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https://www.readbyqxmd.com/read/28076348/reverse-pathway-genetic-approach-identifies-epistasis-in-autism-spectrum-disorders
#1
Ileena Mitra, Alinoë Lavillaureix, Erika Yeh, Michela Traglia, Kathryn Tsang, Carrie E Bearden, Katherine A Rauen, Lauren A Weiss
Although gene-gene interaction, or epistasis, plays a large role in complex traits in model organisms, genome-wide by genome-wide searches for two-way interaction have limited power in human studies. We thus used knowledge of a biological pathway in order to identify a contribution of epistasis to autism spectrum disorders (ASDs) in humans, a reverse-pathway genetic approach. Based on previous observation of increased ASD symptoms in Mendelian disorders of the Ras/MAPK pathway (RASopathies), we showed that common SNPs in RASopathy genes show enrichment for association signal in GWAS (P = 0...
January 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28067895/the-nf1-gene-in-tumor-syndromes-and-melanoma
#2
Maija Kiuru, Klaus J Busam
Activation of the RAS/MAPK pathway is critical in melanoma. Melanoma can be grouped into four molecular subtypes based on their main genetic driver: BRAF-mutant, NRAS-mutant, NF1-mutant, and triple wild-type tumors. The NF1 protein, neurofibromin 1, negatively regulates RAS proteins through GTPase activity. Germline mutations in NF1 cause neurofibromatosis type I, a common genetic tumor syndrome caused by dysregulation of the RAS/MAPK pathway, ie, RASopathy. Melanomas with NF1 mutations typically occur on chronically sun-exposed skin or in older individuals, show a high mutation burden, and are wild-type for BRAF and NRAS...
January 9, 2017: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/28050463/cardiofaciocutaneous-syndrome-case-report-of-a-rare-disorder
#3
Soutrik Seth, Tanmoy Biswas, Biswajit Biswas, Atanu Roy, Asok Kumar Datta
Cardiofaciocutaneous syndrome or CFC syndrome is a rare genetic disorder first described in 1986. It is one of the RASopathies involving multiple organs particularly the heart, skin and face affecting males and females equally. The phenotypic features overlap with 2 other conditions, the Noonan and Costello syndrome. We report on a 22-month-old boy with CFC syndrome presenting with typical craniofacial appearance, heart defects, ectodermal abnormalities, growth failure and developmental delay. Estimated population of affected individuals worldwide is a few hundreds...
November 2016: Journal of Clinical and Diagnostic Research: JCDR
https://www.readbyqxmd.com/read/28049852/in-vivo-severity-ranking-of-ras-pathway-mutations-associated-with-developmental-disorders
#4
Granton A Jindal, Yogesh Goyal, Kei Yamaya, Alan S Futran, Iason Kountouridis, Courtney A Balgobin, Trudi Schüpbach, Rebecca D Burdine, Stanislav Y Shvartsman
Germ-line mutations in components of the Ras/MAPK pathway result in developmental disorders called RASopathies, affecting about 1/1,000 human births. Rapid advances in genome sequencing make it possible to identify multiple disease-related mutations, but there is currently no systematic framework for translating this information into patient-specific predictions of disease progression. As a first step toward addressing this issue, we developed a quantitative, inexpensive, and rapid framework that relies on the early zebrafish embryo to assess mutational effects on a common scale...
January 3, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28027064/novel-pathogenic-variant-in-the-hras-gene-with-lethal-outcome-and-a-broad-phenotypic-spectrum-among-polish-patients-with-costello-syndrome
#5
Magdalena Pelc, Elżbieta Ciara, Aleksandra Jezela-Stanek, Monika Kugaudo, Agata Cieślikowska, Dorota Jurkiewicz, Magdalena Janeczko, Krystyna Chrzanowska, Małgorzata Krajewska-Walasek, Agata Skórka
Costello syndrome (CS) is a rare congenital disorder from the group of RASopathies, characterized by a distinctive facial appearance, failure to thrive, cardiac and skin anomalies, intellectual disability, and a predisposition to neoplasia. CS is associated with germline mutations in the proto-oncogene HRAS, a small GTPase from the Ras family. In this study, a molecular and clinical analysis was carried out in eight Polish patients with the Costello phenotype. A molecular test showed two known heterozygous mutations in the first coding exon of the gene in seven patients: p...
December 23, 2016: Clinical Dysmorphology
https://www.readbyqxmd.com/read/28002430/a-novel-hras-mutation-independently-contributes-to-left-ventricular-hypertrophy-in-a-family-with-a-known-myh7-mutation
#6
Maria Elena Sana, Lawrence A Quilliam, Andrea Spitaleri, Laura Pezzoli, Daniela Marchetti, Chiara Lodrini, Elisabetta Candiago, Anna Rita Lincesso, Paolo Ferrazzi, Maria Iascone
Several genetic conditions can lead to left ventricular hypertrophy (LVH). Among them, hypertrophic cardiomyopathy (HCM), caused by mutations in sarcomere genes, is the most common inherited cardiac disease. Instead, RASopathies, a rare class of disorders characterized by neuro-cardio-facial-cutaneous abnormalities and sometimes presenting with LVH, are caused by mutations in the RAS-MAPK pathway. We report on a 62-years-old male who presented isolated severe obstructive LVH but did not carry the sarcomere mutation previously identified in his affected relatives...
2016: PloS One
https://www.readbyqxmd.com/read/27942422/expansion-of-the-rasopathies
#7
William E Tidyman, Katherine A Rauen
The Ras/mitogen activated protein kinase (MAPK) pathway is essential in the regulation of cell cycle, differentiation, growth, cell senescence and apoptosis, all of which are critical to normal development. A class of neurodevelopmental disorders, RASopathies, is caused by germline mutations in genes of the Ras/MAPK pathway. Through the use of whole exome sequencing and targeted sequencing of selected genes in cohorts of panel-negative RASopathy patients, several new genes have been identified. These include: RIT1, SOS2, RASA2, RRAS and SYNGAP1, that likely represent new, albeit rare, causative RASopathy genes...
September 2016: Current Genetic Medicine Reports
https://www.readbyqxmd.com/read/27940666/rasopathies-are-associated-with-delayed-puberty-are-they-associated-with-precocious-puberty-too
#8
Daniëlle C M van der Kaay, Bat-Sheva Levine, Daniel Doyle, Roberto Mendoza-Londono, Mark R Palmert
RASopathies, such as Noonan, Costello, and cardio-facio-cutaneous syndromes, are developmental disorders caused by mutations in rat sarcoma-mitogen-activated protein kinase pathway genes. Mutations that cause Noonan syndrome have been associated with delayed puberty. Here we report 4 patients with either Costello or cardio-facio-cutaneous syndrome who developed precocious puberty, suggesting complex regulation of the hypothalamic-pituitary-gonadal axis and the timing of puberty by the rat sarcoma-mitogen-activated protein kinase pathway...
December 2016: Pediatrics
https://www.readbyqxmd.com/read/27924582/modeling-rasopathies-with-genetically-modified-mouse-models
#9
Isabel Hernández-Porras, Carmen Guerra
The RAS/MAPK signaling pathway plays key roles in development, cell survival and proliferation, as well as in cancer pathogenesis. Molecular genetic studies have identified a group of developmental syndromes, the RASopathies, caused by germ line mutations in this pathway. The syndromes included within this classification are neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NS-ML, formerly known as LEOPARD syndrome), Costello syndrome (CS), cardio-facio-cutaneous syndrome (CFC), Legius syndrome (LS, NF1-like syndrome), capillary malformation-arteriovenous malformation syndrome (CM-AVM), and hereditary gingival fibromatosis (HGF) type 1...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27900779/mosaic-nras-q61r-mutation-in-a-child-with-giant-congenital-melanocytic-naevus-epidermal-naevus-syndrome-and-hypophosphataemic-rickets
#10
R Ramesh, N Shaw, E K Miles, B Richard, I Colmenero, C Moss
The association of hypophosphataemic rickets with verrucous epidermal naevus (EN) and elevated fibroblast growth factor 23 levels is known as cutaneous-skeletal hypophosphataemia syndrome (CSHS), and can be caused by somatic activating mutations in RAS genes. We report a unique patient with CSHS associated with giant congenital melanocytic naevus (CMN), neurocutaneous melanosis and EN syndrome, manifesting as facial linear sebaceous naevus, developmental delay and ocular dermoids. An activating mutation Q61R in the NRAS gene was found in affected skin and ocular tissue but not blood, implying that the disparate manifestations are due to a multilineage activating mutation (mosaic RASopathy)...
January 2017: Clinical and Experimental Dermatology
https://www.readbyqxmd.com/read/27868344/further-evidence-that-variants-in-ppp1cb-cause-a-rasopathy-similar-to-noonan-syndrome-with-loose-anagen-hair
#11
Regina M Zambrano, Michael Marble, Stuart A Chalew, Christian Lilje, Alfonso Vargas, Yves Lacassie
No abstract text is available yet for this article.
November 21, 2016: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/27862862/variability-in-clinical-and-neuropsychological-features-of-individuals-with-map2k1-mutations
#12
Elizabeth I Pierpont, Margaret Semrud-Clikeman, Mary Ella Pierpont
Mutations in MAP2K1, a gene expressed within the RAS-mitogen activated protein kinase (RAS/MAPK) pathway, are generally associated with the clinical phenotype of cardiofaciocutaneous syndrome. Here we describe two male patients (ages 16 and 20 years) with mutations in MAP2K1 and heterogeneous clinical presentations. Both young men had short stature, some facial features suggesting a RASopathy and minimal cardiac involvement. Detailed medical and neuropsychological findings are presented alongside a comprehensive review of features of patients with MAP2K1 mutations reported in the literature...
November 14, 2016: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/27826699/a-unique-case-of-multiple-non-ossifying-fibromas-with-polyostotic-monomelic-distribution-and-aggressive-clinical-course
#13
Alessandro Corsi, Cristina Remoli, Mara Riminucci, Ernesto Ippolito, John Dimitriou
Multiple non-ossifying fibromas (MNOFs) occur either isolated or in association with other anomalies, are usually localized in the long bones of the lower limbs, may be radiographically confused with other skeletal lesions, and tend to heal spontaneously with the completion of the skeletal growth. Segmental distribution, either monomelic or polymelic and ipsilateral, is rare and commonly observed in the context of developmental diseases known as "RASopathies", which are caused by mutations in genes that encode components or regulators within the Ras/mitogen-activated protein kinase signaling pathway...
February 2017: Skeletal Radiology
https://www.readbyqxmd.com/read/27763634/phenotypic-predictors-and-final-diagnoses-in-patients-referred-for-rasopathy-testing-by-targeted-next-generation-sequencing
#14
Elizabeth J Bhoj, Zhenming Yu, Qiaoning Guan, Rebecca Ahrens-Nicklas, Kajia Cao, Minjie Luo, Tanya Tischler, Matthew A Deardorff, Elaine Zackai, Avni B Santani
INTRODUCTION: RASopathies include disorders generally characterized by developmental delay, specific heart defects, short stature, cardiac hypertrophy, and facial dysmorphisms. Next-generation sequencing (NGS)-based panels have widespread acceptance as a diagnostic tool for RASopathies. MATERIALS AND METHODS: The first 126 patients evaluated by clinical examination and the NGS RASopathy panel at the Children's Hospital of Philadelphia were enrolled. We calculated diagnosis rate, correlated reported clinical findings with positive or negative test results, and identified final molecular diagnoses in 28/96 patients who tested negative for RASopathies...
October 20, 2016: Genetics in Medicine: Official Journal of the American College of Medical Genetics
https://www.readbyqxmd.com/read/27751966/concurrent-occurrence-of-an-inherited-16p13-11-microduplication-and-a-de-novo-19p13-3-microdeletion-involving-map2k2-in-a-patient-with-developmental-delay-distinctive-facial-features-and-lambdoid-synostosis
#15
Keiko Shimojima, Yumiko Ondo, Mayumi Matsufuji, Nozomi Sano, Hisashi Tsuru, Tatsuki Oyoshi, Nayuta Higa, Hiroshi Tokimura, Kazunori Arita, Toshiyuki Yamamoto
A female patient presented with developmental delay, distinctive facial features, and congenital anomalies, including a heart defect and premature lambdoid synostosis. The patient showed a paternally inherited 16p13.11 microduplication and a de novo 19p13.3 microdeletion involving the mitogen-activated protein kinase kinase 2 gene (MAP2K2), in which mutations cause the cardio-facio-cutaneous (CFC) syndrome. Reports of patients with overlapping 19p13.3 microdeletions of this region describe similar clinical manifestations including distinctive facial features: prominent forehead, horizontal/down-slanting palpebral fissures, long midface, pointed chin/angular jaw, sparse eyebrows, and underdeveloped cheekbones...
November 2016: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/27705751/before-and-after-nutritional-transformation-of-dysmorphism-in-a-case-of-costello-syndrome
#16
Annie T G Chiu, Lixing Zhu, Gary T K Mok, Gordon K C Leung, C B Chow, Brian H Y Chung
Costello syndrome is a type of RASopathy mapped to HRAS gene in chromosome 11, characterized by prenatal overgrowth, postnatal failure to thrive, classic facial gestalt and multisystem involvement including cardiomyopathy and intellectual disability. We present a 7 months old child with severe failure to thrive whose "subtle" facial dysmorphism at the time eluded clinical recognition of the syndrome. It was only with optimization of his nutritional status that dysmorphic features became more apparent, which affirmed the molecular diagnosis of Costello syndrome from exome sequencing...
November 2016: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/27699752/-rit1-a-novel-gene-associated-with-noonan-syndrome
#17
I Arroyo-Carrera, M Solo de Zaldivar-Tristancho, R Martin-Fernandez, M Vera-Torres, J F Gonzalez de Buitrago-Amigo, J Botet-Rodriguez
INTRODUCTION: Noonan syndrome is the most frequent of the congenital group of malformation syndromes caused by germline mutations that encode components of the RAS/MAPK pathway, termed RASopathies, one of the most frequent congenital genetic disorders in the clinical practice. Recently RIT1 mutations have been reported in patients with Noonan syndrome. CASE REPORT: A 7 years-old girl with a clinical diagnosis of Noonan syndrome, and with a hypertrophic cardiomyopathy included in her clinical manifestations, where a de novo heterozygous, probably pathogenic, novel mutation in RIT1, c...
October 16, 2016: Revista de Neurologia
https://www.readbyqxmd.com/read/27626068/integrated-tumor-and-germline-whole-exome-sequencing-identifies-mutations-in-mapk-and-pi3k-pathway-genes-in-an-adolescent-with-rosette-forming-glioneuronal-tumor-of-the-fourth-ventricle
#18
Frank Y Lin, Katie Bergstrom, Richard Person, Abhishek Bavle, Leomar Y Ballester, Sarah Scollon, Robin Raesz-Martinez, Andrew Jea, Sherri Birchansky, David A Wheeler, Stacey L Berg, Murali M Chintagumpala, Adekunle M Adesina, Christine Eng, Angshumoy Roy, Sharon E Plon, D Williams Parsons
The integration of genome-scale studies such as whole-exome sequencing (WES) into the clinical care of children with cancer has the potential to provide insight into the genetic basis of an individual's cancer with implications for clinical management. This report describes the results of clinical tumor and germline WES for a patient with a rare tumor diagnosis, rosette-forming glioneuronal tumor of the fourth ventricle (RGNT). Three pathogenic gene alterations with implications for clinical care were identified: somatic activating hotspot mutations in FGFR1 (p...
September 2016: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/27589201/paternal-uniparental-disomy-with-segmental-loss-of-heterozygosity-of-chromosome-11-are-hallmark-characteristics-of-syndromic-and-sporadic-embryonal-rhabdomyosarcoma
#19
Katherine M Robbins, Deborah L Stabley, Jennifer Holbrook, Rebecca Sahraoui, Alexa Sadreameli, Katrina Conard, Laura Baker, Karen W Gripp, Katia Sol-Church
Costello syndrome (CS) arises from a typically paternally derived germline mutation in the proto-oncogene HRAS, and is considered a rasopathy. CS results in failure-to-thrive, intellectual disabilities, short stature, coarse facial features, skeletal abnormalities, congenital heart disease, and a predisposition for cancer, most commonly embryonal rhabdomyosarcoma (ERMS). The goal of this study was to characterize CS ERMS at the molecular level and to determine how divergent it is from sporadic ERMS. We characterized eleven ERMS tumors from eight unrelated CS patients, carrying paternally derived HRAS c...
December 2016: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/27587266/severe-intellectual-disability-and-enhanced-gamma-aminobutyric-acidergic-synaptogenesis-in-a-novel-model-of-rare-rasopathies
#20
Alessandro Papale, Raffaele d'Isa, Elisabetta Menna, Milica Cerovic, Nicola Solari, Neil Hardingham, Marco Cambiaghi, Marco Cursi, Mariano Barbacid, Letizia Leocani, Stefania Fasano, Michela Matteoli, Riccardo Brambilla
BACKGROUND: Dysregulation of Ras-extracellular signal-related kinase (ERK) signaling gives rise to RASopathies, a class of neurodevelopmental syndromes associated with intellectual disability. Recently, much attention has been directed at models bearing mild forms of RASopathies whose behavioral impairments can be attenuated by inhibiting the Ras-ERK cascade in the adult. Little is known about the brain mechanisms in severe forms of these disorders. METHODS: We performed an extensive characterization of a new brain-specific model of severe forms of RASopathies, the KRAS(12V) mutant mouse...
February 1, 2017: Biological Psychiatry
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