Providing more evidence on <i>LZTR1</i> variants in Noonan syndrome patients

Chinton, Josefina; Huckstadt, Victoria; Mucciolo, Mafalda; Lepri, Francesca Romana; Novelli, Antonio; Gravina, Luis Pablo; Obregón, María Gabriela

doi:10.1002/ajmg.a.61445

Cited by 26 publications

(23 citation statements)

References 15 publications

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“…Conversely, a lower prevalence of short stature was observed in individuals with LZTR1 , compared with RAF1 and PTPN11 (Table S2). In the cohort of seven individuals with LZTR1 variants studied in Argentina, short stature was present in only 21% (Chinton et al, 2020). A larger number of individuals with variants in LZTR1 are required to accomplish a definite conclusion.…”

Section: Discussionmentioning

confidence: 99%

“…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: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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“… f Chinton et al, 2020; Ghedira et al, 2017; Johnston et al, 2018; Li et al, 2019; Umeki et al, 2019; Yamamoto et al, 2015. …”

Section: Resultsmentioning

confidence: 99%

Genotype‐cardiac phenotype correlations in a large single‐center cohort of patients affected by RASopathies: Clinical implications and literature review

Leoni

Blandino

Delogu

et al. 2021

American J of Med Genetics Pt A

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Congenital heart disease (CHD) and hypertrophic cardiomyopathy (HCM) are common features in patients affected by RASopathies. The aim of this study was to assess genotype‐ phenotype correlations, focusing on the cardiac features and outcomes of interventions for cardiac conditions, in a single‐center cohort of 116 patients with molecularly confirmed diagnosis of RASopathy, and compare these findings with previously published data. All enrolled patients underwent a comprehensive echocardiographic examination. Relevant information was also retrospectively collected through the analysis of clinical records. As expected, significant associations were found between PTPN11 mutations and pulmonary stenosis (both valvular and supravalvular) and pulmonary valve dysplasia, and between SOS1 mutations and valvular defects. Similarly, HRAS mutations were significantly associated with HCM. Potential associations between less prevalent mutations and cardiac defects were also observed, including RIT1 mutations and HCM, SOS2 mutations and septal defects, and SHOC2 mutations and septal and valve abnormalities. Patients with PTPN11 mutations were the most likely to require both a primary treatment (transcatheter or surgical) and surgical reintervention. Other cardiac anomalies less reported until recently in this population, such as isolated functional and structural mitral valve diseases, as well as a sigmoid‐shaped interventricular septum in the absence of HCM, were also reported. In conclusion, our study confirms previous data but also provides new insights on cardiac involvement in RASopathies. Further research concerning genotype/phenotype associations in RASopathies could lead to a more rational approach to surgery and the consideration of drug therapy in patients at higher risk due to age, severity, anatomy, and comorbidities.

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“…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 ]. Further clinical and genetic analysis is required to establish the pathogenic significance for some of these genes, including RASA2 , SOS2 and BRAF .…”

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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Providing more evidence on LZTR1 variants in Noonan syndrome patients

Cited by 26 publications

References 15 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

Genotype‐cardiac phenotype correlations in a large single‐center cohort of patients affected by RASopathies: Clinical implications and literature review

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

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