NEW YORK (Reuters Health) - Variants in the interferon regulatory factor 6 (IRF6) gene account for 12% of the genetic contribution to cleft lip or palate, according to a report published in the August 19th issue of The New England Journal of Medicine. The findings have important implications for genetic counseling, the authors write.
Dr. Jeffrey C. Murray, from the University of Iowa in Iowa City, and colleagues began looking at IRF6 as a candidate gene after discovering its involvement in Van der Woude’s syndrome, an autosomal dominant cleft disease, two years ago.
In evaluating the gene for mutations, the authors identified a single nucleotide polymorphism (SNP) that resulted in the substitution of isoleucine for valine at position 274. They then tested for this variant in 8003 subjects from 10 populations with ancestry in Europe, Asia, and South America. Of these subjects, 6755 came from families that had at least one member with a cleft.
The authors found that the valine allele, and not the isoleucine variant, was actually overtransmitted in cleft patients. This was surprising since the valine allele is found in nearly 100% of Europeans. However, further analysis of regions inside and outside the gene revealed nine SNPs that appeared to be the actual mediators of cleft lip or palate.
“What we strongly believe is happening is the valine serves as a marker for some other mutation nearby within the gene that’s really doing the deed,” Dr. Murray said in a statement. “In a sense, the valine is hitchhiking with the actual mutation.”
In families with one affected child, the presence of IRF6 variants triples the risk that a future child will also have a cleft lip or palate, the investigators note.
“The most important implication of this study is that it provides a promising lead for identifying other genes linked to cleft lip or palate and elucidating the mechanisms of environmental exposure,” Dr. Aravinda Chakravarti, from Johns Hopkins University in Baltimore, notes in a related editorial.
Source: N Engl J Med 2004;351:769-780,822-824. [ Google search on this article ]
MeSH Headings:Polymorphism, Single NucleotideCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
