Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: Molecular diversity and associated phenotypic spectrum
Open accessAbstract
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.
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BRAF is implicated in Noonan, Leopard, and Cardiofaciocutaneous syndromes, with typical symptoms including prominent forehead, bitemporal narrowing, hypertelorism, short stature, and other skeletal, cardiac, and craniofacial anomalies, frequently accompanied by moderate to severe mental retardation.
“BRAF is implicated in Noonan, Leopard, and Cardiofaciocutaneous syndromes, typical symptoms of which include prominent forehead, bitemporal narrowing, hypertelorism, and short stature, among other skeletal, cardiac, and craniofacial anomalies, frequently accompanied by moderate to severe mental retardation [72, 73].”
From Self-domestication in Homo sapiens: Insights from comparative genomics (2017) · cites this paper as [73]
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- Sarkozy A Digilio MC Zampino G Dallapiccola B Tartaglia M Gelb BD 2009 LEOPARD syndrome: clinical aspects and molecular pathogenesis Zenker M Monographs in Human Genetics - Vol. 17. Noonan syndrome and related disorders: A matter of deregulated RAS signaling Basel Karger Press 55 65
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- Authors
- Sarkozy, A., Carta, C., Moretti, S., Zampino, G., Digilio, M. C., Pantaleoni, F., Scioletti, A. P., Esposito, G., Cordeddu, V., Lepri, F., Petrangeli, V., Dentici, M. L., Mancini, G. M. S., Selicorni, A., Rossi, C., Mazzanti, L., Marino, B., Ferrero, G. B., Silengo, M. C., Memo, L., Stanzial, F., Faravelli, F., Stuppia, L., Puxeddu, E., Gelb, B. D., Dallapiccola, B., & Tartaglia, M.
- Affiliations
- Istituto Superiore di Sanità (IT)
- University of Perugia (IT)
- Università Cattolica del Sacro Cuore (IT)
- Bambino Gesù Children's Hospital (IT)
- University of Chieti-Pescara (IT)
- Casa Sollievo della Sofferenza (IT)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Erasmus MC (NL)
- IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola (IT)
- Policlinico Umberto I (IT)
- University of Turin (IT)
- Ospedale Policlinico San Martino (IT)
- Ospedale di Bolzano (IT)
- Ente Ospedaliero Ospedali Galliera (IT)
- Icahn School of Medicine at Mount Sinai (US)
- ORCID
- Carta, Claudio
- Zampino, Giuseppe
- Digilio, Maria C.
- Pantaleoni, Francesca
- Cordeddu, Viviana
- Lepri, Francesca
- Dentici, Maria L.
- Mancini, Grazia M.S.
- Selicorni, Angelo
- Rossi, Cesare
- Mazzanti, Laura
- Marino, Bruno
- Ferrero, Giovanni B.
- Silengo, Margherita Cirillo
- Memo, Luigi
- Stanzial, Franco
- Stuppia, Liborio
- Puxeddu, Efisio
- Gelb, Bruce D.
- Dallapiccola, Bruno
- Tartaglia, Marco
- Venue
- Human Mutation
- Publisher
- Wiley
- Published
- 2009-04
- Volume
- 30
- Issue
- 4
- Pages
- 695-702
- ISSN
- 1059-7794 (ISSN-L)
- 1098-1004
- PMC
- PMC4028130
- OpenAlex
- W1972449266
- Cited by
- 303
- References
- 53
- Citations by year
- 2026: 11 · 2025: 10 · 2024: 28 · 2023: 9 · 2022: 15 · 2021: 19 · 2020: 11 · 2019: 19 · 2018: 19 · 2017: 26 · 2016: 16 · 2015: 20 · 2014: 20 · 2013: 14 · 2012: 19
- FWCI
- 8.87
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Human Mutation (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- Funders
- National Institutes of Health (5p50hl074728-05)
- National Heart, Lung, and Blood Institute (HL 074728, HL 71207, P50-HL074728, R01HL071207)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD01294, K24HD001294)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- Noonan syndrome, LEOPARD syndrome, cardiofaciocutaneous syndrome, RAS/MAPK pathway, phenotypic spectrum, de novo missense variant, gain-of-function, allele-specific effects, genotype-phenotype correlation, developmental disorders
- MeSH terms
- Abnormalities, Multiple, Face, Female, Gene Frequency, Genotype, Heart Defects, Congenital, Humans, Male, Noonan Syndrome, Phenotype, Skin Abnormalities, Genetic Variation, Cohort Studies, Germ-Line Mutation, Mutation, Missense, LEOPARD Syndrome, Proto-Oncogene Proteins B-raf
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