BRAF – Noonan Syndrome

Noonan syndrome is an autosomal dominant RASopathy characterized by facial dysmorphism, congenital heart defects, and short stature. While PTPN11 and SOS1 are the most common genes implicated, germline mutations in BRAF (HGNC:1097) have been reported in a small subset of Noonan syndrome patients, expanding the allelic spectrum of this disorder. BRAF encodes a serine/threonine kinase acting downstream of RAS in the MAPK pathway, and its hyperactivation is a known driver in other RASopathies and cancers. Evidence from genetic and functional studies supports a disease‐causing role for specific BRAF variants in Noonan syndrome. Clinically, recognition of BRAF‐associated Noonan syndrome has implications for molecular testing, genetic counseling, and potential targeted therapy.

Clinical Validity (Moderate)

Germline BRAF mutations have been identified in six unrelated Noonan syndrome probands, all occurring de novo and absent in healthy parents, consistent with an autosomal dominant mechanism. In a cohort of 270 mutation‐negative Noonan syndrome cases, five individuals carried heterozygous BRAF missense variants (PMID:19206169). An additional patient with LEOPARD syndrome features and preserved cognition harbored a de novo BRAF c.735A>T (p.Leu245Phe) variant (PMID:19416762). A single patient diagnosed clinically with Noonan syndrome was found to carry BRAF c.1495A>G (p.Lys499Glu) in a comprehensive multisyndrome study (PMID:18456719). These six probands, each with a distinct missense change, provide moderate genetic evidence for BRAF–Noonan syndrome association.

Genetic Evidence (Moderate)

Inheritance is autosomal dominant with complete absence of the variant in parental DNA for all reported cases. A total of six probands have been reported: five from a large screening of Noonan syndrome patients and one additional LEOPARD syndrome case with NS features. Variant spectrum includes five unique missense alterations—c.735A>T (p.Leu245Phe), c.1495A>G (p.Lys499Glu), and others—each predicted to alter kinase function. No familial segregation beyond de novo occurrence has been described. The absence of BRAF mutations in >265 other Noonan syndrome patients underscores the rarity but specificity of these alleles.

Functional Evidence (Moderate)

Biochemical assays of germline BRAF mutants demonstrate gain‐of‐function activity, with increased MEK and ERK phosphorylation versus wild‐type BRAF. Selected NS‐associated BRAF proteins exhibit variable but reproducible kinase activation in vitro, matching the pathogenic mechanism seen in cardio‐faciocutaneous syndrome but with distinct allele specificity (PMID:19206169). These functional data concordantly support the role of BRAF missense variants in dysregulated MAPK signaling underlying Noonan syndrome phenotypes.

Conflicting Evidence / Limitations

BRAF mutations account for approximately 1.9% of Noonan syndrome cases, making them a minor contributor to disease. No reports have refuted the association, but the low frequency and lack of multi‐generation segregation data limit the strength of evidence. Additional studies are needed to fully define penetrance and expressivity of BRAF variants in Noonan syndrome.

Integration & Clinical Utility

Collectively, de novo germline BRAF missense variants, coupled with functional kinase activation, substantiate a moderate level of clinical validity for BRAF in Noonan syndrome. Inclusion of BRAF in diagnostic gene panels enables molecular confirmation in atypical or PTPN11/SOS1‐negative Noonan syndrome patients. Recognition of BRAF‐associated Noonan syndrome supports accurate genetic counseling and may inform future targeted therapeutic approaches.

Key Take-home: Germline BRAF gain‐of‐function missense variants cause a rare, autosomal dominant form of Noonan syndrome with typical RASopathy features, warranting inclusion in diagnostic and counseling protocols.

References

• European journal of medical genetics • 2009 • Novel BRAF mutation in a patient with LEOPARD syndrome and normal intelligence PMID:19416762
• Journal of medical genetics • 2008 • Noonan and cardio-facio-cutaneous syndromes: two clinically and genetically overlapping disorders PMID:18456719
• Human mutation • 2009 • Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum PMID:19206169

Evidence Based Scoring (AI generated)