title: A Screen for Genomic Disorders of Infertility Identifies MAST2 Duplications Associated with Nonobstructive Azoospermia in Humans.
abstract: Since the cytogenetic identification of azoospermia factor regions 40 years ago, the Y chromosome has dominated research on the genetics of male infertility. We hypothesized that hotspots of structural rearrangement, which are dispersed across the genome, may mediate rare, recurrent copy number variations (CNVs), leading to severe infertility. We tested this hypothesis by contrasting patterns of rare CNVs in 970 Han Chinese men with idiopathic nonobstructive azoospermia and 1661 ethnicity-matched controls. Our results strongly support our previous claim that sperm production is modulated by genetic variation across the entire genome. The X chromosome in particular was enriched for loci modulating spermatogenesis--rare X-linked deletions larger than 100 kb were twice as common in patients compared with controls (odds ratio [OR] = 2.05, P = 0.01). At rearrangement hotspots across the genome, we observed a 2.4-fold enrichment of singleton CNVs in patients (P < 0.02), and we identified 117 testis genes, such as SYCE1, contained within 47 hotspots that may plausibly mediate genomic disorders of fertility. In our discovery sample we observed 3 case-specific duplications of the autosomal gene MAST2, and in a replication phase we found another 11 duplications in 1457 patients and 1 duplication in 1590 controls (P < 5 × 10(-5), combined data). With a large, polygenic genetic basis, new ways of establishing the pathogenicity of rare, large-effect mutations will be needed to fully reap the benefit of genome data in the management of azoospermia.
authors.affiliation: Department of Genetics, Washington University School of Medicine, St. Louis, Missouri Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Ni
authors.initials: N
authors.lastname: Huang
authors.affiliation: State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, China Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wen
authors.affiliation: State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, China Department of Histology and Embryology, Nanjing Medical University, Nanjing, China.
authors.forename: Xuejiang
authors.initials: X
authors.lastname: Guo
authors.affiliation: Shanghai Human Sperm Bank, Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Li
authors.affiliation: State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, China Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Juncheng
authors.initials: J
authors.lastname: Dai
authors.affiliation: State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, China Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Bixian
authors.initials: B
authors.lastname: Ni
authors.affiliation: State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, China Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.affiliation: State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, China Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lin
authors.affiliation: State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, China Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Andrology, Nanjing Jinling Hospital, Nanjing, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Yao
authors.affiliation: State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, China Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, China Department of Histology and Embryology, Nanjing Medical University, Nanjing, China shajh@njmu.edu.cn.
authors.forename: Jiahao
authors.initials: J
authors.lastname: Sha
authors.affiliation: Department of Genetics, Washington University School of Medicine, St. Louis, Missouri Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri dconrad@genetics.wustl.edu.
authors.forename: Donald F
authors.initials: DF
authors.lastname: Conrad
authors.affiliation: State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, China Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China zhibin_hu@njmu.edu.cn.
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Hu
mesh_terms: D000328:Adult; D022981:Allelic Imbalance / Q000235:genetics; D044466:Asian People; D053713:Azoospermia / Q000235:genetics*; D016022:Case-Control Studies; D041321:Chromosomes, Human, X / Q000235:genetics; D056915:DNA Copy Number Variations; D004268:DNA-Binding Proteins; D018628:Gene Dosage; D020440:Gene Duplication; D040181:Genetic Diseases, X-Linked / Q000235:genetics; D016678:Genome / Q000235:genetics; D006801:Humans; D007248:Infertility, Male / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D015203:Reproducibility of Results; D013091:Spermatogenesis / Q000235:genetics; D013094:Spermatozoa; D013737:Testis / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; C489753:SYCP1 protein, human; C503880:MAST2 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: aneuploidy; genetics; genomics; male infertility