RASopathy

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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. [1]

Contents

List of RASopathies

Known RASopathies include the following: [1] [2]

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. [3] Generally, RASopathies increase the risk of developing cancers. [1] [4] Neurodevelopmental or psychiatric disorders such as attention deficit hyperactivity disorder, autism spectrum disorder, and anxiety occur at higher rates in individuals with RASopathies. [5] [6]

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: [2] [7]

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<span class="mw-page-title-main">Megalencephaly</span> Medical condition

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<span class="mw-page-title-main">Cardiofaciocutaneous syndrome</span> Medical condition

Cardiofaciocutaneous (CFC) syndrome is an extremely rare genetic disorder, and is one of the RASopathies. It was first described in 1986.

<span class="mw-page-title-main">Noonan syndrome</span> Genetic condition involving facial, heart, blood and skeletal features

Noonan syndrome (NS) is a genetic disorder that may present with mildly unusual facial features, short height, congenital heart disease, bleeding problems, and skeletal malformations. Facial features include widely spaced eyes, light-colored eyes, low-set ears, a short neck, and a small lower jaw. Heart problems may include pulmonary valve stenosis. The breast bone may either protrude or be sunken, while the spine may be abnormally curved. Intelligence is often normal. Complications of NS can include leukemia.

<span class="mw-page-title-main">Germline mutation</span> Inherited genetic variation

A germline mutation, or germinal mutation, is any detectable variation within germ cells. Mutations in these cells are the only mutations that can be passed on to offspring, when either a mutated sperm or oocyte come together to form a zygote. After this fertilization event occurs, germ cells divide rapidly to produce all of the cells in the body, causing this mutation to be present in every somatic and germline cell in the offspring; this is also known as a constitutional mutation. Germline mutation is distinct from somatic mutation.

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<span class="mw-page-title-main">Cowden syndrome</span> Medical condition

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<span class="mw-page-title-main">Costello syndrome</span> Medical condition

Costello syndrome, also called faciocutaneoskeletal syndrome or FCS syndrome, is a rare genetic disorder that affects many parts of the body. It is characterized by delayed development and intellectual disabilities, distinctive facial features, unusually flexible joints, and loose folds of extra skin, especially on the hands and feet. Heart abnormalities are common, including a very fast heartbeat (tachycardia), structural heart defects, and overgrowth of the heart muscle. Infants with Costello syndrome may be large at birth, but grow more slowly than other children and have difficulty feeding. Later in life, people with this condition have relatively short stature and many have reduced levels of growth hormones. It is a RASopathy.

<span class="mw-page-title-main">HRAS</span> Protein-coding gene in the species Homo sapiens

GTPase HRas, from "Harvey Rat sarcoma virus", also known as transforming protein p21 is an enzyme that in humans is encoded by the HRAS gene. The HRAS gene is located on the short (p) arm of chromosome 11 at position 15.5, from base pair 522,241 to base pair 525,549. HRas is a small G protein in the Ras subfamily of the Ras superfamily of small GTPases. Once bound to Guanosine triphosphate, H-Ras will activate a Raf kinase like c-Raf, the next step in the MAPK/ERK pathway.

<span class="mw-page-title-main">Noonan syndrome with multiple lentigines</span> Rare autosomal dominant multi-system genetic condition

Noonan syndrome with multiple lentigines (NSML) which is part of a group called Ras/MAPK pathway syndromes, is a rare autosomal dominant, multisystem disease caused by a mutation in the protein tyrosine phosphatase, non-receptor type 11 gene (PTPN11). The disease is a complex of features, mostly involving the skin, skeletal and cardiovascular systems, which may or may not be present in all patients. The nature of how the mutation causes each of the condition's symptoms is not well known; however, research is ongoing. It is a RASopathy.

<span class="mw-page-title-main">Neurofibromin 1</span> Mammalian protein found in Homo sapiens

neurofibromatosis 1 (NF1) is a gene in humans that is located on chromosome 17. NF1 codes for neurofibromin, a GTPase-activating protein that negatively regulates RAS/MAPK pathway activity by accelerating the hydrolysis of Ras-bound GTP. NF1 has a high mutation rate and mutations in NF1 can alter cellular growth control, and neural development, resulting in neurofibromatosis type 1. Symptoms of NF1 include disfiguring cutaneous neurofibromas (CNF), café au lait pigment spots, plexiform neurofibromas (PN), skeletal defects, optic nerve gliomas, life-threatening malignant peripheral nerve sheath tumors (MPNST), pheochromocytoma, attention deficits, learning deficits and other cognitive disabilities.

<span class="mw-page-title-main">SYNGAP1</span> Protein in Homo sapiens

Synaptic Ras GTPase-activating protein 1, also known as synaptic Ras-GAP 1 or SYNGAP1, is a protein that in humans is encoded by the SYNGAP1 gene. SYNGAP1 is a ras GTPase-activating protein that is critical for the development of cognition and proper synapse function. Mutations in humans can cause intellectual disability, epilepsy, autism and sensory processing deficits.

<span class="mw-page-title-main">LZTR1</span> Protein-coding gene in the species Homo sapiens

Leucine-zipper-like transcriptional regulator 1 is a protein that in humans is encoded by the LZTR1 gene.

Germline mosaicism, also called gonadal mosaicism, is a type of genetic mosaicism where more than one set of genetic information is found specifically within the gamete cells; conversely, somatic mosaicism is a type of genetic mosaicism found in somatic cells. Germline mosaicism can be present at the same time as somatic mosaicism or individually, depending on when the conditions occur. Pure germline mosaicism refers to mosaicism found exclusively in the gametes and not in any somatic cells. Germline mosaicism can be caused either by a mutation that occurs after conception, or by epigenetic regulation, alterations to DNA such as methylation that do not involve changes in the DNA coding sequence.

<span class="mw-page-title-main">Parkes Weber syndrome</span> Medical condition

Parkes Weber syndrome (PWS) is a congenital disorder of the vascular system. It is an extremely rare condition, and its exact prevalence is unknown. It is named after British dermatologist Frederick Parkes Weber, who first described the syndrome in 1907.

<span class="mw-page-title-main">Macrocephaly-capillary malformation</span> Medical condition

Macrocephaly-capillary malformation (M-CM) is a multiple malformation syndrome causing abnormal body and head overgrowth and cutaneous, vascular, neurologic, and limb abnormalities. Though not every patient has all features, commonly found signs include macrocephaly, congenital macrosomia, extensive cutaneous capillary malformation, body asymmetry, polydactyly or syndactyly of the hands and feet, lax joints, doughy skin, variable developmental delay and other neurologic problems such as seizures and low muscle tone.

<span class="mw-page-title-main">Legius syndrome</span> Medical condition

Legius syndrome (LS) is an autosomal dominant condition characterized by cafe au lait spots. It was first described in 2007 and is often mistaken for neurofibromatosis type I. It is caused by mutations in the SPRED1 gene. It is also known as neurofibromatosis type 1-like syndrome.

<span class="mw-page-title-main">RAS-associated autoimmune leukoproliferative disorder</span> Medical condition

RAS-associated autoimmune leukoproliferative disorder (RALD) is a rare genetic disorder of the immune system. RALD is characterized by lymphadenopathy, splenomegaly, autoimmunity, and elevation in granulocytes and monocytes. It shares many features with autoimmune lymphoproliferative syndrome and is caused by somatic mutations in NRAS or KRAS. This was first described by investigators João Oliveira and Michael Lenardo from the National Institutes of Health.

Neu–Laxova syndrome is a rare autosomal recessive disorder characterized by severe intrauterine growth restriction and multiple congenital malformations. Neu–Laxova syndrome is a very severe disorder, leading to stillbirth or death shortly after birth. It was first described by Dr. Richard Neu in 1971 and Dr. Renata Laxova in 1972 as a lethal disorder in siblings with multiple malformations. Neu–Laxova syndrome is an extremely rare disorder with less than 100 cases reported in medical literature.

SYNGAP1-related intellectual disability is a monogenetic developmental and epileptic encephalopathy that affects the central nervous system. Symptoms include intellectual disability, epilepsy, autism, sensory processing deficits, hypotonia and unstable gait.

References

  1. 1 2 3 Rauen KA (2022). "Defining RASopathy". Disease Models & Mechanisms. 15 (2). doi:10.1242/dmm.049344. PMC   8821523 . PMID   35103797.
  2. 1 2 Tidyman WE, Rauen KA (2016). "Pathogenetics of the RASopathies". Human Molecular Genetics. 25 (R2): R123–R132. doi:10.1093/hmg/ddw191. PMC   6283265 . PMID   27412009.
  3. Riller Q, Rieux-Laucat F (2021). "RASopathies: From germline mutations to somatic and multigenic diseases". Biomedical Journal. 44 (4): 422–432. doi:10.1016/j.bj.2021.06.004. PMC   8514848 . PMID   34175492.
  4. Dunnett-Kane V, Burkitt-Wright E, Blackhall FH, Malliri A, Evans DG, Lindsay CR (2020). "Germline and sporadic cancers driven by the RAS pathway: parallels and contrasts". Annals of Oncology. 31 (7): 873–883. doi:10.1016/j.annonc.2020.03.291. PMC   7322396 . PMID   32240795.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. Rai B, Naylor PE, Siqueiros-Sanchez M, Wintermark M, Raman MM, Jo B; et al. (2023). "Novel effects of Ras-MAPK pathogenic variants on the developing human brain and their link to gene expression and inhibition abilities". Translational Psychiatry. 13 (1): 245. doi:10.1038/s41398-023-02504-4. PMC   10322993 . PMID   37407569.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. Zenker M (2022). "Clinical overview on RASopathies". American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 190 (4): 414–424. doi: 10.1002/ajmg.c.32015 . PMID   36428239.
  7. Aoki Y, Niihori T, Inoue S, Matsubara Y (2016). "Recent advances in RASopathies". Journal of Human Genetics. 61 (1): 33–9. doi:10.1038/jhg.2015.114. PMID   26446362.{{cite journal}}: CS1 maint: multiple names: authors list (link)