{{short description|Family of genetic conditions caused by mutations affecting Ras genes}}

The '''RASopathies''' are a group of developmental syndromes caused by germline mutations in genes belonging to the Ras/MAPK pathway. Common features include intellectual disability, congenital heart defects, skin abnormalities, and craniofacial abnormalities.<ref name=":0" /><ref name="pmid35103797"/>

== MAPK pathway == The most prevalent signaling cascade governed by multi-kinase inhibitors is the mitogen-activated protein kinase (MAPK) pathway. This well-established MAPK pathway in cell biology governs several crucial cellular. It encompasses the RAS/RAF/MEK/ERK signaling cascade. RAF kinase is a primary mediator of the MAPK pathway, responsible for the sequential activation of downstream targets, such as MEK pathway and the transcription factor extracellular signal-related kinase (ERK), which control numerous cellular and physiological processes, including organism development, cell cycle control, cell proliferation, differentiation, migration, survival, apoptosis and cell death. With this cascade, various isoforms of RAS, RAF, MEK, and ERK exhibit differences in efficacy, function, and, notably, carcinogenic potential. Defects in this signaling cascade are associated with diseases. The pathophysiology of NF1, Noonan, Watson and Legius syndromes fit into the RASopathy model. The RASopathies are a group of developmental syndromes caused by germline mutations in genes belonging to the Ras/MAPK pathway. Costello Syndrome and Cardiofaciocutaneous syndrome are also included in RASopathy. Common features include intellectual disability, congenital heart defects, skin abnormalities, craniofacial abnormalities and tendency for tumor formation.<ref>{{Cite journal |last1=Bahar |first1=Md Entaz |last2=Kim |first2=Hyun Joon |last3=Kim |first3=Deok Ryong |date=2023-12-18 |title=Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies |url=https://doi.org/10.1038/s41392-023-01705-z |journal=Signal Transduction and Targeted Therapy |volume=8 |issue=1 |article-number=455 |doi=10.1038/s41392-023-01705-z |pmid=38105263 |issn=2059-3635|pmc=10725898 }}</ref>

== List of RASopathies == Known RASopathies include the following:<ref name=":0">{{Cite journal |last1=Boxel-Woolf |first1=Tom Van |last2=McCarthy |first2=Kathleen M. |title=Speech and language skills in a case of Watson syndrome |journal=Clinical Linguistics & Phonetics |date=2025 |volume=0 |pages=1–24 |doi=10.1080/02699206.2025.2472051 |issn=0269-9206 |pmid=40077991|doi-access=free }}</ref><ref name="pmid35103797"/><ref name="pmid27412009"/> * Capillary malformation-AV malformation syndrome (CV-AVM) * Cardiofaciocutaneous syndrome (CFC) * Neurofibromatosis type I (NF1) * Watson syndrome * Noonan syndrome (NS) * Costello syndrome (CS) * Legius syndrome, also known as NF1-like syndrome * Noonan syndrome with multiple lentigines (NSML), formerly called LEOPARD syndrome * SYNGAP1-related intellectual disability

Somatic mutations in the Ras/MAPK pathway can cause cancers and disorders such as RAS-associated autoimmune leukoproliferative disorder (RALD) or juvenile myelomonocytic leukemia (JMML). These syndromes may share some features with RASopathies but are not considered true RASopathies if caused by somatic mutation.<ref name="pmid34175492"/> Generally, RASopathies increase the risk of developing cancers.<ref name="pmid35103797"/><ref name="pmid32240795"/> Neurodevelopmental or psychiatric disorders such as attention deficit hyperactivity disorder, autism spectrum disorder, and anxiety occur at higher rates in individuals with RASopathies.<ref name="pmid37407569"/><ref name="pmid36428239"/>

== Genetics == RASopathies are caused by germline mutations which result in overall activation of the Ras/MAPK pathway. Mutations in the following genes are associated with one or more types of RASopathy:<ref name="pmid27412009"/><ref name="pmid26446362"/> {{div col |colwidth=10em}} * HRAS * KRAS * NRAS * RRAS * RIT1 * NF1 * RASA1 * RASA2 * SYNGAP1 * SOS1 * SOS2 * CBL * PTPN11 * BRAF * RAF1 * MAP2K1 * MAP2K2 * MAP3K8 * SPRED1 * SPRY1 * MYST4 * LZTR1 * A2ML1 {{div col end}}

==References== <references>

<ref name="pmid35103797">{{cite journal| author=Rauen KA| title=Defining RASopathy | journal= Disease Models & Mechanisms| year= 2022 | volume= 15 | issue= 2 | article-number=dmm049344 | pmid=35103797 | doi=10.1242/dmm.049344 | pmc=8821523}} </ref> <ref name="pmid27412009">{{cite journal| author=Tidyman WE, Rauen KA| title=Pathogenetics of the RASopathies. | journal= Human Molecular Genetics| year= 2016 | volume= 25 | issue= R2 | pages= R123–R132 | pmid=27412009 | doi=10.1093/hmg/ddw191 | pmc=6283265}} </ref> <ref name="pmid34175492">{{cite journal| author=Riller Q, Rieux-Laucat F| title=RASopathies: From germline mutations to somatic and multigenic diseases | journal= Biomedical Journal| year= 2021 | volume= 44 | issue= 4 | pages= 422–432 | pmid=34175492 | doi=10.1016/j.bj.2021.06.004 | pmc=8514848}} </ref> <ref name="pmid32240795">{{cite journal| author=Dunnett-Kane V, Burkitt-Wright E, Blackhall FH, Malliri A, Evans DG, Lindsay CR| title=Germline and sporadic cancers driven by the RAS pathway: parallels and contrasts| journal= Annals of Oncology| year= 2020 | volume= 31 | issue= 7 | pages= 873–883 | pmid=32240795 | doi=10.1016/j.annonc.2020.03.291 | pmc=7322396}}</ref> <ref name="pmid37407569">{{cite journal| author=Rai B, Naylor PE, Siqueiros-Sanchez M, Wintermark M, Raman MM, Jo B | display-authors=etal| title=Novel effects of Ras-MAPK pathogenic variants on the developing human brain and their link to gene expression and inhibition abilities. | journal= Translational Psychiatry| year= 2023 | volume= 13 | issue= 1 | pages= 245 | pmid=37407569 | doi=10.1038/s41398-023-02504-4 | pmc=10322993}} </ref> <ref name="pmid36428239">{{cite journal| author=Zenker M| title=Clinical overview on RASopathies. | journal= American Journal of Medical Genetics Part C: Seminars in Medical Genetics| year= 2022 | volume= 190 | issue= 4 | pages= 414–424 | pmid=36428239 | doi=10.1002/ajmg.c.32015| doi-access=free }} </ref> <ref name="pmid26446362">{{cite journal| author=Aoki Y, Niihori T, Inoue S, Matsubara Y| title=Recent advances in RASopathies | journal= Journal of Human Genetics| year= 2016 | volume= 61 | issue= 1 | pages= 33–9 | pmid=26446362 | doi=10.1038/jhg.2015.114}} </ref>

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Category:Congenital vascular defects Category:Deficiencies of intracellular signaling peptides and proteins Category:Enzyme defects Category:Genodermatoses Category:Lymphocytic immune system disorders Category:Melanocytic nevi and neoplasms Category:Neuro-cardio-facial-cutaneous syndromes Category:Neurodevelopmental disorders Category:RASopathies Category:Valvular heart disease