title: Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum.
abstract: Noonan, LEOPARD, and cardiofaciocutaneous syndromes (NS, LS, and CFCS) are developmental disorders with overlapping features including distinctive facial dysmorphia, reduced growth, cardiac defects, skeletal and ectodermal anomalies, and variable cognitive deficits. Dysregulated RAS-mitogen-activated protein kinase (MAPK) signal traffic has been established to represent the molecular pathogenic cause underlying these conditions. To investigate the phenotypic spectrum and molecular diversity of germline mutations affecting BRAF, which encodes a serine/threonine kinase functioning as a RAS effector frequently mutated in CFCS, subjects with a diagnosis of NS (N=270), LS (N=6), and CFCS (N=33), and no mutation in PTPN11, SOS1, KRAS, RAF1, MEK1, or MEK2, were screened for the entire coding sequence of the gene. Besides the expected high prevalence of mutations observed among CFCS patients (52%), a de novo heterozygous missense change was identified in one subject with LS (17%) and five individuals with NS (1.9%). Mutations mapped to multiple protein domains and largely did not overlap with cancer-associated defects. NS-causing mutations had not been documented in CFCS, suggesting that the phenotypes arising from germline BRAF defects might be allele specific. Selected mutant BRAF proteins promoted variable gain of function of the kinase, but appeared less activating compared to the recurrent cancer-associated p.Val600Glu mutant. Our findings provide evidence for a wide phenotypic diversity associated with mutations affecting BRAF, and occurrence of a clinical continuum associated with these molecular lesions.
authors.affiliation: IRCCS, San Giovanni Rotondo, Dipartimento di Medicina Sperimentale e Patologia, Università La Sapienza, Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Sarkozy
authors.forename: Claudio
authors.initials: C
authors.lastname: Carta
authors.forename: Sonia
authors.initials: S
authors.lastname: Moretti
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zampino
authors.forename: Maria C
authors.initials: MC
authors.lastname: Digilio
authors.forename: Francesca
authors.initials: F
authors.lastname: Pantaleoni
authors.forename: Anna Paola
authors.initials: AP
authors.lastname: Scioletti
authors.forename: Giorgia
authors.initials: G
authors.lastname: Esposito
authors.forename: Viviana
authors.initials: V
authors.lastname: Cordeddu
authors.forename: Francesca
authors.initials: F
authors.lastname: Lepri
authors.forename: Valentina
authors.initials: V
authors.lastname: Petrangeli
authors.forename: Maria L
authors.initials: ML
authors.lastname: Dentici
authors.forename: Grazia M S
authors.initials: GM
authors.lastname: Mancini
authors.forename: Angelo
authors.initials: A
authors.lastname: Selicorni
authors.forename: Cesare
authors.initials: C
authors.lastname: Rossi
authors.forename: Laura
authors.initials: L
authors.lastname: Mazzanti
authors.forename: Bruno
authors.initials: B
authors.lastname: Marino
authors.forename: Giovanni B
authors.initials: GB
authors.lastname: Ferrero
authors.forename: Margherita Cirillo
authors.initials: MC
authors.lastname: Silengo
authors.forename: Luigi
authors.initials: L
authors.lastname: Memo
authors.forename: Franco
authors.initials: F
authors.lastname: Stanzial
authors.forename: Francesca
authors.initials: F
authors.lastname: Faravelli
authors.forename: Liborio
authors.initials: L
authors.lastname: Stuppia
authors.forename: Efisio
authors.initials: E
authors.lastname: Puxeddu
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Gelb
authors.forename: Bruno
authors.initials: B
authors.lastname: Dallapiccola
authors.forename: Marco
authors.initials: M
authors.lastname: Tartaglia
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D015331:Cohort Studies; D005145:Face / Q000002:abnormalities; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D018095:Germ-Line Mutation; D006330:Heart Defects, Congenital / Q000473:pathology; D006801:Humans; D044542:LEOPARD Syndrome / Q000235:genetics* / Q000473:pathology; D008297:Male; D020125:Mutation, Missense; D009634:Noonan Syndrome / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012868:Skin Abnormalities
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf