cell proliferation and the MAPK pathway. Conclusions This work illustrates the complex network underlying the RASopathies and the potential of phosphoproteomics for dissecting the molecular mechanisms in these syndromes. A combined study of associated genes, their interactome and phosphorylation events in RASopathies, elucidates key players and mechanisms to direct future research, diagnosis and therapeutic windows.

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Clinical and molecular characterization of children with Noonan syndrome and other RASopathies in Argentina

Cited by 12 publications

References 21 publications

Phenotype–genotype analysis of 242 individuals with RASopathies: 18‐year experience of a tertiary center in Brazil

Phenotype–genotype analysis of 242 individuals with RASopathies: 18‐year experience of a tertiary center in Brazil

Clinical and molecular analysis of 26 individuals with Noonan syndrome in a reference institution in Colombia

Integrated in silico MS-based phosphoproteomics and network enrichment analysis of RASopathy proteins

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