Expansion of the RASopathies

• 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.

Wallace MR, et al. Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science. 1990;249(4965):181–6.

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.

Viskochil D, et al. Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. Cell. 1990;62(1):187–92.

Tartaglia M, et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001;29(4):465–8.

Roberts AE, et al. Germline gain-of-function mutations in SOS1 cause Noonan syndrome. Nat Genet. 2007;39(1):70–4.

Tartaglia M, et al. Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nat Genet. 2007;39(1):75–9.

Razzaque MA, et al. Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Nat Genet. 2007;39(8):1013–7.

Pandit B, et al. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet. 2007;39(8):1007–12.

Schubbert S, et al. Germline KRAS mutations cause Noonan syndrome. Nat Genet. 2006;38(3):331–6.

Cirstea IC, et al. A restricted spectrum of NRAS mutations causes Noonan syndrome. Nat Genet. 2010;42(1):27–9.

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.

Niemeyer CM, et al. Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nat Genet. 2010;42(9):794–800.

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.

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.

Brems H, et al. Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. Nat Genet. 2007;39(9):1120–6.

Aoki Y, et al. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet. 2005;37(10):1038–40.

Niihori T, et al. Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. Nat Genet. 2006;38(3):294–6.

Rodriguez-Viciana P, et al. Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome. Science. 2006;311(5765):1287–90.

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.

Rajalingam K, et al. Ras oncogenes and their downstream targets. Biochim Biophys Acta. 2007;1773(8):1177–95.

Yoon S, Seger R. The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions. Growth Factors. 2006;24(1):21–44.

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.

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.

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.

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.

Bertola DR, et al. Further evidence of the importance of RIT1 in Noonan syndrome. Am J Med Genet A. 2014;164A(11):2952–7.

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.

• 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.

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.

Yamamoto GL, et al. Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome. J Med Genet. 2015;52(6):413–21.

Cordeddu V, et al. Activating mutations affecting the Dbl homology domain of SOS2 cause Noonan syndrome. Hum Mutat. 2015;36(11):1080–7.

Viskochil D. Genetics of neurofibromatosis 1 and the NF1 gene. J Child Neurol. 2002;17(8):562–70 discussion 571–2, 646–51.

Arafeh R, et al. Recurrent inactivating RASA2 mutations in melanoma. Nat Genet. 2015;47(12):1408–10.

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.

Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D. RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer. 2011;11(11):761–74.

• 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.

Hamdan FF, et al. Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation. N Engl J Med. 2009;360(6):599–605.

Hamdan FF, et al. De novo SYNGAP1 mutations in nonsyndromic intellectual disability and autism. Biol Psychiatry. 2011;69(9):898–901.

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.

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.

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.

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.

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.

van Trier DC, et al. External ear anomalies and hearing impairment in Noonan Syndrome. Int J Pediatr Otorhinolaryngol. 2015;79(6):874–8.

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.

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.

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.

Dhanoa BS, et al. Update on the Kelch-like (KLHL) gene family. Hum Genomics. 2013;7:13.

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.

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.

Clark AM, et al. Mutational activation of the MAP3K8 protooncogene in lung cancer. Genes Chromosomes Cancer. 2004;41(2):99–108.

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.

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.

Geckinli BB, et al. Clinical report of a patient with de novo trisomy 12q23.1q24.33. Genet Couns. 2015;26(4):393–400.

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.

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.

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.

Yu S, Graf WD. BRAF gene deletion broadens the clinical spectrum neuro-cardio-facial-cutaneous syndromes. J Child Neurol. 2011;26(12):1593–6.

Nowaczyk MJ, et al. Deletion of MAP2K2/MEK2: a novel mechanism for a RASopathy? Clin Genet. 2014;85(2):138–46.

Risheg H, et al. Clinical comparison of overlapping deletions of 19p13.3. Am J Med Genet A. 2013;161A(5):1110–6.

• 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.