BACKGROUND Asthenoteratospermia with multiple morphological abnormalities in the sperm flagella (MMAF) is a significant cause of male infertility. WDR19 is a core component in the IFT-A complex and has a critical role in intraflagellar transport. However, the role of WDR19 mutations in male infertility has yet to be examined. METHODS AND RESULTS We performed whole exome sequencing (WES) for 65 asthenoteratospermia individuals and identified a proband who carried a homozygous WDR19 (c.A3811G, p.K1271E) mutation from a consanguineous family. Systematic examinations, including CT scanning and retinal imaging, excluded previous ciliopathic syndromes in the proband. Moreover, semen analysis of this patient showed that the progressive rate decreased to zero, and the sperm flagella showed multiple morphological abnormalities. Scanning and transmission electron microscopy assays indicated that the ultrastructure of sperm flagella in the patient was completely destroyed, while immunofluorescence revealed that WDR19 was absent from the sperm neck and flagella. Moreover, IFT140 and IFT88, predicted to interact with WDR19 directly, were mis-allocated in the WDR19-mutated sperm. Notably, the MMAF subject harboring WDR19 variant and his partner successfully achieved clinical pregnancy through intracytoplasmic sperm injection (ICSI). CONCLUSIONS We identified WDR19 as a novel pathogenic gene for male infertility caused by asthenoteratospermia in the absence of other ciliopathic phenotypes, and that patients carrying WDR19 variant can have favorable pregnancy outcomes following ICSI.

中文翻译：

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WDR19 中的一种新的纯合突变会诱导精子鞭毛中的微管解体和非综合征性弱精子症。

背景技术弱精子症伴精子鞭毛多种形态异常（MMAF）是男性不育的重要原因。WDR19 是 IFT-A 复合物的核心成分，在鞭毛内运输中发挥着关键作用。然而，WDR19 突变在男性不育中的作用仍有待研究。方法和结果我们对 65 名弱精子症个体进行了全外显子组测序 (WES)，并鉴定了一名来自近亲家庭的携带纯合 WDR19 (c.A3811G，p.K1271E) 突变的先证者。系统检查，包括 CT 扫描和视网膜成像，排除了先证者先前的纤毛病综合征。此外，该患者的精液分析显示，进展率降至零，精子鞭毛出现多种形态异常。扫描和透射电子显微镜检测表明，患者精子鞭毛的超微结构被完全破坏，而免疫荧光显示精子颈部和鞭毛中不存在WDR19。此外，预计与 WDR19 直接相互作用的 IFT140 和 IFT88 在 WDR19 突变精子中被错误分配。值得注意的是，携带WDR19变异体的MMAF受试者及其伴侣通过胞浆内单精子注射（ICSI）成功实现了临床妊娠。结论 我们确定 WDR19 是在没有其他纤毛病表型的情况下由弱精子症引起的男性不育的新致病基因，并且携带 WDR19 变异的患者在 ICSI 后可以获得良好的妊娠结局。