Panel testing for rasopathies identified a novel HRAS mutation (c.179G>A; p.Gly60Asp) in three individuals with attenuated features of Costello syndrome.
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.
We report a patient with typical Costello syndrome and a novel heterozygous missense mutation in codon 117 (c.350A>G, p.Lys117Arg) of the HRAS gene, resulting in constitutive activation of the RAS/MAPK pathway similar to the typical p.Gly12Ser and p.Gly12Ala mutations.
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.
Several studies have shown that CS-associated HRAS mutations are clustered in codons 12 and 13, and mutations in other codons have also been identified.
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.
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.
Patients with the HRAS mutation c.173C>T (p.T58I) might go undiagnosed because of the milder phenotype compared with other mutations causing Costello syndrome.
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.
Remarkably, our cohort of individuals with KRAS mutations showed a high clinical variability, ranging from Noonan syndrome to CFC, and also included two patients who met the clinical criteria of Costello syndrome.
We report on a novel KRAS gene mutation in a patient presenting the clinical features typical of Costello syndrome and the additional findings seen in Noonan syndrome.
Molecular and clinical analysis of RAF1 in Noonan syndrome and related disorders: dephosphorylation of serine 259 as the essential mechanism for mutant activation.
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.