Abstract：
Non-obstructive azoospermia (NOA) resulting from primary spermatogenic failure represents one of the most severe forms of male infertility, largely because therapeutic options are very limited. Beyond their diagnostic value, genetic tests for NOA also hold prognostic potential. Specifically, genetic diagnosis enables the establishment of genotype-testicular phenotype correlations, which, in some cases, provide a negative predictive value for testicular sperm extraction (TESE), thereby preventing unnecessary surgical procedures. In this study, we employed whole-genome sequencing (WGS) to investigate two generations of an Iranian family with NOA and identified a homozygous splicing variant in TDRKH (NM_001083965.2: c.562-2A>T). TDRKH encodes a conserved mitochondrial membrane-anchored factor essential for piRNA biogenesis in germ cells. In Tdrkh knockout mice, de-repression of retrotransposons in germ cells leads to spermatogenic arrest and male infertility. Previously, our team reported TDRKH involvement in human NOA cases through the investigation of a North African cohort. This current study marks the second report of TDRKH\'s role in NOA and human male infertility, underscoring the significance of the piRNA pathway in spermatogenesis. Furthermore, across both studies, we demonstrated that men carrying TDRKH variants, similar to knockout mice, exhibit complete spermatogenic arrest, correlating with failed testicular sperm retrieval.
摘要：
原发性生精失败导致的非梗阻性无精子症（NOA）是男性不育的最严重形式之一，主要是因为治疗选择非常有限。除了它们的诊断价值，NOA的基因检测也具有预后潜力。具体来说,基因诊断能够建立基因型-睾丸表型相关性，which,在某些情况下,提供睾丸精子提取(TESE)的阴性预测值，从而防止不必要的外科手术。在这项研究中,我们采用全基因组测序(WGS)对一个伊朗NOA家族的两代人进行了调查,并在TDRKH中鉴定了一个纯合剪接变体(NM_001083965.2:c.562-2A>T).TDRKH编码生殖细胞中piRNA生物发生所必需的保守线粒体膜锚定因子。在Tdrkh基因敲除小鼠中，生殖细胞中反转录转座子的去抑制导致生精停滞和男性不育。以前,我们的团队通过对北非队列的调查报告了TDRKH参与人类NOA病例.这项研究标志着TDRKH在NOA和人类男性不育中的作用的第二次报告，强调了piRNA途径在精子发生中的重要性。此外，在这两项研究中，我们证明了携带TDRKH变体的男性，类似于敲除小鼠，表现出完全的生精停滞，与睾丸精子回收失败有关。
