New genes discovered for the congenital malformation hypospadias

Loes van der Zanden - VK

In a large Danish  study in boys with the congenital urological malformation hypospadias 17 new genetic variants were found plus a variant in the DGKK gene, that was already discovered in 2010 in Nijmegen. The Radboud university medical center had an important contribution in this Danish study with DNA of almost 1,400 children from the AGORA (Aetiologic research on Genetic, Occupational and environmental Risk factors for Anomalies in children) data- and biobank. The results of this study were recently published in Nature Genetics.

Hypospadias is a common congenital malformation in boys where the urethra opens on the underside of the penis. It occurs in about 3-7 of 1,000 newborn boys.  These boys often need to be operated at an early age. Unfortunately, many children encounter severe medical, psychosocial, and sexual problems later in life.

The in Denmark performed study was a so-called genome wide association study, in which more than 500.000 genetic variants were investigated. At first, 33 variants seemed to show a strong association with hypospadias in Danish children. Further investigation with DNA of children from the AGORA biobank in Nijmegen and children from Sweden revealed 18 genes to be important in the etiology of hypospadias. The strongest variant was the earlier in Nijmegen discovered one in the DGKK gene. Boys with an abnormal DGKK-gene have a 2,5 times increased risk to be born with hypospadias compared to other boys. The other discovered genes increased this risk 1,2 to 1,6 times. A number of these genes play an important role in the embryonic development. Building on this, follow-up studies on the molecular level have the possibility to improve our understanding of the causes of this malformation.

This is an excellent example of the international collaboration arising from the AGORA data collection, that started 10 years ago. By this sustainable network of epidemiologists, geneticist and pediatricians the Radboud university medical center is an important partner in the world of hypospadias, but also for other congenital malformations, such as anorectal and kidney malformations.

Photo: Dr Loes van der Zanden, one of the leading authors

Frank Geller, Bjarke Feenstra, Lisbeth Carstensen, Tune H Pers, Iris A L M van Rooij, Izabella Baranowska Körberg, Shweta Choudhry, Juha M Karjalainen, Tine H Schnack, Mads V Hollegaard, Wout F J Feitz, Nel Roeleveld, David M Hougaard, Joel N Hirschhorn, Lude Franke, Laurence S Baskin, Agneta Nordenskjöld, Loes F M van der Zanden, Mads Melbye (2014). Genome-wide association analyses identify variants in developmental genes associated with hypospadias. Nature Genetics 46; 957-963.

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