Current Genetic Medicine Reports

, Volume 4, Issue 3, pp 57–64 | Cite as

Expansion of the RASopathies

  • William E. Tidyman
  • Katherine A. RauenEmail author
Clinical Genetics (J Stoler, Section editor)
Part of the following topical collections:
  1. Clinical Genetics


Purpose of Review

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.

Recent Findings

New genes have been identified and include RIT1, SOS2, RASA2, RRAS and SYNGAP1, that likely represent new, albeit rare, causative RASopathy genes. In addition, A2ML1, LZTR1, MYST4, SPRY1 and MAP3K8 may represent new rare genes for RASopathies, but, additional functional studies regarding the mutations are warranted. In addition, recent reports have demonstrated that chromosomal copy number variation in regions encompassing Ras/MAPK pathway genes may be a novel pathogenetic mechanism expanding the RASopathies.


The identification of potential new genes and chromosomal copy number variation being associated with the RASopathies is very exciting and broadens our understanding of the biology of Ras signaling and the RASopathies.


Noonan syndrome RASopathy Ras/MAPK pathway RIT1 Signal transduction SYNGAP MAP3K8 



The authors thank patients and families for their ongoing support of research in Genomic Medicine. This work was supported in part by NIH Grant HD048502 (K.A.R.).

Compliance with Ethical Guidelines


William E. Tidyman and Katherine A. Rauen declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently are highlighted as: • Of importance

  1. 1.
    • Rauen KA. The RASopathies. Annu Rev Genomics Hum Genet. 2013;14:355–69. This is a current review of the RASopathies including phenotypic features and genetics. Google Scholar
  2. 2.
    Wallace MR, et al. Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science. 1990;249(4965):181–6.CrossRefPubMedGoogle Scholar
  3. 3.
    Cawthon RM, et al. Identification and characterization of transcripts from the neurofibromatosis 1 region: the sequence and genomic structure of EVI2 and mapping of other transcripts. Genomics. 1990;7(4):555–65.CrossRefPubMedGoogle Scholar
  4. 4.
    Viskochil D, et al. Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. Cell. 1990;62(1):187–92.CrossRefPubMedGoogle Scholar
  5. 5.
    Tartaglia M, et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001;29(4):465–8.CrossRefPubMedGoogle Scholar
  6. 6.
    Roberts AE, et al. Germline gain-of-function mutations in SOS1 cause Noonan syndrome. Nat Genet. 2007;39(1):70–4.CrossRefPubMedGoogle Scholar
  7. 7.
    Tartaglia M, et al. Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nat Genet. 2007;39(1):75–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Razzaque MA, et al. Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Nat Genet. 2007;39(8):1013–7.CrossRefPubMedGoogle Scholar
  9. 9.
    Pandit B, et al. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet. 2007;39(8):1007–12.CrossRefPubMedGoogle Scholar
  10. 10.
    Schubbert S, et al. Germline KRAS mutations cause Noonan syndrome. Nat Genet. 2006;38(3):331–6.CrossRefPubMedGoogle Scholar
  11. 11.
    Cirstea IC, et al. A restricted spectrum of NRAS mutations causes Noonan syndrome. Nat Genet. 2010;42(1):27–9.CrossRefPubMedGoogle Scholar
  12. 12.
    Cordeddu V, et al. Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair. Nat Genet. 2009;41(9):1022–6.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Niemeyer CM, et al. Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nat Genet. 2010;42(9):794–800.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Martinelli S, et al. Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype. Am J Hum Genet. 2010;87(2):250–7.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Digilio MC, et al. Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. Am J Hum Genet. 2002;71(2):389–94.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Brems H, et al. Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. Nat Genet. 2007;39(9):1120–6.CrossRefPubMedGoogle Scholar
  17. 17.
    Aoki Y, et al. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet. 2005;37(10):1038–40.CrossRefPubMedGoogle Scholar
  18. 18.
    Niihori T, et al. Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. Nat Genet. 2006;38(3):294–6.CrossRefPubMedGoogle Scholar
  19. 19.
    Rodriguez-Viciana P, et al. Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome. Science. 2006;311(5765):1287–90.CrossRefPubMedGoogle Scholar
  20. 20.
    Eerola I, et al. Capillary malformation-arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations. Am J Hum Genet. 2003;73(6):1240–9.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Rajalingam K, et al. Ras oncogenes and their downstream targets. Biochim Biophys Acta. 2007;1773(8):1177–95.CrossRefPubMedGoogle Scholar
  22. 22.
    Yoon S, Seger R. The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions. Growth Factors. 2006;24(1):21–44.CrossRefPubMedGoogle Scholar
  23. 23.
    Marin TM, et al. Rapamycin reverses hypertrophic cardiomyopathy in a mouse model of LEOPARD syndrome-associated PTPN11 mutation. J Clin Invest. 2011;121(3):1026–43.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Chen PC, et al. Activation of multiple signaling pathways causes developmental defects in mice with a Noonan syndrome-associated Sos1 mutation. J Clin Invest. 2010;120(12):4353–65.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Aoki Y, et al. Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome. Am J Hum Genet. 2013;93(1):173–80.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Rusyn EV, et al. Rit, a non-lipid-modified Ras-related protein, transforms NIH3T3 cells without activating the ERK, JNK, p38 MAPK or PI3K/Akt pathways. Oncogene. 2000;19(41):4685–94.CrossRefPubMedGoogle Scholar
  27. 27.
    Bertola DR, et al. Further evidence of the importance of RIT1 in Noonan syndrome. Am J Med Genet A. 2014;164A(11):2952–7.CrossRefPubMedGoogle Scholar
  28. 28.
    Gos M, et al. Contribution of RIT1 mutations to the pathogenesis of Noonan syndrome: four new cases and further evidence of heterogeneity. Am J Med Genet A. 2014;164A(9):2310–6.CrossRefPubMedGoogle Scholar
  29. 29.
    • Chen PC, et al. Next-generation sequencing identifies rare variants associated with Noonan syndrome. Proc Natl Acad Sci USA. 2014;111(31):11473–8. This is a very comprehensive study using whole-exome-sequencing and gene targeted sequencing to discover new genes associated with the RASopathies. Google Scholar
  30. 30.
    Shi GX, Andres DA. Rit contributes to nerve growth factor-induced neuronal differentiation via activation of B-Raf-extracellular signal-regulated kinase and p38 mitogen-activated protein kinase cascades. Mol Cell Biol. 2005;25(2):830–46.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Yamamoto GL, et al. Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome. J Med Genet. 2015;52(6):413–21.CrossRefPubMedGoogle Scholar
  32. 32.
    Cordeddu V, et al. Activating mutations affecting the Dbl homology domain of SOS2 cause Noonan syndrome. Hum Mutat. 2015;36(11):1080–7.CrossRefPubMedGoogle Scholar
  33. 33.
    Viskochil D. Genetics of neurofibromatosis 1 and the NF1 gene. J Child Neurol. 2002;17(8):562–70 discussion 571–2, 646–51.CrossRefPubMedGoogle Scholar
  34. 34.
    Arafeh R, et al. Recurrent inactivating RASA2 mutations in melanoma. Nat Genet. 2015;47(12):1408–10.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Flex E, et al. Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis. Hum Mol Genet. 2014;23(16):4315–27.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D. RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer. 2011;11(11):761–74.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    • Jeyabalan N, Clement JP. SYNGAP1: mind the gap. Front Cell Neurosci. 2016;10:32. This is a current through review on the RasGAP protein SynGAP. Google Scholar
  38. 38.
    Hamdan FF, et al. Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation. N Engl J Med. 2009;360(6):599–605.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Hamdan FF, et al. De novo SYNGAP1 mutations in nonsyndromic intellectual disability and autism. Biol Psychiatry. 2011;69(9):898–901.CrossRefPubMedGoogle Scholar
  40. 40.
    Komiyama NH, et al. SynGAP regulates ERK/MAPK signaling, synaptic plasticity, and learning in the complex with postsynaptic density 95 and NMDA receptor. J Neurosci. 2002;22(22):9721–32.PubMedGoogle Scholar
  41. 41.
    Muhia M, et al. Disruption of hippocampus-regulated behavioural and cognitive processes by heterozygous constitutive deletion of SynGAP. Eur J Neurosci. 2010;31(3):529–43.CrossRefPubMedGoogle Scholar
  42. 42.
    Vissers LE, et al. Heterozygous germline mutations in A2ML1 are associated with a disorder clinically related to Noonan syndrome. Eur J Hum Genet. 2015;23(3):317–24.CrossRefPubMedGoogle Scholar
  43. 43.
    Galliano MF, et al. A novel protease inhibitor of the alpha2-macroglobulin family expressed in the human epidermis. J Biol Chem. 2006;281(9):5780–9.CrossRefPubMedGoogle Scholar
  44. 44.
    Schepens I, et al. The protease inhibitor alpha-2-macroglobulin-like-1 is the p170 antigen recognized by paraneoplastic pemphigus autoantibodies in human. PLoS One. 2010;5(8):e12250.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    van Trier DC, et al. External ear anomalies and hearing impairment in Noonan Syndrome. Int J Pediatr Otorhinolaryngol. 2015;79(6):874–8.CrossRefPubMedGoogle Scholar
  46. 46.
    Barnes H, et al. Tyrosine-phosphorylated low density lipoprotein receptor-related protein 1 (Lrp1) associates with the adaptor protein SHC in SRC-transformed cells. J Biol Chem. 2001;276(22):19119–25.PubMedGoogle Scholar
  47. 47.
    Craig J, et al. The LDL receptor-related protein 1 (LRP1) regulates the PDGF signaling pathway by binding the protein phosphatase SHP-2 and modulating SHP-2- mediated PDGF signaling events. PLoS One. 2013;8(7):e70432.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Nacak TG, et al. The BTB-kelch protein LZTR-1 is a novel Golgi protein that is degraded upon induction of apoptosis. J Biol Chem. 2006;281(8):5065–71.CrossRefPubMedGoogle Scholar
  49. 49.
    Dhanoa BS, et al. Update on the Kelch-like (KLHL) gene family. Hum Genomics. 2013;7:13.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Piotrowski A, et al. Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas. Nat Genet. 2014;46(2):182–7.CrossRefPubMedGoogle Scholar
  51. 51.
    Kraft M, et al. Disruption of the histone acetyltransferase MYST4 leads to a Noonan syndrome-like phenotype and hyperactivated MAPK signaling in humans and mice. J Clin Invest. 2011;121(9):3479–91.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Clark AM, et al. Mutational activation of the MAP3K8 protooncogene in lung cancer. Genes Chromosomes Cancer. 2004;41(2):99–108.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Shchelochkov OA, et al. Duplication of chromosome band 12q24.11q24.23 results in apparent Noonan syndrome. Am J Med Genet A. 2008;146A(8):1042–8.CrossRefPubMedGoogle Scholar
  54. 54.
    Graham JM Jr, et al. Genomic duplication of PTPN11 is an uncommon cause of Noonan syndrome. Am J Med Genet A. 2009;149A(10):2122–8.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Geckinli BB, et al. Clinical report of a patient with de novo trisomy 12q23.1q24.33. Genet Couns. 2015;26(4):393–400.PubMedGoogle Scholar
  56. 56.
    Chen JL, et al. Rare copy number variations containing genes involved in RASopathies: deletion of SHOC2 and duplication of PTPN11. Mol Cytogenet. 2014;7:28.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Luo C, et al. Microduplication of 3p25.2 encompassing RAF1 associated with congenital heart disease suggestive of Noonan syndrome. Am J Med Genet A. 2012;158A(8):1918–23.CrossRefPubMedGoogle Scholar
  58. 58.
    Lissewski C, et al. Copy number variants including RAS pathway genes-How much RASopathy is in the phenotype? Am J Med Genet A. 2015;167A(11):2685–90.CrossRefPubMedGoogle Scholar
  59. 59.
    Yu S, Graf WD. BRAF gene deletion broadens the clinical spectrum neuro-cardio-facial-cutaneous syndromes. J Child Neurol. 2011;26(12):1593–6.CrossRefPubMedGoogle Scholar
  60. 60.
    Nowaczyk MJ, et al. Deletion of MAP2K2/MEK2: a novel mechanism for a RASopathy? Clin Genet. 2014;85(2):138–46.CrossRefPubMedGoogle Scholar
  61. 61.
    Risheg H, et al. Clinical comparison of overlapping deletions of 19p13.3. Am J Med Genet A. 2013;161A(5):1110–6.CrossRefPubMedGoogle Scholar
  62. 62.
    • Richards S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–24. This paper provides guidelines that will help standardize the criteria for the assignment of a new gene variant as being causative for a given disorder. Google Scholar

Copyright information

© Springer Science + Business Media New York 2016

Authors and Affiliations

  1. 1.Division of Behavioral and Developmental Pediatrics, Department of PediatricsUniversity of California DavisSacramentoUSA
  2. 2.UC Davis MIND InstituteSacramentoUSA
  3. 3.Division of Genomic Medicine, Department of PediatricsUniversity of California DavisSacramentoUSA

Personalised recommendations