Assessing Genotype-Phenotype Correlation in Costello Syndrome with the Use of a Severity Score

Elizabeth McCormick

Costello syndrome, a rare but variable genetic disorder characterized by a failure to thrive in infancy, skeletal, muscular, cardiac, and neurological abnormalities, tumor predisposition, and intellectual disability, is caused by an alteration of the HRAS gene.  Several different mutations in the HRAS gene result in the constellation of features that characterize Costello syndrome. It is possible that different mutations in this gene may lead to differing degrees of effect.  In order to assess a possible genotype-phenotype correlation, a severity scoring system was developed and each individual with Costello syndrome was scored based on certain manifestations of Costello syndrome present in early childhood, childhood, and young adulthood.  Individuals were then grouped based on the HRAS mutation present.  These mutation groups were analyzed and compared for any significant differences among severity of Costello syndrome phenotype.  Mixed model repeated measures ANOVA with unstructured within subject correlation, pairwise comparisons, and contrast were used for analysis.  Individuals with the G12A and G12C mutations in HRAS were more severely affected than those with other HRAS mutations.  However, the small sample (n=78) of individuals studied limits the significance of these results.