G2Cdb::Human Disease report

Disease id
D00000303
Name
Cardiofaciocutaneous syndrome
Nervous system disease
yes

Genes (2)

Gene Name/Description Mutations Found Literature Mutations Type Genetic association?
G00000031 HRAS
v-Ha-ras Harvey rat sarcoma viral oncogene homolog
Y (17054105) Microinsertion (MI) N
G00001422 MAP2K1
mitogen-activated protein kinase kinase 1
Y (16439621) Microinsertion (MI) Y

References

  • Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome.

    Zampino G, Pantaleoni F, Carta C, Cobellis G, Vasta I, Neri C, Pogna EA, De Feo E, Delogu A, Sarkozy A, Atzeri F, Selicorni A, Rauen KA, Cytrynbaum CS, Weksberg R, Dallapiccola B, Ballabio A, Gelb BD, Neri G and Tartaglia M

    Istituto di Clinica Pediatrica, Università Cattolica del Sacro Cuore, Rome, Italy.

    Activating mutations in v-Ha-ras Harvey rat sarcoma viral oncogene homolog (HRAS) have recently been identified as the molecular cause underlying Costello syndrome (CS). To further investigate the phenotypic spectrum associated with germline HRAS mutations and characterize their molecular diversity, subjects with a diagnosis of CS (N = 9), Noonan syndrome (NS; N = 36), cardiofaciocutaneous syndrome (CFCS; N = 4), or with a phenotype suggestive of these conditions but without a definitive diagnosis (N = 12) were screened for the entire coding sequence of the gene. A de novo heterozygous HRAS change was detected in all the subjects diagnosed with CS, while no lesion was observed with any of the other phenotypes. While eight cases shared the recurrent c.34G>A change, a novel c.436G>A transition was observed in one individual. The latter affected residue, p.Ala146, which contributes to guanosine triphosphate (GTP)/guanosine diphosphate (GDP) binding, defining a novel class of activating HRAS lesions that perturb development. Clinical characterization indicated that p.Gly12Ser was associated with a homogeneous phenotype. By analyzing the genomic region flanking the HRAS mutations, we traced the parental origin of lesions in nine informative families and demonstrated that de novo mutations were inherited from the father in all cases. We noted an advanced age at conception in unaffected fathers transmitting the mutation.

    Funded by: NHLBI NIH HHS: HL71207; NICHD NIH HHS: HD01294, HD048502; Telethon: GGP04172

    Human mutation 2007;28;3;265-72

  • Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome.

    Rodriguez-Viciana P, Tetsu O, Tidyman WE, Estep AL, Conger BA, Cruz MS, McCormick F and Rauen KA

    Comprehensive Cancer Center and Cancer Research Institute, University of California, San Francisco, CA 94115, USA.

    Cardio-facio-cutaneous (CFC) syndrome is a sporadic developmental disorder involving characteristic craniofacial features, cardiac defects, ectodermal abnormalities, and developmental delay. We demonstrate that heterogeneous de novo missense mutations in three genes within the mitogen-activated protein kinase (MAPK) pathway cause CFC syndrome. The majority of cases (18 out of 23) are caused by mutations in BRAF, a gene frequently mutated in cancer. Of the 11 mutations identified, two result in amino acid substitutions that occur in tumors, but most are unique and suggest previously unknown mechanisms of B-Raf activation. Furthermore, three of five individuals without BRAF mutations had missense mutations in either MEK1 or MEK2, downstream effectors of B-Raf. Our findings highlight the involvement of the MAPK pathway in human development and will provide a molecular diagnosis of CFC syndrome.

    Funded by: NICHD NIH HHS: HD048502

    Science (New York, N.Y.) 2006;311;5765;1287-90

Literature (2)

Pubmed - other

  • Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome.

    Zampino G, Pantaleoni F, Carta C, Cobellis G, Vasta I, Neri C, Pogna EA, De Feo E, Delogu A, Sarkozy A, Atzeri F, Selicorni A, Rauen KA, Cytrynbaum CS, Weksberg R, Dallapiccola B, Ballabio A, Gelb BD, Neri G and Tartaglia M

    Istituto di Clinica Pediatrica, Università Cattolica del Sacro Cuore, Rome, Italy.

    Activating mutations in v-Ha-ras Harvey rat sarcoma viral oncogene homolog (HRAS) have recently been identified as the molecular cause underlying Costello syndrome (CS). To further investigate the phenotypic spectrum associated with germline HRAS mutations and characterize their molecular diversity, subjects with a diagnosis of CS (N = 9), Noonan syndrome (NS; N = 36), cardiofaciocutaneous syndrome (CFCS; N = 4), or with a phenotype suggestive of these conditions but without a definitive diagnosis (N = 12) were screened for the entire coding sequence of the gene. A de novo heterozygous HRAS change was detected in all the subjects diagnosed with CS, while no lesion was observed with any of the other phenotypes. While eight cases shared the recurrent c.34G>A change, a novel c.436G>A transition was observed in one individual. The latter affected residue, p.Ala146, which contributes to guanosine triphosphate (GTP)/guanosine diphosphate (GDP) binding, defining a novel class of activating HRAS lesions that perturb development. Clinical characterization indicated that p.Gly12Ser was associated with a homogeneous phenotype. By analyzing the genomic region flanking the HRAS mutations, we traced the parental origin of lesions in nine informative families and demonstrated that de novo mutations were inherited from the father in all cases. We noted an advanced age at conception in unaffected fathers transmitting the mutation.

    Funded by: NHLBI NIH HHS: HL71207; NICHD NIH HHS: HD01294, HD048502; Telethon: GGP04172

    Human mutation 2007;28;3;265-72

  • Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome.

    Rodriguez-Viciana P, Tetsu O, Tidyman WE, Estep AL, Conger BA, Cruz MS, McCormick F and Rauen KA

    Comprehensive Cancer Center and Cancer Research Institute, University of California, San Francisco, CA 94115, USA.

    Cardio-facio-cutaneous (CFC) syndrome is a sporadic developmental disorder involving characteristic craniofacial features, cardiac defects, ectodermal abnormalities, and developmental delay. We demonstrate that heterogeneous de novo missense mutations in three genes within the mitogen-activated protein kinase (MAPK) pathway cause CFC syndrome. The majority of cases (18 out of 23) are caused by mutations in BRAF, a gene frequently mutated in cancer. Of the 11 mutations identified, two result in amino acid substitutions that occur in tumors, but most are unique and suggest previously unknown mechanisms of B-Raf activation. Furthermore, three of five individuals without BRAF mutations had missense mutations in either MEK1 or MEK2, downstream effectors of B-Raf. Our findings highlight the involvement of the MAPK pathway in human development and will provide a molecular diagnosis of CFC syndrome.

    Funded by: NICHD NIH HHS: HD048502

    Science (New York, N.Y.) 2006;311;5765;1287-90

© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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