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Clinical and molecular spectra of BRAF-associated RASopathy


Noonan syndrome (NS) and cardio-facio-cutaneous (CFC) syndrome are the most common subtypes of RASopathy. As an effector of Ras, BRAF is one of the molecules responsible for RASopathy. We investigated the phenotypic and genotypic features of 26 patients with BRAF-associated RASopathy. The clinical diagnoses were CFC (n = 21, 80.8%), NS (n = 3, 11.5%), NS/CFC (n = 1, 3.8%), and undefined syndromic intellectual disability (ID) (n = 1, 3.8%). The mostly shared phenotypes were ID (90.5%), cutaneous manifestations (84.6%), congenital heart defects (76.9%), short stature (76.9%), and dysmorphic features such as short neck (65.4%) and low-set ears (65.4%). Importantly, moderate to severe ID (57.1%) and epilepsy (26.9%) were noted. Eighteen different missense mutations were found, including a novel mutation, p.Phe498Tyr. p.Gln257Arg (n = 9, 34.6%) was the most common mutation, and the mutations were clustered in the cysteine-rich domain or protein kinase domain. A review of previously reported cases along with our findings revealed the existence of multiple sub-phenotypes of RASopathy within a single genotype, indicating that BRAF-associated RASopathy is not variant-specific. Our study further delineated the diverse and expanded clinical phenotypes of BRAF-associated RASopathy with their molecular genetic characteristics.

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Fig. 1
Fig. 2
Fig. 3: BRAF protein domain structure and the location of mutations identified in the study patients.


  1. Noonan JA. Hypertelorism with Turner phenotype. A new syndrome with associated congenital heart disease. Am J Dis Child. 1968;116:373–80.

    CAS  PubMed  Article  Google Scholar 

  2. Tajan M, Paccoud R, Branka S, Edouard T, Yart A. The RASopathy family: consequences of germline activation of the RAS/MAPK pathway. Endocr Rev. 2018;39:676–700.

    PubMed  Article  Google Scholar 

  3. Niihori T, Nagai K, Fujita A, Ohashi H, Okamoto N, Okada S, et al. Germline-activating RRAS2 mutations cause noonan syndrome. Am J Hum Genet. 2019;104:1233–40.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. Rodriguez-Viciana P, Tetsu O, Tidyman WE, Estep AL, Conger BA, Cruz MS, et al. Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome. Science. 2006;311:1287–90.

    CAS  PubMed  Article  Google Scholar 

  5. Niihori T, Aoki Y, Narumi Y, Neri G, Cave H, Verloes A, et al. Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. Nat Genet. 2006;38:294–6.

    CAS  PubMed  Article  Google Scholar 

  6. Sarkozy A, Carta C, Moretti S, Zampino G, Digilio MC, Pantaleoni F, et al. Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum. Hum Mutat. 2009;30:695–702.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. Rauen KA. The RASopathies. Annu Rev Genomics Hum Genet. 2013;14:355–69.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–54.

    CAS  PubMed  Article  Google Scholar 

  9. Kim JH, Yun S, Hwang SS, Shim JO, Chae HW, Lee YJ, et al. The 2017 Korean National Growth Charts for children and adolescents: development, improvement, and prospects. Korean J Pediatr. 2018;61:135–49.

    PubMed  PubMed Central  Article  Google Scholar 

  10. Hyun SE, Lee BC, Suh BK, Chung SC, Ko CW, Kim HS, et al. Reference values for serum levels of insulin-like growth factor-I and insulin-like growth factor binding protein-3 in Korean children and adolescents. Clin Biochem. 2012;45:16–21.

    CAS  PubMed  Article  Google Scholar 

  11. Seo GH, Kim T, Choi IH, Park Jy, Lee J, Kim S, et al. Diagnostic yield and clinical utility of whole exome sequencing using an automated variant prioritization system, EVIDENCE. Clin Genet. 2020;9:1–9.

  12. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, 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;17:405–24.

    PubMed  PubMed Central  Article  Google Scholar 

  13. Lee BH, Kim JM, Jin HY, Kim GH, Choi JH, Yoo HW. Spectrum of mutations in Noonan syndrome and their correlation with phenotypes. J Pediatr. 2011;159:1029–35.

    PubMed  Article  Google Scholar 

  14. Ko JM, Kim JM, Kim GH, Yoo HW. PTPN11, SOS1, KRAS, and RAF1 gene analysis, and genotype-phenotype correlation in Korean patients with Noonan syndrome. J Hum Genet. 2008;53:999–1006.

    CAS  PubMed  Article  Google Scholar 

  15. Pierpont EI, Tworog-Dube E, Roberts AE. Attention skills and executive functioning in children with Noonan syndrome and their unaffected siblings. Dev Med Child Neurol. 2015;57:385–92.

    PubMed  Article  Google Scholar 

  16. Kim YE, Baek ST. Neurodevelopmental aspects of RASopathies. Mol Cells. 2019;42:441–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. Camarero G, Tyrsin OY, Xiang C, Pfeiffer V, Pleiser S, Wiese S, et al. Cortical migration defects in mice expressing A-RAF from the B-RAF locus. Mol Cell Biol. 2006;26:7103–15.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. Yeh E, Dao DQ, Wu ZY, Kandalam SM, Camacho FM, Tom C, et al. Patient-derived iPSCs show premature neural differentiation and neuron type-specific phenotypes relevant to neurodevelopment. Mol Psychiatry. 2018;23:1687–98.

    CAS  PubMed  Article  Google Scholar 

  19. Shaw AC, Kalidas K, Crosby AH, Jeffery S, Patton MA. The natural history of Noonan syndrome: a long-term follow-up study. Arch Dis Child. 2007;92:128–32.

    CAS  PubMed  Article  Google Scholar 

  20. Koh HY, Kim SH, Jang J, Kim H, Han S, Lim JS, et al. BRAF somatic mutation contributes to intrinsic epileptogenicity in pediatric brain tumors. Nat Med. 2018;24:1662–8.

    CAS  PubMed  Article  Google Scholar 

  21. Urosevic J, Sauzeau V, Soto-Montenegro ML, Reig S, Desco M, Wright EM, et al. Constitutive activation of B-Raf in the mouse germ line provides a model for human cardio-facio-cutaneous syndrome. Proc Natl Acad Sci USA. 2011;108:5015–20.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  22. Gripp KW, Lin AE, Nicholson L, Allen W, Cramer A, Jones KL, et al. Further delineation of the phenotype resulting from BRAF or MEK1 germline mutations helps differentiate cardio-facio-cutaneous syndrome from Costello syndrome. Am J Med Genet A. 2007;143A:1472–80.

    CAS  PubMed  Article  Google Scholar 

  23. Lepri F, De Luca A, Stella L, Rossi C, Baldassarre G, Pantaleoni F, et al. SOS1 mutations in Noonan syndrome: molecular spectrum, structural insights on pathogenic effects, and genotype-phenotype correlations. Hum Mutat. 2011;32:760–72.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. Mazzanti L, Cacciari E, Cicognani A, Bergamaschi R, Scarano E, Forabosco A. Noonan-like syndrome with loose anagen hair: a new syndrome? Am J Med Genet A. 2003;118A:279–86.

    PubMed  Article  Google Scholar 

  25. Bessis D, Miquel J, Bourrat E, Chiaverini C, Morice-Picard F, Abadie C, et al. Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation. Br J Dermatol. 2019;180:1438–48.

    CAS  PubMed  Article  Google Scholar 

  26. Jhang WK, Choi JH, Lee BH, Kim GH, Yoo HW. Cardiac manifestations and associations with gene mutations in patients diagnosed with RASopathies. Pediatr Cardiol. 2016;37:1539–47.

    PubMed  Article  Google Scholar 

  27. Allanson JE, Annerén G, Aoki Y, Armour CM, Bondeson M, Cave H, et al. Cardio‐facio‐cutaneous syndrome: does genotype predict phenotype? Am J Med Genet C Semin Med Genet. 2011;157:129–35.

    PubMed Central  Article  Google Scholar 

  28. Nava C, Hanna N, Michot C, Pereira S, Pouvreau N, Niihori T, et al. Cardio-facio-cutaneous and Noonan syndromes due to mutations in the RAS/MAPK signalling pathway: genotype-phenotype relationships and overlap with Costello syndrome. J Med Genet. 2007;44:763–71.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. Grimberg A, Cohen P. Optimizing growth hormone therapy in children. Horm Res. 1997;48 (Suppl 5):11–5.

    CAS  PubMed  Article  Google Scholar 

  30. Zeitler P, Siriwardana G. Stimulation of mitogen-activated protein kinase pathway in rat somatotrophs by growth hormone-releasing hormone. Endocrine. 2000;12:257–64.

    CAS  PubMed  Article  Google Scholar 

  31. Lee PA, Ross J, Germak JA, Gut R. Effect of 4 years of growth hormone therapy in children with Noonan syndrome in the American Norditropin Studies: Web-Enabled Research (ANSWER) Program® registry. Int J Pediatr Endocrinol. 2012;2012:15.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  32. Jeong I, Kang E, Cho JH, Kim GH, Lee BH, Choi JH, et al. Long-term efficacy of recombinant human growth hormone therapy in short-statured patients with Noonan syndrome. Ann Pediatr Endocrinol Metab. 2016;21:26–30.

    PubMed  PubMed Central  Article  Google Scholar 

  33. Celik N, Cinaz P, Bideci A, Yuce O, Emeksiz HC, Doger E, et al. Cardio-facio-cutaneous syndrome with precocious puberty, growth hormone deficiency and hyperprolactinemia. J Clin Res Pediatr Endocrinol. 2014;6:55–8.

    PubMed  PubMed Central  Article  Google Scholar 

  34. Abe Y, Aoki Y, Kuriyama S, Kawame H, Okamoto N, Kurosawa K, et al. Prevalence and clinical features of Costello syndrome and cardio-facio-cutaneous syndrome in Japan: findings from a nationwide epidemiological survey. Am J Med Genet A. 2012;158A:1083–94.

    PubMed  Article  Google Scholar 

  35. Garnett MJ, Marais R. Guilty as charged: B-RAF is a human oncogene. Cancer Cell. 2004;6:313–9.

    CAS  PubMed  Article  Google Scholar 

  36. Ohtake A, Aoki Y, Saito Y, Niihori T, Shibuya A, Kure S, et al. Non-hodgkin lymphoma in a patient with cardiofaciocutaneous syndrome. J Pediatr Hematol Oncol. 2011;33:e342–6.

    PubMed  Article  Google Scholar 

  37. Kavamura MI, Peres CA, Alchorne MM, Brunoni D. CFC index for the diagnosis of cardiofaciocutaneous syndrome. Am J Med Genet. 2002;112:12–6.

    CAS  PubMed  Article  Google Scholar 

  38. Pierpont ME, Magoulas PL, Adi S, Kavamura MI, Neri G, Noonan J, et al. Cardio-facio-cutaneous syndrome: clinical features, diagnosis, and management guidelines. Pediatrics. 2014;134:e1149–62.

    PubMed  PubMed Central  Article  Google Scholar 

  39. Yoon G, Rosenberg J, Blaser S, Rauen KA. Neurological complications of cardio-facio-cutaneous syndrome. Dev Med Child Neurol. 2007;49:894–9.

    PubMed  Article  Google Scholar 

  40. Neri G, Allanson J, Kavamura MI. No reason yet to change diagnostic criteria for Noonan, Costello and cardio-facio-cutaneous syndromes. J Med Genet. 2008;45:832.

    CAS  PubMed  Article  Google Scholar 

  41. Razzaque MA, Nishizawa T, Komoike Y, Yagi H, Furutani M, Amo R, et al. Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Nat Genet. 2007;39:1013–7.

    CAS  PubMed  Article  Google Scholar 

  42. Nystrom AM, Ekvall S, Berglund E, Bjorkqvist M, Braathen G, Duchen K, et al. Noonan and cardio-facio-cutaneous syndromes: two clinically and genetically overlapping disorders. J Med Genet. 2008;45:500–6.

    PubMed  Article  CAS  Google Scholar 

  43. Schulz AL, Albrecht B, Arici C, van der Burgt I, Buske A, Gillessen-Kaesbach G, et al. Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome. Clin Genet. 2008;73:62–70.

    CAS  PubMed  Article  Google Scholar 

  44. Dixon-Salazar TJ, Silhavy JL, Udpa N, Schroth J, Bielas S, Schaffer AE, et al. Exome sequencing can improve diagnosis and alter patient management. Sci Transl Med. 2012;4:138ra78.

    PubMed  PubMed Central  Article  Google Scholar 

  45. Lu H, Villafane N, Dogruluk T, Grzeskowiak CL, Kong K, Tsang YH, et al. Engineering and functional characterization of fusion genes identifies novel oncogenic drivers of cancer. Cancer Res. 2017;77:3502–12.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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We are deeply grateful to the patients and their families for providing their clinical information. We would like to give particular thanks to subject 21 and his family for allowing us to publish his photograph.


This work was supported by the Institute for Information and Communications Technology Promotion (IITP) and by a grant from the government of South Korea (MSIT) (Grant Number 2018-0-00861; Intelligent SW Technology Development for Medical Data Analysis) and the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (NRF-2018M3A9H1078335).

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Correspondence to Beom Hee Lee.

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Lee, Y., Choi, Y., Seo, G.H. et al. Clinical and molecular spectra of BRAF-associated RASopathy. J Hum Genet 66, 389–399 (2021).

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