Assessing genotype-phenotype correlation in Costello syndrome using a severity score

作者：McCormick Elizabeth M; Hopkins Elizabeth; Conway Laura; Catalano Sarah; Hossain Jobayer; Sol Church Katia; Stabley Deborah L; Gripp Karen W^*

来源：Genetics in Medicine, 2013, 15(7): 554-557.

DOI：10.1038/gim.2013.6

• Costello syndrome
• genotype-phenotype correlation
• HRAS
• severity score

Purpose: 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.
Conclusion: 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.

• 出版日期2013-7