Hypospadias 4, X-Linked, Susceptibility To

For a phenotypic description and a discussion of genetic heterogeneity of hypospadias, see HYSP1 (300633).

Mapping

Van der Zanden et al. (2011) performed a genomewide association study using pooled DNA from 436 individuals with hypospadias and 494 controls of European descent and selected the highest ranking single-nucleotide polymorphisms (SNPs) for individual genotyping in the discovery sample, an additional Dutch sample of 133 cases and their parents, and a Swedish series of 266 cases and 402 controls. Individual genotyping of 2 SNPs (rs1934179 and rs7063116) in DGKK (300837), encoding diacylglycerol kinase-kappa, produced compelling evidence for association with hypospadias in the discovery sample (allele-specific OR = 2.5, p = 2.5 x 10(-11) and OR = 2.3, p = 2.9 x 10(-9), respectively) and in the Dutch (OR = 3.9, p = 2.4 x 10(-5) and OR = 3.8, p = 3.4 x 10(-5)), and Swedish (OR = 2.5, p = 2.6 x 10(-8) and OR = 2.2, p = 2.7 x 10(-6)) replication samples. Expression studies showed expression of DGKK in preputial tissues of cases and controls, which was lower in carriers of the risk allele of rs1934179 (P = 0.047). The authors proposed DGKK as a major risk gene for hypospadias.