Clinical manifestations in patients with SOS1 mutations range from Noonan syndrome to CFC syndrome

Yoko Narumi, Yoko Aoki, Tetsuya Niihori, Masahiro Sakurai, Hélène Cavé, Alain Verloes, Kimio Nishio, Hirofumi Ohashi, Kenji Kurosawa, Nobuhiko Okamoto, Hiroshi Kawame, Seiji Mizuno, Tatsuro Kondoh, Marie Claude Addor, Anne Coeslier-Dieux, Catherine Vincent-Delorme, Koichi Tabayashi, Masashi Aoki, Tomoko Kobayashi, Afag GuliyevaShigeo Kure, Yoichi Matsubara

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29 Citations (Scopus)


Noonan syndrome (NS) and cardio-facio-cutaneous (CFC) syndrome are autosomal dominant disorders characterized by heart defects, facial dysmorphism, ectodermal abnormalities, and mental retardation. There is a significant clinical overlap between NS and CFC syndrome, but ectodermal abnormalities and mental retardation are more frequent in CFC syndrome. Mutations in PTPN11 and KRAS have been identified in patients with NS and those in KRAS, BRAF and MAP2K1/2 have been identified in patients with CFC syndrome, establishing a new role of the RAS/MAPK pathway in human development. Recently, mutations in the son of sevenless gene (SOS1) have also been identified in patients with NS. To clarify the clinical spectrum of patients with SOS1 mutations, we analyzed 24 patients with NS, including 3 patients in a three-generation family, and 30 patients with CFC syndrome without PTPN11, KRAS, HRAS, BRAF, and MAP2K1/2 (MEK1/2) mutations. We identified two SOS1 mutations in four NS patients, including three patients in the above-mentioned three-generation family. In the patients with a CFC phenotype, three mutations, including a novel three amino-acid insertion, were identified in one CFC patient and two patients with both NS and CFC phenotypes. These three patients exhibited ectodermal abnormalities, such as curly hair, sparse eyebrows, and dry skin, and two of them showed mental retardation. Our results suggest that patients with SOS1 mutations range from NS to CFC syndrome.

Original languageEnglish
Pages (from-to)834-841
Number of pages8
JournalJournal of Human Genetics
Issue number9
Publication statusPublished - 2008 Sept


  • Cardio-facio-cutaneous syndrome
  • Noonan syndrome
  • PTPN11
  • RAF
  • RAS


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