Globozoospermia is a rare phenotype of primary male infertility inducing the production of round-headed spermatozoa without acrosome. Anomalies of DPY19L2 account for 50–70% of all cases and the entire deletion of the gene is by far the most frequent defect identified. Here, we present a large cohort of 69 patients with 20–100% of globozoospermia. Genetic analyses including multiplex ligation-dependent probe amplification, Sanger sequencing and whole-exome sequencing identified 25 subjects with a homozygous DPY19L2 deletion (36%) and 14 carrying other DPY19L2 defects (20%). Overall, 11 deleterious single-nucleotide variants were identified including eight novel and three already published mutations. Patients with a higher rate of round-headed spermatozoa were more often diagnosed and had a higher proportion of loss of function anomalies, highlighting a good genotype phenotype correlation. No gene defects were identified in patients carrying < 50% of globozoospermia while diagnosis efficiency rose to 77% for patients with > 50% of globozoospermia. In addition, results from whole-exome sequencing were scrutinized for 23 patients with a DPY19L2 negative diagnosis, searching for deleterious variants in the nine other genes described to be associated with globozoospermia in human (C2CD6, C7orf61, CCDC62, CCIN, DNAH17, GGN, PICK1, SPATA16, and ZPBP1). Only one homozygous novel truncating variant was identified in the GGN gene in one patient, confirming the association of GGN with globozoospermia. In view of these results, we propose a novel diagnostic strategy focusing on patients with at least 50% of globozoospermia and based on a classical qualitative PCR to detect DPY19L2 homozygous deletions. In the absence of the latter, we recommend to perform whole-exome sequencing to search for defects in DPY19L2 as well as in the other previously described candidate genes.

globozoospermia是一种罕见的原发性男性不育症表型，可诱导产生不带顶体的圆头精子。DPY19L2的异常占所有病例的50-70％，而基因的整个缺失是迄今为止发现的最常见的缺陷。在这里，我们提出了69名患者的大队列研究，其中有20–100％的小精子症。遗传分析，包括多重连接依赖性探针扩增，Sanger测序和全外显子测序，确定了25名纯合DPY19L2缺失的受试者（36％）和14名携带其他DPY19L2的受试者缺陷（20％）。总体上，鉴定出11种有害的单核苷酸变体，包括8个新的和3个已经发表的突变。圆头精子发生率较高的患者被诊断得更多，并且功能丧失异常的比例更高，这突出了良好的基因型表型相关性。携带小于50％的小精子症的患者没有发现基因缺陷，而携带大于50％的小精子症的患者的诊断效率提高到77％。此外，对全外显子组测序的结果进行了仔细检查，对23例诊断为DPY19L2阴性的患者进行了研究，以寻找与人类球孢子症相关的其他9个基因的有害变异（C2CD6，C7orf61，CCDC62，CCIN，DNAH17，GGN，PICK1，SPATA16和ZPBP1）。一名患者的GGN基因中仅鉴定出一种纯合的新型截短变体，证实了GGN与小精子症的关联。鉴于这些结果，我们提出了一种新的诊断策略，重点针对患有至少50％的球孢子症的患者，并基于经典的定性PCR检测DPY19L2纯合缺失。在没有后者的情况下，我们建议执行全外显子组测序以搜索DPY19L2以及先前描述的其他候选基因中的缺陷。