Medical Genetics Unit (UGM), Faculty of Medicine, Saint Joseph University, Beirut, Lebanon.
Institut Neuromyogène, Equipe Métabolisme énergétique et développement neuronal, CNRS UMR 5310, INSERM U1217, Université Lyon 1, Lyon, France.
Mol Hum Reprod. 2021 May 29;27(6). doi: 10.1093/molehr/gaab034.
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.
男性不育症影响大约 7%的普通男性人群。在 0.4-1.4%的不育男性中观察到平衡的结构性染色体重排，被认为是不育的一个既定原因。然而，潜在的病理生理机制仍需阐明。为了鉴定可能与三位不同平衡易位携带者的精子发生缺陷有关的候选基因，我们采用了一种结合标准和高通量细胞遗传学和分子技术的策略。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，而外显子组测序用于排除患者中与染色体重排无关的任何分子事件的存在。在这三位患者中，我们都对所有易位断点进行了特征分析。我们鉴定了四个变体：在患者 1 中 LACTB2 基因的位置效应、患者 2 中 CTDP1 基因的杂合性缺失、患者 3 中 DNAH5 基因的两个单核苷酸变异（SNVs）和 17q12 的杂合性缺失。本研究中鉴定的变体需要进一步验证，以评估它们在男性不育症中的作用。本研究表明，除了结构性重排对减数分裂的机械效应外，断点还可能导致额外的改变，如基因缺失或位置效应。此外，可能碰巧存在额外的 SNVs 或拷贝数变异，这可以解释染色体重排对精子发生的不同影响。总之，本研究证实了在基因组范围内结合不同细胞遗传学和分子技术来研究精子发生障碍和结构性重排患者的相关性。
