Abstract
ContextThe 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.ObjectivesIn 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.ResultsWe 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).ConclusionsBy 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.
Highlights
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
Male factor infertility affects about 7% of men in the general population and the etiology of altered spermatogenesis remains unknown in about 40% of cases (‘‘idiopathic infertility’’) and it is likely that a large proportion of them are caused by still unknown genetic factors [1]
Since homologous sequences at the border of a CNV may act as a substrate for non-allelic homologous recombination (NAHR), we checked the nature of regions flanking the identified CNVs in order to understand whether NAHR is likely to occur (UCSC Genome Browser)
Summary
Male factor infertility affects about 7% of men in the general population and the etiology of altered spermatogenesis remains unknown in about 40% of cases (‘‘idiopathic infertility’’) and it is likely that a large proportion of them are caused by still unknown genetic factors [1]. Besides abnormal karyotype and Y chromosome microdeletions no other recurrent genetic anomalies have been identified in men with primary testicular failure, raising questions about the appropriateness of the investigative approaches used so far [2,3,4]. High resolution array Comparative Genomic Hybridisation (array-CGH) studies identified new spermatogenesis candidate genes on autosomes and on the X chromosome and some recurring and private patientspecific CNVs with potential clinical interest [7,8]. Both sex chromosomes are enriched with genes prevalently or exclusively expressed in the testis [9,10]. The question whether the X chromosome contains AZF-like regions has not been sufficiently explored so far
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