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Disruptions in the piRNA pathway typically lead to severe spermatogenic defects and thus male infertility. The <jats:italic>HENMT1<\/jats:italic> gene is a key player in piRNAs primary biogenesis and dysfunction of HENMT1 protein in meiotic and haploid germ cells resulted in the loss of piRNA methylation, piRNA instability, and TE de\u2010repression. Henmt1\u2010knockout mice exhibit a severe oligo\u2010astheno\u2010teratozoospermia (OAT) phenotype, whereas patients with <jats:italic>HENMT1<\/jats:italic> variants display more severe azoospermia phenotypes, ranging from meiotic arrest to hypospermatogenesis. Through whole\u2010exome sequencing (WES) of infertile patient cohorts, we identified two new patients with variants in the <jats:italic>HENMT1<\/jats:italic> gene presenting spermatozoa in their ejcaulate, providing us the opportunity to study spermatozoa from these patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objectives<\/jats:title><jats:p>Investigate the spermatozoa of two patients harboring an <jats:italic>HENMT1<\/jats:italic> variant to determine whether or not these scarce spermatozoa could be used with assisted reproductive technologies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and methods<\/jats:title><jats:p><jats:italic>HENMT1<\/jats:italic> variants identified by WES were validated through Sanger sequencing. Comprehensive semen analysis was conducted, and sperm cells were subjected to transmission electron microscopy for structural examination, in situ hybridization for aneuploidy assessment, and aniline blue staining for DNA compaction status. Subsequently, we assessed their suitability for in vitro fertilization using intracytoplasmic sperm injection (IVF\u2010ICSI).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our investigations revealed a severe OAT phenotype similar to <jats:italic>knockout<\/jats:italic> mice, revealing altered sperm concentration, mobility, morphology, aneuploidy and nuclear compaction defects. Multiple IVF\u2010ICSI attempts were also performed, but no live births were achieved.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>We confirm the crucial role of <jats:italic>HENMT1<\/jats:italic> in spermatogenesis and highlight a phenotypic continuum associated with <jats:italic>HENMT1<\/jats:italic> variants. Unfortunately, the clinical outcome of these genetic predispositions remains unfavorable, regardless of the patient's phenotype.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The presence of spermatozoa is insufficient to anticipate ICSI pregnancy success in <jats:italic>HENMT1<\/jats:italic> patients.<\/jats:p><\/jats:sec>","DOI":"10.1111\/andr.13730","type":"journal-article","created":{"date-parts":[[2024,8,9]],"date-time":"2024-08-09T14:09:15Z","timestamp":1723212555000},"page":"1137-1148","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Phenotypic continuum and poor intracytoplasmic sperm injection intracytoplasmic sperm injection prognosis in patients harboring <i>HENMT1<\/i> variants"],"prefix":"10.1111","volume":"13","author":[{"given":"Zeina","family":"Wehbe","sequence":"first","affiliation":[{"name":"Universit\u00e9 Grenoble Alpes Institute for Advanced Biosciences (IAB)  La 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