Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome

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.

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.

Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan

Tetsuya Niihori, Yoko Aoki, Yoko Narumi, Kumi Kato, Shigeo Kure & Yoichi Matsubara

Università Cattolica, Istituto di Genetica Medica, Rome, Italy

Department of Genetics, Hôpital Robert Debré (APHP), Paris, France

Department of Planning and Research, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka, Japan

Clinical and Molecular Genetics Unit, Institute of Child Health, London, UK

Department of Pediatrics, Academic Medical Center, Amsterdam, The Netherlands

Institut für Humangenetik, Universität Essen, Essen, Germany

Medical Genetics Center, Federal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil

Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama, Japan

Division of Medical Genetics, Saitama Children's Medical Center, Saitama, Japan

Genetic Department, Pitie-Salpetriere University Hospital, Paris, France

Dipartimento di Scienze Pediatriche Mediche e Chirurgiche, Unità Operativa Complessa Patologia Neonatale e Terapia Intensiva, Azienda Ospedaliera Universitaria G. Martino, Messina, Italy

Department of Medical Genetics, University of the Ryukyus School of Medicine, Okinawa, Japan

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokahama, Japan

Comprehensive Research and Education Center for Planning of Drug Development and Clinical Evaluation, 21st Century COE Program, Tohoku University, Sendai, Japan

KRAS gene mutations identified in CFC syndrome. (PDF 762 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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