Male infertility affects about 7% of the general male population. Balanced structural chromosomal rearrangements are observed in 0.4–1.4% of infertile males and are considered as a well-established cause of infertility. However, underlying pathophysiological mechanisms still need to be clarified. A strategy combining standard and high throughput cytogenetic and molecular technologies was applied in order to identify the candidate genes that might be implicated in the spermatogenesis defect in three male carriers of different balanced translocations. Fluorescence in situ hybridization (FISH) and whole-genome paired-end sequencing were used to characterize translocation breakpoints at the molecular level while exome sequencing was performed in order to exclude the presence of any molecular event independent from the chromosomal rearrangement in the patients. All translocation breakpoints were characterized in the three patients. We identified four variants: a position effect on LACTB2 gene in Patient 1, a heterozygous CTDP1 gene disruption in Patient 2, two single-nucleotide variations (SNVs) in DNAH5 gene and a heterozygous 17q12 deletion in Patient 3. The variants identified in this study need further validation to assess their roles in male infertility. This study shows that beside the mechanical effect of structural rearrangement on meiosis, breakpoints could result in additional alterations such as gene disruption or position effect. Moreover, additional SNVs or copy number variations may be fortuitously present and could explain the variable impact of chromosomal rearrangements on spermatogenesis. In conclusion, this study confirms the relevance of combining different cytogenetic and molecular techniques to investigate patients with spermatogenesis disorders and structural rearrangements on genomic scale.

中文翻译：

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通过下一代测序破译不育男性的平衡易位以确定精子发生障碍的候选基因

男性不育症影响大约 7% 的一般男性人口。在 0.4-1.4% 的不育男性中观察到平衡的结构染色体重排，并被认为是公认的不育原因。然而，潜在的病理生理机制仍有待阐明。采用结合标准和高通量细胞遗传学和分子技术的策略，以确定可能与不同平衡易位的三种男性携带者的精子发生缺陷有关的候选基因。荧光原位杂交 (FISH) 和全基因组配对末端测序用于在分子水平上表征易位断点，同时进行外显子组测序以排除任何独立于患者染色体重排的分子事件的存在。所有易位断点均在三名患者中进行了表征。我们鉴定了四种变异：患者 1 中 LACTB2 基因的位置效应、患者 2 中的杂合 CTDP1 基因破坏、DNAH5 基因中的两个单核苷酸变异 (SNV) 和患者 3 中的杂合 17q12 缺失。本研究中鉴定的变异需要进一步验证以评估它们在男性不育症中的作用。这项研究表明，除了结构重排对减数分裂的机械效应外，断点可能导致额外的改变，例如基因破坏或位置效应。此外，可能偶然存在额外的 SNV 或拷贝数变异，并可以解释染色体重排对精子发生的可变影响。总之，这项研究证实了结合不同的细胞遗传学和分子技术来研究患有精子发生障碍和基因组规模结构重排的患者的相关性。