Costello syndrome is caused by HRAS germline mutations affecting Gly(12) or Gly(13) in >90% of cases and these are associated with a relatively homogeneous phenotype.
Costello syndrome (CS) is a rare genetic disorder caused, in the majority of cases, by germline missense HRAS mutations affecting Gly(12) promoting enhanced signaling through the MAPK and PI3K-AKT signaling cascades.
A case mimicking CS with SOS1 T158A substitution, which has not been reported previously in CS, revealed the complex relationship between the genotype and phenotype of overlapping syndromes of the RAS/RAF/MEK/ERK pathway.
Duplication of Glu37 in the switch I region of HRAS impairs effector/GAP binding and underlies Costello syndrome by promoting enhanced growth factor-dependent MAPK and AKT activation.
Here, we report on a novel heterozygous HRAS germline mutation (c.187_207dup, p.E63_D69dup) in a girl presenting with a phenotype at the milder end of the Costello syndrome spectrum.
Molecular and clinical analysis of RAF1 in Noonan syndrome and related disorders: dephosphorylation of serine 259 as the essential mechanism for mutant activation.
One of these conditions, Costello syndrome (CS), is typically caused by an activating de novo germline mutation in HRAS and is characterized by a wide range of cardiac, musculoskeletal, dermatological and developmental abnormalities.
Panel testing for rasopathies identified a novel HRAS mutation (c.179G>A; p.Gly60Asp) in three individuals with attenuated features of Costello syndrome.