RAF1 – Costello Syndrome

Germline RAF1 variants have been infrequently reported in patients with clinical features of Costello syndrome, which is classically caused by HRAS mutations. In a cohort of 80 individuals with suspected RASopathies, targeted next-generation sequencing identified a single heterozygous RAF1 c.785A>T (p.Asn262Ile) in a patient with Costello-like features; this finding was confirmed by Sanger sequencing without available familial segregation data ([PMID:24451042]).

Functional studies of RAF1 mutations in the conserved region 2 (CR2) domain, including c.776C>T (p.Ser259Phe), demonstrate that loss of inhibitory phosphorylation at Ser259 leads to reduced 14-3-3 binding and partial ERK activation in vitro, consistent with a gain-of-function mechanism underlying RASopathy phenotypes ([PMID:20052757]). Taken together, the association between RAF1 and Costello syndrome is supported by a single proband and concordant functional data; however, the current evidence meets only a Limited level of clinical validity. Additional cases with segregation and comprehensive phenotyping are required to establish a stronger gene–disease relationship. Key take-home: RAF1 screening can reveal rare gain-of-function alleles in RASopathies but warrants cautious interpretation pending further validation.

References

• BMC medical genetics • 2014 • Diagnosis of Noonan syndrome and related disorders using target next generation sequencing. PMID:24451042
• Human Mutation • 2010 • Molecular and clinical analysis of RAF1 in Noonan syndrome and related disorders: dephosphorylation of serine 259 as the essential mechanism for mutant activation. PMID:20052757

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