• PMID: 23555275
• Gene Name: DMRT1
• Condition: Spermatogenic failure, idiopathic azoospermia
• Association: The combined results indicate that DMRT1 loss-of-function mutations are a risk factor and potential genetic cause of human spermatogenic failure. This study identifies other recurrent CNVs as potential causes of idiopathic azoospermia and generates hypoth
• Population size: 8655
• Population details: 8655 (1302 idiopathic spermatogenic impairment or azoospermia, 7353 controls)
• Sex: Male
• Infertility type: Male infertility
• Other associated phenotypes: Spermatogenic failure, idiopathic azoospermia

Human spermatogenic failure purges deleterious mutation load from the autosomes and both sex chromosomes, including the gene DMRT1

Lopes AM, Aston KI, Thompson E, Carvalho F, Gonçalves J, Huang N, Matthiesen R, Noordam MJ, Quintela I, Ramu A, Seabra C, Wilfert AB, Dai J, Downie JM, Fernandes S, Guo X, Sha J, Amorim A, Barros A, Carracedo A, Hu Z, Hurles ME, Moskovtsev S, Ober C, Paduch DA, Schiffman JD, Schlegel PN, Sousa M, Carrell DT, Conrad DF.

Gonadal failure, along with early pregnancy loss and perinatal death, may be an important filter that limits the propagation of harmful mutations in the human population. We hypothesized that men with spermatogenic impairment, a disease with unknown genetic architecture and a common cause of male infertility, are enriched for rare deleterious mutations compared to men with normal spermatogenesis. After assaying genomewide SNPs and CNVs in 323 Caucasian men with idiopathic spermatogenic impairment and more than 1,100 controls, we estimate that each rare autosomal deletion detected in our study multiplicatively changes a man's risk of disease by 10% (OR 1.10 [1.04-1.16], p<2 × 10(-3)), rare X-linked CNVs by 29%, (OR 1.29 [1.11-1.50], p<1 × 10(-3)), and rare Y-linked duplications by 88% (OR 1.88 [1.13-3.13], p<0.03). By contrasting the properties of our case-specific CNVs with those of CNV callsets from cases of autism, schizophrenia, bipolar disorder, and intellectual disability, we propose that the CNV burden in spermatogenic impairment is distinct from the burden of large, dominant mutations described for neurodevelopmental disorders. We identified two patients with deletions of DMRT1, a gene on chromosome 9p24.3 orthologous to the putative sex determination locus of the avian ZW chromosome system. In an independent sample of Han Chinese men, we identified 3 more DMRT1 deletions in 979 cases of idiopathic azoospermia and none in 1,734 controls, and found none in an additional 4,519 controls from public databases. The combined results indicate that DMRT1 loss-of-function mutations are a risk factor and potential genetic cause of human spermatogenic failure (frequency of 0.38% in 1306 cases and 0% in 7,754 controls, p = 6.2 × 10(-5)). Our study identifies other recurrent CNVs as potential causes of idiopathic azoospermia and generates hypotheses for directing future studies on the genetic basis of male infertility and IVF outcomes. FAU - Lopes, Alexandra M AU - Lopes AM AD - Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal. FAU - Aston, Kenneth I AU - Aston KI FAU - Thompson, Emma AU - Thompson E FAU - Carvalho, Filipa AU - Carvalho F FAU - Gonçalves, João AU - Gonçalves J FAU - Huang, Ni AU - Huang N FAU - Matthiesen, Rune AU - Matthiesen R FAU - Noordam, Michiel J AU - Noordam MJ FAU - Quintela, Inés AU - Quintela I FAU - Ramu, Avinash AU - Ramu A FAU - Seabra, Catarina AU - Seabra C FAU - Wilfert, Amy B AU - Wilfert AB FAU - Dai, Juncheng AU - Dai J FAU - Downie, Jonathan M AU - Downie JM FAU - Fernandes, Susana AU - Fernandes S FAU - Guo, Xuejiang AU - Guo X FAU - Sha, Jiahao AU - Sha J FAU - Amorim, António AU - Amorim A FAU - Barros, Alberto AU - Barros A FAU - Carracedo, Angel AU - Carracedo A FAU - Hu, Zhibin AU - Hu Z FAU - Hurles, Matthew E AU - Hurles ME FAU - Moskovtsev, Sergey AU - Moskovtsev S FAU - Ober, Carole AU - Ober C FAU - Paduch, Darius A AU - Paduch DA FAU - Schiffman, Joshua D AU - Schiffman JD FAU - Schlegel, Peter N AU - Schlegel PN FAU - Sousa, Mário AU - Sousa M FAU - Carrell, Douglas T AU - Carrell DT