Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: Molecular diversity and associated phenotypic spectrum

✍ Scribed by Anna Sarkozy; Claudio Carta; Sonia Moretti; Giuseppe Zampino; Maria C. Digilio; Francesca Pantaleoni; Anna Paola Scioletti; Giorgia Esposito; Viviana Cordeddu; Francesca Lepri; Valentina Petrangeli; Maria L. Dentici; Grazia M.S. Mancini; Angelo Selicorni; Cesare Rossi; Laura Mazzanti; Bruno Marino; Giovanni B. Ferrero; Margherita Cirillo Silengo; Luigi Memo; Franco Stanzial; Francesca Faravelli; Liborio Stuppia; Efisio Puxeddu; Bruce D. Gelb; Bruno Dallapiccola; Marco Tartaglia

• Publisher: John Wiley and Sons
• Year: 2009
• Tongue: English
• Weight: 289 KB
• Volume: 30
• Category: Article
• ISSN: 1059-7794
• DOI: 10.1002/humu.20955

✦ Synopsis

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 5 270), LS (N 5 6), and CFCS (N 5 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.