High resolution X chromosome-specific array-CGH detects new CNVs in infertile males.
BACKGROUND
The role of CNVs in male infertility is poorly defined, and only those linked to the Y chromosome have been the object of extensive research. Although it has been predicted that the X chromosome is also enriched in spermatogenesis genes, no clinically relevant gene mutations have been identified so far.


OBJECTIVE
In order to advance our understanding of the role of X-linked genetic factors in male infertility, we applied high resolution X chromosome specific array-CGH in 199 men with different sperm count followed by the analysis of selected, patient-specific deletions in large groups of cases and normozoospermic controls.


RESULTS
We identified 73 CNVs, among which 55 are novel, providing the largest collection of X-linked CNVs in relation to spermatogenesis. We found 12 patient-specific deletions with potential clinical implication. Cancer Testis Antigen gene family members were the most frequently affected genes, and represent new genetic targets in relationship with altered spermatogenesis. One of the most relevant findings of our study is the significantly higher global burden of deletions in patients compared to controls due to an excessive rate of deletions/person (0.57 versus 0.21, respectively; p = 8.785×10(-6)) and to a higher mean sequence loss/person (11.79 Kb and 8.13 Kb, respectively; p = 3.435×10(-4)).


CONCLUSIONS
By the analysis of the X chromosome at the highest resolution available to date, in a large group of subjects with known sperm count we observed a deletion burden in relation to spermatogenic impairment and the lack of highly recurrent deletions on the X chromosome. We identified a number of potentially important patient-specific CNVs and candidate spermatogenesis genes, which represent novel targets for future investigations.
Unit of Sexual Medicine and Andrology, Molecular Genetic Laboratory, Department of Clinical Physiopathology, University of Florence, Florence, Italy. c.krausz@ dfc.unifi.it
Csilla
C
Krausz
Claudia
C
Giachini
Deborah
D
Lo Giacco
Fabrice
F
Daguin
Chiara
C
Chianese
Elisabet
E
Ars
Eduard
E
Ruiz-Castane
Gianni
G
Forti
Elena
E
Rossi
D053713:Azoospermia / Q000235:genetics; D016022:Case-Control Studies; D002872:Chromosome Deletion; D041321:Chromosomes, Human, X / Q000235:genetics*; D055028:Comparative Genomic Hybridization / Q000379:methods*; D004247:DNA / Q000032:analysis / Q000235:genetics; D056915:DNA Copy Number Variations; D006801:Humans; D007248:Infertility, Male / Q000235:genetics* / Q000473:pathology; D008297:Male; D009845:Oligospermia / Q000235:genetics; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012661:Semen / Q000378:metabolism; D013076:Sperm Count; D013091:Spermatogenesis / Q000235:genetics; D013737:Testis / Q000378:metabolism / Q000473:pathology
D004247:DNA