BRAF – Noonan syndrome with multiple lentigines

Heterozygous germline BRAF variants have been identified in a small number of individuals with Noonan syndrome with multiple lentigines (LEOPARD syndrome), an autosomal dominant RASopathy characterized by lentigines, cardiac anomalies, facial dysmorphism and other systemic features. A de novo c.735A>T (p.Leu245Phe) variant was reported in a patient with LEOPARD syndrome and normal cognition, expanding the allelic spectrum beyond PTPN11 and RAF1 (PMID:19416762). In a large BRAF screening of developmental RASopathies, one of six LEOPARD syndrome subjects carried a BRAF missense change, illustrating rare allele‐specific involvement (PMID:19206169). In a cohort of 19 LEOPARD syndrome patients, bidirectional sequencing revealed a single c.770A>G (p.Gln257Arg) substitution, confirming BRAF as a minor locus in 5% of cases and correlating with hypertrophic cardiomyopathy and other LS endophenotypes (PMID:24775816).

Functional insights from oncogenic and developmental studies implicate BRAF gain‐of‐function as a shared mechanism across RASopathies. Structural and biochemical analyses of activation‐segment mutations demonstrate enhanced MEK/ERK signaling, with the V599E cancer‐associated allele serving as a model for pathway dysregulation (PMID:12781369; PMID:12917419). Although direct assays of LEOPARD‐specific variants remain lacking, these data support a pathogenic role of BRAF missense changes in driving cardiac and cutaneous features via MAPK hyperactivation. Further studies are needed to delineate genotype–phenotype correlations and to inform diagnostic testing and targeted therapy.

Key take-home: BRAF should be considered in the molecular evaluation of LEOPARD syndrome, particularly in patients negative for PTPN11 and RAF1, with functional assays poised to clarify variant‐specific effects on MAPK signaling.

References

• European journal of medical genetics • 2009 • Novel BRAF mutation in a patient with LEOPARD syndrome and normal intelligence. PMID:19416762
• Human mutation • 2009 • Germline BRAF mutations in Noonan, LEOPARD, and cardio-faciocutaneous syndromes: molecular diversity and associated phenotypic spectrum. PMID:19206169
• Revista espanola de cardiologia (English ed.) • 2013 • LEOPARD syndrome: a variant of Noonan syndrome strongly associated with hypertrophic cardiomyopathy. PMID:24775816
• Biochimica et biophysica acta • 2003 • Raf proteins and cancer: B-Raf is identified as a mutational target. PMID:12781369
• The Journal of biological chemistry • 2003 • Mutation of B-Raf in human choroidal melanoma cells mediates cell proliferation and transformation through the MEK/ERK pathway. PMID:12917419

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