Cardio-facio-cutaneous (CFC) syndrome is characterized by a distinctive facial appearance, heart defects and mental retardation. It phenotypically overlaps with Noonan and Costello syndrome, which are caused by mutations in PTPN11 and HRAS, respectively. In 43 individuals with CFC, we identified two heterozygous KRAS mutations in three individuals and eight BRAF mutations in 16 individuals, suggesting that dysregulation of the RAS-RAF-ERK pathway is a common molecular basis for the three related disorders.
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We wish to thank the individuals and their families who participated in this study and the doctors who referred the cases. The support of CFC International in facilitating the collection of patient samples is gratefully acknowledged. We are grateful to J. Miyazaki, Osaka University, for supplying the pCAGGS expression vector. This work was supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan and Grants-in-Aid from the Ministry of Health, Labor, and Welfare of Japan.
The authors declare no competing financial interests.
KRAS gene mutations identified in CFC syndrome. (PDF 762 kb)
BRAF mutations in five families. (PDF 522 kb)
Stimulation of ELK transcription in KRAS and BRAF mutations. (PDF 28 kb)
Crystal structure of the BRAF kinase domain and mutations identified in individuals with CFC. (PDF 988 kb)
Summary of clinical features of individuals with CFC with mutations. (PDF 39 kb)
Comparison between individuals with KRAS and BRAF mutations with respect to clinical manifestations. (PDF 56 kb)
Clinical features of 19 CFC individuals with mutations. (PDF 112 kb)
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Niihori, T., Aoki, Y., Narumi, Y. et al. Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. Nat Genet 38, 294–296 (2006). https://doi.org/10.1038/ng1749
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