The novel <i>RAF1</i> mutation p.(Gly361Ala) located outside the kinase domain of the CR3 region in two patients with Noonan syndrome, including one with a rare brain tumor

Harms, Frederike L.; Alawi, Malik; Amor, David J.; Tan, Tiong Yang; Čuturilo, Goran; Lißewski, Christina; Brinkmann, Julia; Schanze, Denny; Kutsche, Kerstin; Zenker, Martin

doi:10.1002/ajmg.a.38569

Cited by 14 publications

(10 citation statements)

References 61 publications

(88 reference statements)

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“…However, we did not observe a typical cutaneous phenotype for NSML with RAF1 mutation in the absence of characteristic widespread ML. Acquired MMN appeared to be a hallmark of RAF1 mutation, present in about one‐third of patients, as previously described . In two patients, small MMN could barely be distinguished clinically from dark‐brown lentigines in the absence of dermoscopic examination (Fig.…”

Section: Discussionsupporting

confidence: 62%

Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation

Bessis

Miquel

Bourrat³

et al. 2019

Br J Dermatol

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Summary Background Data on dermatological manifestations of Noonan syndrome (NS) remain heterogeneous and are based on limited dermatological expertise. Objectives To describe the dermatological manifestations of NS, compare them with the literature findings, and test for dermatological phenotype–genotype correlations with or without the presence of PTPN11 mutations. Methods We performed a large 4‐year, prospective, multicentric, collaborative dermatological and genetic study. Results Overall, 129 patients with NS were enrolled, including 65 patients with PTPN11‐NS, 34 patients with PTPN11‐NS with multiple lentigines (NSML), and 30 patients with NS who had a mutation other than PTPN11. Easy bruising was the most frequent dermatological finding in PTPN11‐NS, present in 53·8% of patients. Multiple lentigines and café‐au‐lait macules (n ≥ 3) were present in 94% and 80% of cases of NSML linked to specific mutations of PTPN11, respectively. Atypical forms of NSML could be associated with NS with RAF1 or NRAS mutations. In univariate analysis, patients without a PTPN11 mutation showed (i) a significantly higher frequency of keratinization disorders (P = 0·001), including keratosis pilaris (P = 0·005), ulerythema ophryogenes (P = 0·0001) and palmar and/or plantar hyperkeratosis (P = 0·06, trend association), and (ii) a significantly higher frequency of scarce scalp hair (P = 0·035) and scarce or absent eyelashes (P = 0·06, trend association) than those with PTPN11 mutations. Conclusions The cutaneous phenotype of NS with a PTPN11 mutation is generally mild and nonspecific, whereas the absence of a PTPN11 mutation is associated with a high frequency of keratinization disorders and hair abnormalities.

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Section: Discussionsupporting

confidence: 62%

Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation

Bessis

Miquel

Bourrat³

et al. 2019

Br J Dermatol

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“…Most of the genes are regulators of the MAPK/ERK1/2 pathway. Syndromes in which affected individuals were reported with osteoclast-like giant cell lesions include cherubism [5], Noonan syndrome [6][7][8][9][10][11][12][13][14], osteoglophonic dysplasia [15], neurofibromatosis type 1 [16], cardiofaciocutaneous syndrome [9,17,18], LEOPARD syndrome [7,11], oculoectodermal syndrome [19], Schimmelpenning syndrome [20], and Jaffe-Campanacci syndrome [21].…”

Section: Introductionmentioning

confidence: 99%

Making sense of giant cell lesions of the jaws (GCLJ): lessons learned from next‐generation sequencing

Gomes

Diniz

Bastos

et al. 2019

The Journal of Pathology

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Next-generation sequencing has revealed mutations in several bone-related lesions and was recently used to uncover the genetic basis of giant cell lesions of the jaws (GCLJ). Consistent with their benign nature, GCLJ show a low tumor mutation burden. They also harbor somatic, heterozygous, mutually exclusive mutations in TRPV4, KRAS, or FGFR1. These signature mutations occur only in a subset of lesional cells, suggesting the existence of a 'landscaping effect', with mutant cells inducing abnormal accumulation of non-mutant cells that form the tumor mass. Osteoclast-rich lesions with histological similarities to GCLJ can occur in the jaws sporadically or in association with genetically inherited syndromes. Based on recent results, the pathogenesis of a subgroup of sporadic GCLJ seems closely related to non-ossifying fibroma of long bones, with both lesions sharing MAPK pathway-activating mutations. In this review, we extrapolate from these recent findings to contextualize GCLJ genetics and we highlight the therapeutic implications of this new information.

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“…The WES approach enables studies of the patients within an environmental and clinical context through large-scale cohort trials and data processing with a focus on the associations among molecular biology, disease and health phenotypes to assure a more accurate diagnosis, leading to the establishment of individualized disease prevention and treatment programmes (Tetreault et al, 2015; Collins et al, 2016; Tebani et al, 2016). Moreover, WES has allowed the identification of new genes associated to the clinical description of patients with RASopathies (Niguidula et al, 2018; Matias et al, 2019), such as RIT1 (Aoki et al, 2013), A2ML1 (Vissers et al, 2015), RASA2, SPRY1 (Chen et al, 2014), SOS2, LZTR1 (Yamamoto et al, 2015; Umeki et al, 2019), PPP1CB (Gripp et al, 2016), CBL (Coe et al, 2017), and MRAS (Higgins et al, 2017), as well as new mutations in genes of the RAS/MAPK pathway (Carapito et al, 2014; Sana et al, 2016; Coe et al, 2017; Harms et al, 2018; Valera et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

miRNA Genetic Variants Alter Their Secondary Structure and Expression in Patients With RASopathies Syndromes

et al. 2019

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RASopathies are a group of rare genetic diseases caused by germline mutations in genes involved in the RAS–mitogen-activated protein kinase (RAS-MAPK) pathway. Whole-exome sequencing (WES) is a powerful approach for identifying new variants in coding and noncoding DNA sequences, including miRNAs. miRNAs are fine-tuning negative regulators of gene expression. The presence of variants in miRNAs could lead to malfunctions of regulation, resulting in diseases. Here, we identified 41 variants in mature miRNAs through WES analysis in five patients with previous clinical diagnosis of RASopathies syndromes. The pathways, biological processes, and diseases that were over-represented among the target genes of the mature miRNAs harboring variants included the RAS, MAPK, RAP1, and PIK3-Akt signaling pathways, neuronal differentiation, neurogenesis and nervous system development, congenital cardiac defects (hypertrophic cardiomyopathy, dilated cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy), and the phenotypes and syndromes of RASopathies (Noonan syndrome, Legius syndrome, Costello syndrome, Cafe au lait spots multiple, subaortic stenosis, pulmonary valve stenosis, and LEOPARD syndrome). Furthermore, eight selected variants in nine mature miRNAs (hsa-miR-1304, hsa-miR-146a, hsa-miR-196a2, hsa-miR-499a/hsa-miR-499b, hsa-miR-449b, hsa-miR-548l, hsa-miR-575, and hsa-miR-593) may have caused alterations in the secondary structures of miRNA precursor. Selected miRNAs containing variants such as hsa-miR-146a-3p, hsa-miR-196a-3p, hsa-miR-548l, hsa-miR-449b-5p, hsa-miR-575, and hsa-miR499a-3p could regulate classical genes associated with Rasopathies and RAS-MAPK pathways, contributing to modify the expression pattern of miRNAs in patients. RT-qPCR expression analysis revealed four differentially expressed miRNAs that were downregulated: miRNA-146a-3p in P1, P2, P3, P4, and P5, miR-1304-3p in P2, P3, P4, and P5, miR-196a2-3p in P3, and miR-499b-5p in P1. miR-499a-3p was upregulated in P1, P3, and P5. These results indicate that miRNAs show different expression patterns when these variants are present in patients. Therefore, this study characterized the role of miRNAs harboring variants related to RASopathies for the first time and indicated the possible implications of these variants for phenotypes of RASopathies such as congenital cardiac defects and cardio-cerebrovascular diseases. The expression and existence of miRNA variants may be used in the study of biomarkers of the RASopathies.

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The novel RAF1 mutation p.(Gly361Ala) located outside the kinase domain of the CR3 region in two patients with Noonan syndrome, including one with a rare brain tumor

Cited by 14 publications

References 61 publications

Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation

Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation

Making sense of giant cell lesions of the jaws (GCLJ): lessons learned from next‐generation sequencing

miRNA Genetic Variants Alter Their Secondary Structure and Expression in Patients With RASopathies Syndromes

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