Meiosis is pivotal for sexual reproduction and fertility. Meiotic programmed DNA double-strand breaks (DSBs) initiate homologous recombination, ensuring faithful chromosome segregation and generation of gametes. However, few studies have focused on meiotic DSB formation in human reproduction. Here, we report four infertile siblings born to a consanguineous marriage, with three brothers suffering from non-obstructive azoospermia and one sister suffering from unexplained infertility with normal menstrual cycles and normal ovary sizes with follicular activity. An autosomal recessive mutation in TOP6BL was found co-segregating with infertility in this family. Investigation of one male patient revealed failure in programmed meiotic DSB formation and meiotic arrest prior to pachytene stage of prophase I. Mouse models carrying similar mutations to that in patients recapitulated the spermatogenic abnormalities of the patient. Pathogenicity of the mutation in the female patient was supported by observations in mice that meiotic programmed DSBs failed to form in mutant oocytes and oocyte maturation failure due to absence of meiotic recombination. Our study thus illustrates the phenotypical characteristics and the genotype-phenotype correlations of meiotic DSB formation failure in humans.

减数分裂是有性生殖和生育的关键。减数分裂程序化的 DNA 双链断裂 (DSB) 启动同源重组，确保忠实的染色体分离和配子的产生。然而，很少有研究关注人类生殖过程中减数分裂 DSB 的形成。在这里，我们报告了四个因近亲结婚而生的不育兄弟姐妹，其中三个兄弟患有非梗阻性无精子症，一个姐妹患有不明原因的不孕症，月经周期正常，卵巢大小正常，卵泡活动正常。TOP6BL常染色体隐性突变在这个家庭中被发现与不育症共同分离。对一名男性患者的调查显示，在前期 I 的粗线期之前，程序性减数分裂 DSB 形成和减数分裂停滞失败。携带与患者相似突变的小鼠模型重现了患者的生精异常。女性患者突变的致病性得到了小鼠观察结果的支持，即减数分裂编程的 DSB 未能在突变卵母细胞中形成，并且由于缺乏减数分裂重组导致卵母细胞成熟失败。因此，我们的研究说明了人类减数分裂 DSB 形成失败的表型特征和基因型-表型相关性。