High Resolution X Chromosome-Specific Array-CGH Detects New CNVs in Infertile Males

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.

Genetics of male infertility: from research to clinic

“…With the exception of the AR gene, no other causative mutations/polymorphisms have been described with clinical relevance. Novel data on X chromosome-linked genes derives from recent array-CGH studies (see paragraph below) and the most interesting findings concern genes belonging to the cancer testis antigen (CTA) family (Krausz & Giachini 2012) and to a meiosis genes, TEX11 (Yatsenko et al 2015) (Fig. 1B).…”

“…To date, the only CNVs proved to be in a clear-cut cause-effect relationship with spermatogenic impairment are the AZF microdeletions on the Y chromosome (Vogt et al 1996. Furthermore, the relationship between CNVs and male infertility was also investigated on a larger scale by performing array-CGH on the whole genome (Tüttelmann et al 2011, Stouffs et al 2012, Lopes et al 2013 or at R166 C Krausz and others high resolution on the X chromosome (Krausz et al 2012). The three studies that compared the CNV load between patients and controls all converged on a significantly higher burden of CNVs in men with spermatogenic disturbances (Tü ttelmann et al 2011, Krausz et al 2012, Lopes et al 2013).…”

The humanRHOXgene cluster: target genes and functional analysis of gene variants in infertile men

“…Towards this end, the coding region of RHOX was sequenced in 250 idiopathic infertile patients suffering from severe oligozoospermia (total sperm count ≤ 10x10 6 , concentration ≤ 5x10 6 /ml) to identify Single Nucleotide Polymorphisms (SNPs, minor allele frequency [MAF]>0.01) and rare genetic variants (also termed mutations, MAF<0.01). This analysis revealed a non-synonymous mutation c.515G>A (p.Arg172His) and a synonymous mutation c.522C>T (p.Asp174Asp) in RHOXF1 (Table 2), both located downstream of the homeodomain (Fig.…”

Management of non‐obstructive azoospermia

“…Several genes on the X-chromosome are known to specifically act on the testis and play an important role in meiosis [22]. Recent studies have frequently detected altered copy number variants (CNVs) of X-chromosome genes in patients with failure of spermatogenesis, although further investigation is needed for clinical application of this finding [23,24].…”