title: X chromosome-linked CNVs in male infertility: discovery of overall duplication load and recurrent, patient-specific gains with potential clinical relevance.
abstract: BACKGROUND
  Spermatogenesis is a highly complex process involving several thousand genes, only a minority of which have been studied in infertile men. In a previous study, we identified a number of Copy Number Variants (CNVs) by high-resolution array-Comparative Genomic Hybridization (a-CGH) analysis of the X chromosome, including 16 patient-specific X chromosome-linked gains. Of these, five gains (DUP1A, DUP5, DUP20, DUP26 and DUP40) were selected for further analysis to evaluate their clinical significance.
  
  
  METHODS
  The copy number state of the five selected loci was analyzed by quantitative-PCR on a total of 276 idiopathic infertile patients and 327 controls in a conventional case-control setting (199 subjects belonged to the previous a-CGH study). For one interesting locus (intersecting DUP1A) additional 338 subjects were analyzed.
  
  
  CONCLUSIONS
  All gains were confirmed as patient-specific and the difference in duplication load between patients and controls is significant (p = 1.65 × 10(-4)). Two of the CNVs are private variants, whereas 3 are found recurrently in patients and none of the controls. These CNVs include, or are in close proximity to, genes with testis-specific expression. DUP1A, mapping to the PAR1, is found at the highest frequency (1.4%) that was significantly different from controls (0%) (p = 0.047 after Bonferroni correction). Two mechanisms are proposed by which DUP1A may cause spermatogenic failure: i) by affecting the correct regulation of a gene with potential role in spermatogenesis; ii) by disturbing recombination between PAR1 regions during meiosis. This study allowed the identification of novel spermatogenesis candidate genes linked to the 5 CNVs and the discovery of the first recurrent, X-linked gain with potential clinical relevance.
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence and Centre of Excellence DeNothe, Florence, Italy; Molecular Biology Laboratory, Fundació Puigvert, Universitat Autonoma de Barcelona, Barcelona, Spain.
authors.forename: Chiara
authors.initials: C
authors.lastname: Chianese
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence and Centre of Excellence DeNothe, Florence, Italy.
authors.forename: Adam C
authors.initials: AC
authors.lastname: Gunning
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence and Centre of Excellence DeNothe, Florence, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Giachini
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence and Centre of Excellence DeNothe, Florence, Italy.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Daguin
authors.affiliation: Division of Endocrinology, Department of Clinical and Molecular Sciences, Umberto I Hospital, Polytechnic University of Marche, Ancona, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Balercia
authors.affiliation: Molecular Biology Laboratory, Fundació Puigvert, Universitat Autonoma de Barcelona, Barcelona, Spain.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Ars
authors.affiliation: Molecular Biology Laboratory, Fundació Puigvert, Universitat Autonoma de Barcelona, Barcelona, Spain; Andrology Service, Fundació Puigvert, Universitat Autonoma de Barcelona, Barcelona, Spain.
authors.forename: Deborah
authors.initials: D
authors.lastname: Lo Giacco
authors.affiliation: Andrology Service, Fundació Puigvert, Universitat Autonoma de Barcelona, Barcelona, Spain.
authors.forename: Eduard
authors.initials: E
authors.lastname: Ruiz-Castañé
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence and Centre of Excellence DeNothe, Florence, Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Forti
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence and Centre of Excellence DeNothe, Florence, Italy; Andrology Service, Fundació Puigvert, Universitat Autonoma de Barcelona, Barcelona, Spain.
authors.forename: Csilla
authors.initials: C
authors.lastname: Krausz
mesh_terms: D016022:Case-Control Studies; D041321:Chromosomes, Human, X / Q000235:genetics*; D056915:DNA Copy Number Variations; D020440:Gene Duplication; D006801:Humans; D007248:Infertility, Male / Q000235:genetics*; D008297:Male