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TDRD5 is essential for retrotransposon silencing and pachytene piRNA biogenesis; however, a causal link between <jats:italic>TDRD5<\/jats:italic> variants and human infertility has not yet been established.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>To identify the likely pathogenic variants of <jats:italic>TDRD5<\/jats:italic> in infertile men, characterised by azoospermia or severe oligozoospermia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Material and methods<\/jats:title><jats:p>Potential candidate variants were identified and confirmed using whole\u2010exome and Sanger sequencing. Haematoxylin and eosin staining, immunofluorescence, and ultrastructural analyses were performed to investigate the structural and functional abnormalities of spermatozoa. The pathogenicity of the identified <jats:italic>TDRD5<\/jats:italic> variants was verified using in vitro experiments. Functional effects of the C\u2010terminal nonsense variant were assessed via histology, immunofluorescence staining, and small\u2010RNA sequencing. Intracytoplasmic sperm injection (ICSI) was also performed to evaluate the efficacy of the clinical treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified a homozygous missense variant (c.3043G\u00a0&gt;\u00a0A, p.A1015T) and a homozygous nonsense variant (c.2293G\u00a0&gt;\u00a0T, p.E765*) of <jats:italic>TDRD5<\/jats:italic> in two unrelated infertile men. Both patients exhibited severe oligoasthenoteratozoospermia, characterised by the presence of spermatozoa with multiple heads and\/or flagella, as well as acrosomal hypoplasia. In vitro experiments revealed that the p.A1015T variant caused a diffuse distribution of TDRD5 granules, whereas the p.E765* variant led to the production of a C\u2010terminal truncated protein with nuclear localisation, instead of the typical cytoplasmic localisation observed for the wild\u2010type protein. Functional investigations also revealed that truncation of the C\u2010terminal region of TDRD5 could potentially lead to a decline in the expression levels of intermitochondrial cement and chromatoid body components, such as MIWI (PIWIL1) and UPF1, and a slight decrease in the abundance of pachytene piRNA, ultimately resulting in compromised spermiogenesis. ICSI may be an effective treatment for these deficiencies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion and conclusion<\/jats:title><jats:p>This study implicates <jats:italic>TDRD5<\/jats:italic> as a novel candidate gene in the pathogenesis of human male infertility, emphasising the contribution of piRNA pathway genes to male infertility. In addition, our data suggest that ICSI could be a promising treatment for infertile men harbouring <jats:italic>TDRD5<\/jats:italic> variants.<\/jats:p><\/jats:sec>","DOI":"10.1111\/andr.13676","type":"journal-article","created":{"date-parts":[[2024,6,7]],"date-time":"2024-06-07T09:29:11Z","timestamp":1717752551000},"page":"1270-1284","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Homozygous deleterious variants in the C\u2010terminal of <i>TDRD5<\/i> impair spermiogenesis, causing severe oligoasthenoteratozoospermia in humans"],"prefix":"10.1111","volume":"13","author":[{"given":"Rui","family":"Guo","sequence":"first","affiliation":[{"name":"NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University  Hefei Anhui China"},{"name":"Department of Obstetrics and Gynecology The First Affiliated Hospital of Anhui Medical University  Hefei Anhui 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