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Opening New Avenues in Birth Defects Research
CHORI Collaboration Confirms Novel Gene Association with Hypospadias

November 13, 2012 – CHORI Scientist Edward Lammer, MD, in collaboration with Associate Professor Suzan L. Carmichael, PhD, of Stanford University’s Division of Neonatal and Developmental Medicine, and their colleagues, have confirmed that genetic variants of a little understood gene, diacylglycerol kinase kappa (DGKK), are associated with hypospadias. One of the most common birth defects worldwide, affecting 4 to 6 per thousand male births, hypopadias is a structural malformation in which the opening of the urethra develops on the underside of the penis. Cases can be mild to severe, with the more severe cases requiring surgery and often associated with additional complications.

"Our study points very strongly to this gene playing some important role in regulating the risk for hypospadias," says Dr. Lammer. "It's a big lead in eventually understanding this birth defect and opens a whole new area of research in identifying the causes of hypospadias."
“It’s a big lead in eventually understanding this birth defect and opens a whole new area of research in identifying the causes of hypospadias.”

The new study, e-published on November 13 in the Journal of Urology, built on the only other study to identify DGKK as a potential player in hypospadias, a Dutch genome-wide association study (GWAS). Unlike Dr. Carmichael and Lammer's study, a GWAS looks at genetic variants across the entire human genome.

"While it is a useful tool for identifying possible candidate genes as a first step, GWAS can often result in false positives," says Dr. Carmichael.

In this case, however, Drs. Carmichael and Lammer have confirmed in a thorough investigation of 36 different variants in the DGKK gene that it is in fact strongly associated with hypospadias.

"We were able to replicate the results of the Dutch study in a much larger and racially and ethnically diverse population, while looking at more variants across the spectrum of the entire gene," says Dr. Carmichael of the new study, which utilized data from the California Birth Defects Monitoring Program to compare the distribution of genetic variants across the DGKK gene in boys with and without hypospadias.
“What we found is that the genetic variations within the DGKK gene were definitely different in boys with hypospadias, confirming that that this gene is a risk factor for the birth defect,” says Dr. Lammer.
"What we found is that the genetic variations within the DGKK gene were definitely different in boys with hypospadias, confirming that that this gene is a risk factor for the birth defect," says Dr. Lammer.

Next steps in the collaboration will potentially involve sequencing the DGKK gene in order identify as many variants as possible.

"While the specific variants we identified are unlikely to be the functional components of the gene itself, they may be markers for functional variants," explains Dr. Carmichael. "The variants we found give us clues as to where to look further within the gene for functional variants that may be driving the association."
Once the function of the gene is fully understood, investigators may be able to eventually identify ways in which variations in DGKK function actually impact urethral development and whether its function is impacted by potentially preventable environmental factors, such as exposure to medications, hormones or chemicals. For now, however, the new study by Drs. Carmichael and Lammer has opened up new avenues for researchers to finally identify the genetic variations that cause hypospadias.

"While we have along way to go to really understand the function and role of this gene, we now have a path to follow," says Dr. Lammer.

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Friday, January 25, 2013 7:39 AM

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