For some birth defects, including oral clefts and CHDs, several novel susceptibility loci have been identified and replicated through GWAS, including 8q24 for oral clefts, DGKK for hypospadias, and 4p16 for CHDs.
Our meta-analysis supports the hypothesis that DGKK is a common risk gene for hypospadias, particularly in cases of mild or moderate hypospadias in Caucasian populations.
We examined the association of 27 DGKK single nucleotide polymorphisms with hypospadias relative to population based nonmalformed controls born in selected California counties from 1990 to 2003.
Our data provide evidence that pathogenic mutations can underlie both mild and severe hypospadias and that HSD3B2 mutations cause non-syndromic hypospadias as a sole clinical manifestation.
A total of 395 boys with hypospadias were prospectively screened for a family history with a standardized questionnaire, extensive clinical description, family tree and sequencing of AR, SF1, SRD5A2 and MAMLD1.
The mastermind-like domain-containing 1 gene (<i>MAMLD1</i>, formerly <i>CXorf6</i>) is a new candidate gene and its mutation has been shown in some cases of hypospadias.
Mastermind-like domain containing 1/chromosome X open reading frame 6 mutation and activating transcription factor 3 variants have been shown to be associated with the incidence of isolated hypospadias.
These findings suggest that the MAMLD1 mutations cause hypospadias primarily because of compromised testosterone production around the critical period of sex development, and provide useful information for the molecular network involved in fetal testosterone production.