Gene mutations in the HRAS sequence are present in most patients affected with Costello syndrome, according to a new study in the American Journal of Medical Genetics. The mutations occurred de novo in patients, meaning, they were not observed in their parents' genes.
Costello Syndrome is very rare, with only 150 cases reported worldwide. It is associated with mental retardation, distinctive facial characteristics, cardiovascular abnormalities, and a predisposition for tumors. Patients often develop soft tissue tumors in childhood and bladder cancer as young adults.
A previous genetic study of 12 Japanese and Italian patients with Costello syndrome found mutations in the HRAS gene sequence. To confirm this connection and expand the understanding of the possible cause of Costello syndrome, researchers, led by Karen W. Gripp of A. I. DuPont Hospital for Children in Wilmington, Delaware, performed mutation analyses on 40 North American and European patients.
The researchers identified patients with the syndrome through affiliated organizations and physician referral. They extracted DNA from blood, saliva or cell lines and performed DNA sequencing. When possible, they also sequenced the genes of the patients' parents.
The results were striking. Among the patients with Costello syndrome, "We detected missense mutations in HRAS in 33 (82.5%) patients," the authors report. "All mutations affected either codon 12 or 13 of the protein product, with G12S occurring in 30 (90.9%) patients of the mutation-positive cases."
The researchers reviewed the clinical presentation of the patients who did not have HRAS mutation and found inconsistencies in their facial characteristics. They suggest that these patients may not have Costello syndrome, but rather cardio-facio-cutaneous syndrome. Lack of an identifiable HRAS mutation should not yet exclude the diagnosis of Costello syndrome, however, the results of this study should allow doctors to confirm a clinical diagnosis of Costello syndrome.
Of the 19 sets of parents tested, none carried the sequence change found in their children, indicating that the mutation occurred in the parents' germ cells. The nature of the missense mutations, along with the paternal age effect observed in Costello syndrome suggests a paternal origin of the mutations, the researchers report.
"Five different HRAS mutations have now been reported in Costello syndrome, however genotype-phenotype correlation remains incomplete," the authors conclude. And while it is too early to apply their findings to the recommendations for clinical care, they hope to collect additional data to achieve this goal.
Offering hope to those affected by the syndrome, they conclude, "The identification of these mutations in combination with the knowledge from cancer research on HRAS and the MAPK pathway will allow for the use of medications directed at this pathway."