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KRAS – Costello Syndrome

Costello syndrome is a rare autosomal dominant RASopathy characterized by failure to thrive, severe hypotonia, and predisposition to tumors. Germline missense variants in KRAS have been reported in five unrelated individuals with clinical features of Costello syndrome: a de novo c.466T>G (p.Phe156Val) (PMID:17601930), two cases among 31 patients with cardio-facio-cutaneous and Costello syndrome (PMID:18042262), and two among 260 individuals screened for KRAS mutations (PMID:17056636). All occurred de novo with no reported familial segregation.

Functional studies demonstrate that these KRAS mutants stabilize the GTP-bound active conformation, enhance intrinsic nucleotide exchange, and dysregulate downstream MAPK signaling in vitro (PMID:17875937). Structural modeling of C-terminal isoform-specific mutations (e.g., p.Asp153Val) predicts perturbation of the guanine-binding pocket and increased GTP affinity (PMID:16773572). These data provide moderate functional evidence for a gain-of-function mechanism. No studies have refuted this association.

Key Take-home: Germline KRAS missense variants cause a de novo, autosomal dominant form of Costello syndrome, with limited genetic data and concordant functional validation supporting clinical testing in RASopathy patients.

References

  • Journal of medical genetics • 2007 • De novo HRAS and KRAS mutations in two siblings with short stature and neuro-cardio-facio-cutaneous features PMID:17601930
  • Clinical genetics • 2008 • Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome PMID:18042262
  • Journal of medical genetics • 2007 • Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations PMID:17056636
  • Molecular and cellular biology • 2007 • Biochemical and functional characterization of germ line KRAS mutations PMID:17875937
  • American journal of human genetics • 2006 • Germline missense mutations affecting KRAS Isoform B are associated with a severe Noonan syndrome phenotype PMID:16773572

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

5 unrelated probands (all de novo) across 3 studies; no segregation data; functional concordance

Genetic Evidence

Limited

5 missense variants in KRAS identified in 5 individuals with Costello syndrome; de novo occurrence

Functional Evidence

Moderate

In vitro assays show KRAS mutants increase GTP-bound active conformation and downstream MAPK signaling ([PMID:17875937], [PMID:16773572])