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Revolutionizing the Research of Birth Defects
CHORI Scientists Utilize Cross-disciplinary Approach
to Pioneer Novel Application of Array Comparative Genomic Hybridization to Birth Defects Analysis

In a new breakthrough in research technique, CHORI scientists Kazutoyo Osoegawa, PhD, and Pieter de Jong, PhD, from the de Jong lab, collaborated with CHORI scientist Edward Lammer, MD, the clinical geneticist for the Center for Disease Control's Center for Excellence in Birth Defects, Research and Prevention, to investigate the potential for utilizing array-comparative genomic hybridization (array-CGH) in order to identify possible candidate genes for certain types of birth defects.

Cleft lip and cleft palate are orofacial birth defects that affect approximately 1 to 2 per 1,000 births. As they are fairly common, studies have long been underway to elucidate the genes that might be responsible for causing cleft lip and cleft palate. Such studies, however, have utilized only two kinds of genetic analysis, linkage analysis and association studies, both of which have some limitations.

"Not only do you need a large number of samples for the analysis to be significant, but even if you can narrow kind of narrow down where a candidate gene might be located, it's very difficult to pinpoint," explains Dr. Osoegawa. "Linkage analysis for example, might identify a potential candidate gene region as large as 10 megabases.

Array-CGH, however, surveys every chromosome, genome-wide, for microdeletions and/or duplications that would never be seen with standard chromosomal studies.

In simple terms, the technique labels test samples, taken from affected DNA, and reference samples, representing unaffected DNA, in two different colors.

The technique is only feasible due to the development of hundreds of thousands of BAC clones in the de Jong lab, which are used as the reference samples for genome mapping and sequencing. As Dr. Lammer explains, "Essentially every BAC microdeletion microarray used around the world right now uses clones from the de Jong lab to make their arrays."

As a result, Drs. Osoegawa, De Jong and Lammer were able to explore the possibility of using array-CGH to analyze cleft lip and cleft palate, starting first with the well-studied Van der Woude (VW) syndrome as a test case to validate the technique.

"A mutation can be found in about 70 percent of all VW syndrome cases," Dr. Osoegawa explains. "We guessed that deletions must be involved in the other 30 percent, and in this population we confirmed this by finding 5 deletions out of 20 subjects."

With the technique clearly validated, the authors then went on to analyze syndromic cases - in which other conditions in
addition to cleft lip and palate are also present - and non-syndromic cases, in which the subject only has cleft lip and/or cleft palate.

"In total we analyzed about 200 DNA samples and we were able to find 2 or 3 candidate genes," says Dr. Osoegawa. "We feel that's pretty effective in terms of narrowing down and identifying candidate gene locis compared to the other methods."

Given how successful the array-CGH has proven, CHORI investigators are hopeful that the publication proves a harbinger of many more birth defects studies applying the novel technology.

"The results of this study are really quite exciting, and should spur lots of people on to apply this technique to kids with common birth defects, or even isolated birth defects," says Dr. Lammer. "At least that's the message we're trying to give."

In the mean time, the group of researchers hopes to expand their investigations to identify more candidate genomes for cleft lip and cleft palate, as well as putting the array-CGH to potential use in the analysis of other diseases.


Monday, May 16, 2011 11:33 PM

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