Several research groups recently showed that CFH increases the risk for advanced AMD. However until this study, the relationship between CFH, soft drusen, and advanced AMD was unclear.

In an article to be published online on November 29 by PLoS Medicine, the researchers working at the deCODE genetics Inc., Reykjavik, Iceland, the Moran Eye Center and Eccels Institute of Human Genetics of the University of Utah, USA, and the University of Iceland, found that CFH is a major risk factor for soft drusen. The researchers looked at the CFH gene and its relationship with the presence of soft drusen and AMD in 581 Icelandic patients with advanced and 435 with early AMD, and also 322 US patients with advanced and 109 with early AMD.

AMD is the most common cause of visual loss and is preceded by formation of soft drusen. However, only a portion of patients who develop soft drusen will go on to develop advanced AMD. "We have discovered that the CFH variant is a major risk factor for soft drusen, but does not appear to determine who ultimately progresses to advanced AMD, as previously proposed" , said Dr. Kristinn P. Magnusson, who led the deCODE genetics research team with Dr. Jeffrey Gulcher. Dr. Kang Zhang led the University of Utah team. The authors conclude that it is likely that there are other important genes yet to be found that contribute to the risk of age-related macular degeneration, especially among those who already have soft drusen.

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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."

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