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BRAF – Costello syndrome

Comprehensive mutation screening in 31 HRAS-negative individuals meeting clinical criteria for Costello syndrome failed to identify any germline BRAF pathogenic variants, indicating that BRAF does not contribute to true CS etiology (Clinical genetics • 2008 • Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome. PMID:18042262). A solitary report of a de novo BRAF c.1741A>G (p.Asn581Asp) variant in a patient initially labelled as CS was subsequently recognized as cardio-facio-cutaneous syndrome, reflecting phenotypic overlap and diagnostic misclassification rather than a bona fide BRAF–CS association (Genetic counseling (Geneva, Switzerland) • 2012 • A cardio-facio-cutaneous syndrome case with tight Achilles tendons. PMID:22876591).

In vitro assays confirm that germline BRAF mutations hyperactivate the RAF-MEK-ERK cascade, yet the resulting clinical spectrum aligns with cardio-facio-cutaneous syndrome and diverges from HRAS-driven Costello syndrome, as evidenced by distinct features such as polyhydramnios frequency, growth hormone deficiency, and tumor type (American journal of medical genetics. Part A • 2007 • Further delineation of the phenotype resulting from BRAF or MEK1 germline mutations helps differentiate cardio-facio-cutaneous syndrome from Costello syndrome. PMID:17551924). These findings support a limited clinical validity for a BRAF–Costello syndrome relationship.

Key take-home: HRAS remains the primary diagnostic gene for Costello syndrome; BRAF testing should focus on cardio-facio-cutaneous syndrome.

References

  • Clinical genetics • 2008 • Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome. PMID:18042262
  • American journal of medical genetics. Part A • 2007 • Further delineation of the phenotype resulting from BRAF or MEK1 germline mutations helps differentiate cardio-facio-cutaneous syndrome from Costello syndrome. PMID:17551924
  • Genetic counseling (Geneva, Switzerland) • 2012 • A cardio-facio-cutaneous syndrome case with tight Achilles tendons. PMID:22876591

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

No germline BRAF mutations in 31 HRAS-negative CS patients ([PMID:18042262]); reported variants occur in CFCS misdiagnosed as CS

Genetic Evidence

Limited

Absence of pathogenic BRAF variants in CS cohorts; single misclassified CFCS case supports minimal genetic link ([PMID:22876591])

Functional Evidence

Limited

Germline BRAF mutants activate MAPK but yield CFCS phenotype distinct from CS ([PMID:17551924])