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Recurrent X chromosome-linked deletions: discovery of new genetic factors in male infertility
  1. D Lo Giacco1,2,
  2. C Chianese3,
  3. E Ars1,2,
  4. E Ruiz-Castañé2,
  5. G Forti3,
  6. C Krausz2,3
  1. 1Molecular Biology Laboratory, Fundació Puigvert Universitat Autònoma de Barcelona, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Barcelona, Spain
  2. 2Andrology Service, Fundació Puigvert, Universitat Autònoma de Barcelona, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Barcelona, Spain
  3. 3Department of Experimental and Clinical Biomedical Sciences, University of Florence, Italy
  1. Correspondence to Professor Csilla Krausz, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Pieraccini 6, Florence 50139, Italy; csillagabriella.krausz{at}unifi.it, c.krausz{at}dfc.unifi.it

Abstract

Background The role of X-linked genes and copy-number variations (CNVs) in male infertility remains poorly explored. Our previous array-CGH analyses showed three recurrent deletions in Xq exclusively (CNV67) and prevalently (CNV64, CNV69) found in patients. Molecular and clinical characterisation of these CNVs was performed in this study.

Methods 627 idiopathic infertile patients and 628 controls were tested for each deletion with PCR+/−. We used PCR+/− to map deletion junctions and long-range PCR and direct sequencing to define breakpoints.

Results CNV64 was found in 5.7% of patients and in 3.1% of controls (p=0.013; OR=1.89; 95% CI 1.1 to 3.3) and CNV69 was found in 3.5% of patients and 1.6% of controls (p=0.023; OR=2.204; 95% CI 1.05 to 4.62). For CNV69 we identified two breakpoints, types A and B, with the latter being significantly more frequent in patients than controls (p=0.011; OR=9.19; 95% CI 1.16 to 72.8). CNV67 was detected exclusively in patients (1.1%) and was maternally transmitted. The semen phenotype of one carrier (11-041) versus his normozoospermic non-carrier brother strongly indicates a pathogenic effect of the deletion on spermatogenesis. MAGEA9, an ampliconic gene reported as independently acquired on the human X chromosome with exclusive physiological expression in the testis, is likely to be involved in CNV67.

Conclusions We provide the first evidence for X chromosome-linked recurrent deletions associated with spermatogenic impairment. CNV67, specific to spermatogenic anomaly and with a frequency of 1.1% in oligo/azoospermic men, resembles the AZF regions on the Y chromosome with potential clinical implications.

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