Abstract
A genetic origin is estimated in 30% of infertile men with the common phenotypes of oligo- or azoospermia, but the pathogenesis of spermatogenic failure remains frequently obscure. To determine the involvement of Copy Number Variants (CNVs) in the origin of male infertility, patients with idiopathic severe oligozoospermia (N = 89), Sertoli-cell-only syndrome (SCOS, N = 37)) and controls with normozoospermia (N = 100) were analysed by array-CGH using the 244A/400K array sets (Agilent Technologies). The mean number of CNVs and the amount of DNA gain/loss were comparable between all groups. Ten recurring CNVs were only found in patients with severe oligozoospermia, three only in SCOS and one CNV in both groups with spermatogenic failure but not in normozoospermic men. Sex-chromosomal, mostly private CNVs were significantly overrepresented in patients with SCOS. CNVs found several times in all groups were analysed in a case-control design and four additional candidate genes and two regions without known genes were associated with SCOS (P<1×10−3). In conclusion, by applying array-CGH to study male infertility for the first time, we provide a number of candidate genes possibly causing or being risk factors for the men's spermatogenic failure. The recurring, patient-specific and private, sex-chromosomal CNVs as well as those associated with SCOS are candidates for further, larger case-control and re-sequencing studies.
Highlights
Infertility, which affects 10–15% of all couples, is attributed to a malefactor in around 50%
Copy Number Variants (CNVs) have not been analysed in men with spermatogenic failure and we hypothesised that CNVs cause spermatogenic failure by either of the following mechanisms: An increased number or specific distribution of CNVs could result in defective recombination, meiotic failure and loss of germ cells
No significant differences in number of CNVs (Fig. 2) or amount of DNA change were found between controls and the two study groups
Summary
Infertility, which affects 10–15% of all couples, is attributed to a male (co-)factor in around 50%. Male infertility is mostly caused by spermatogenic failure, clinically noted as oligo- or azoospermia. Male infertility of genetic origin supposedly affects about 1 in 40 adult men and can be considered a common, complex disease. The currently established genetic causes of male infertility comprise abnormalities on all genomic levels from chromosomal abnormalities, in particular Klinefelter syndrome, to Y-chromosomal (azoospermia factor, AZF) deletions, to mutations of the cystic fibrosis transmembrane conductance regulator (CFTR, all gene information - name, location, IDs - available as Table S1) gene. Routinely performed in clinical workup [4] karyotyping, AZF deletion screening and CFTR sequencing elucidate the reason for infertility in only 5% of unselected and around 20% of azoospermic patients [1,2]
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