A second independent locus within DMRT1 is associated with testicular germ cell tumor susceptibility.

Susceptibility to testicular germ cell tumors (TGCT) has a significant heritable component, and genome-wide association studies (GWASs) have identified association with variants in several genes, including KITLG, SPRY4, BAK1, TERT, DMRT1 and ATF7IP. In our GWAS, we genotyped 349 TGCT cases and 919 controls and replicated top hits in an independent set of 439 cases and 960 controls in an attempt to find novel TGCT susceptibility loci. We identified a second marker (rs7040024) in the doublesex and mab-3-related transcription factor 1 (DMRT1) gene that is independent of the previously described risk allele (rs755383) at this locus. In combined analysis that mutually conditions on both DMRT1 single nucleotide polymorphism markers, TGCT cases had elevated odds of carriage of the rs7040024 major A allele [per-allele odds ratio (OR) = 1.48, 95% confidence interval (CI) 1.23, 1.78; P = 2.52 × 10(-5)] compared with controls, while the association with rs755383 persisted (per allele OR = 1.26, 95% CI 1.08, 1.47, P = 0.0036). In similar analyses, the association of rs7040024 among men with seminomatous tumors did not differ from that among men with non-seminomatous tumors. In combination with KITLG, the strongest TGCT susceptibility locus found to date, men with TGCT had greatly elevated odds (OR = 14.1, 95% CI 5.12, 38.6; P = 2.98 × 10(-7)) of being double homozygotes for the risk (major) alleles at DMRT (rs7040024) and KITLG (rs4474514) when compared with men without TGCT. Our findings continue to corroborate that genes influencing male germ cell development and differentiation have emerged as the major players in inherited TGCT susceptibility.

Rapid detection of submicroscopic chromosomal rearrangements in children with multiple congenital anomalies using high density oligonucleotide arrays.

Chromosomal rearrangements such as microdeletions and interstitial duplications are the underlying cause of many human genetic disorders. These disorders can manifest in the form of multiple congenital anomalies (MCA), which are a significant cause of morbidity and mortality in children. The major limitations of cytogenetic tests currently used for the detection of such chromosomal rearrangements are low resolution and limited coverage of the genome. Thus, it is likely that children with MCA may have submicroscopic chromosomal rearrangements that are not detectable by current techniques. We report the use of a commercially available, oligonucleotide-based microarray for genome-wide analysis of copy number alterations. First, we validated the microarray in patients with known chromosomal rearrangements. Next, we identified previously undetected, de novo chromosomal deletions in patients with MCA who have had a normal high-resolution karyotype and subtelomeric fluorescence in situ hybridization (FISH) analysis. These findings indicate that high-density, oligonucleotide-based microarrays can be successfully used as tools for the detection of chromosomal rearrangement in clinical samples. Their higher resolution and commercial availability make this type of microarray highly desirable for application in the diagnosis of patients with multiple congenital defects.