title: Assessing genotype-phenotype correlation in Costello syndrome using a severity score.
abstract: OBJECTIVE
  Costello syndrome, a rare genetic disorder with multisystemic involvement, is caused by germline HRAS mutations. Because several different missense mutations have been reported, a severity scoring system was developed to assess a possible genotype-phenotype correlation.
  
  
  METHODS
  Records of 78 individuals with Costello syndrome were scored in early childhood, childhood, and young adulthood by a reviewer blinded to the individuals' specific mutations. These scores were based on certain medically relevant feeding, neurologic, orthopedic, endocrine, cardiac, malignancy, and mortality manifestations. Individuals' severity scores were then grouped by the particular HRAS mutation. The mixed-model approach for repeated-measures analysis of variance with unstructured within-subject correlation, pairwise comparisons, and contrast were used to determine whether the severity scores differed by mutation.
  
  
  RESULTS
  Although the sample size was small, individuals with the p.G12A or p.G12C HRAS change were more severely affected than those with other HRAS mutations. Regardless of the mutation, severity did not increase significantly over time.
  
  
  CONCLUSIONS
  Despite its limitations, including the small number of individuals with rare mutations and possibly incomplete medical records, this work providing the first quantitative assessment of phenotypic severity in a Costello syndrome cohort supports a medically relevant genotype-phenotype correlation.
authors: Division of Medical Genetics, Alfred I. duPont Hospital for Children, Wilmington, Delaware, USA.
authors: Elizabeth M
authors: EM
authors: McCormick
authors: Elizabeth
authors: E
authors: Hopkins
authors: Laura
authors: L
authors: Conway
authors: Sarah
authors: S
authors: Catalano
authors: Jobayer
authors: J
authors: Hossain
authors: Katia
authors: K
authors: Sol-Church
authors: Deborah L
authors: DL
authors: Stabley
authors: Karen W
authors: KW
authors: Gripp
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D002648:Child; D002675:Child, Preschool; D056685:Costello Syndrome / Q000209:etiology* / Q000235:genetics / Q000401:mortality; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D009154:Mutation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)