Non-obstructive azoospermia (NOA), the lack of spermatozoa in semen due to impaired spermatogenesis affects nearly 1% of men. In about half of cases, an underlying cause for NOA cannot be identified. This study aimed to identify novel variants associated with idiopathic NOA. We identified a nonconsanguineous family in which multiple sons displayed the NOA phenotype. We performed whole-exome sequencing in three affected brothers with NOA, their two unaffected brothers and their father, and identified compound heterozygous frameshift variants (one novel and one extremely rare) in Telomere Repeat Binding Bouquet Formation Protein 2 (TERB2) that segregated perfectly with NOA. TERB2 interacts with TERB1 and Membrane Anchored Junction Protein (MAJIN) to form the tripartite meiotic telomere complex (MTC), which has been shown in mouse models to be necessary for the completion of meiosis and both male and female fertility. Given our novel findings of TERB2 variants in NOA men, along with the integral role of the three MTC proteins in spermatogenesis, we subsequently explored exome sequence data from 1495 NOA men to investigate the role of MTC gene variants in spermatogenic impairment. Remarkably, we identified two NOA patients with likely damaging rare homozygous stop and missense variants in TERB1 and one NOA patient with a rare homozygous missense variant in MAJIN. Available testis histology data from three of the NOA patients indicate germ cell maturation arrest, consistent with mouse phenotypes. These findings suggest that variants in MTC genes may be an important cause of NOA in both consanguineous and outbred populations.

非梗阻性无精子症 (NOA)，由于精子发生受损导致精液中缺乏精子，影响了近 1% 的男性。在大约一半的情况下，无法确定 NOA 的根本原因。本研究旨在鉴定与特发性 NOA 相关的新变异。我们确定了一个非血缘家庭，其中多个儿子表现出 NOA 表型。我们对三个患有 NOA 的受影响兄弟、他们两个未受影响的兄弟和他们的父亲进行了全外显子组测序，并在端粒重复结合花束形成蛋白 2 ( TERB2) 与 NOA 完美隔离。TERB2 与 TERB1 和膜锚定连接蛋白 (MAJIN) 相互作用，形成三方减数分裂端粒复合体 (MTC)，这在小鼠模型中已被证明是完成减数分裂和男性和女性生育所必需的。鉴于我们在 NOA 男性中TERB2变异的新发现，以及三种 MTC 蛋白在精子发生中的整体作用，我们随后探索了 1495 名 NOA 男性的外显子组序列数据，以研究 MTC 基因变异在生精障碍中的作用。值得注意的是，我们在TERB1 中发现了两名可能具有破坏性的罕见纯合终止和错义变异的NOA 患者和一名在MAJIN 中具有罕见纯合错义变异的 NOA 患者. 来自三名 NOA 患者的可用睾丸组织学数据表明生殖细胞成熟停滞，与小鼠表型一致。这些发现表明 MTC 基因的变异可能是近亲和远交种群中 NOA 的重要原因。