A Novel Variant of the ACTRT1 Gene is Potentially Associated with Oligoasthenoteratozoospermia, Acrosome Detachment, and Fertilization Failure

Background: Male infertility is a common reproductive disorder, affecting about 7% of men in the general population. Despite its prevalence, the cause of infertility is often unknown. This case report presents the results of a comprehensive evaluation of a patient with severe oligoteratozoospermia and primary infertility. Methods: The patient underwent clinical, andrological, and genetic examinations, including semen analysis, transmission electron microscopy, cytogenetic examination, molecular analysis of the AZF locus and the CFTR gene, whole exome sequencing and Sanger sequencing. Results: Semen analysis revealed severe oligoasthenoteratozoospermia. Transmission electron microscopy showed acrosome detachment from the nucleus in 49% of the spermatozoa. A high percentage of spermatozoa with insufficiently condensed ("immature") chromatin (54%) was also observed. No chromosomal abnormalities, Y chromosome microdeletions, or pathogenic CFTR gene variants were identified. Whole exome sequencing revealed a novel c.821G>C variant (chrX:127185365G>C; NM_138289.4) in the ACTRT1 gene (Xq25). This variant was hemizygous in the patient and heterozygous in his mother, as determined by Sanger sequencing. According to the ACMG guidelines (PM2, PP3), this missense variant in the ACTRT1 gene was classified as a variant of uncertain clinical significance (VUS). Amino acid conservation and 3D protein modeling predict that the identified variant has a deleterious effect on the protein. Conclusions: This study demonstrates that hemizygous variants of the ACTRT1 gene can cause X-linked specific teratozoospermia characterized by acrosome detachment from the sperm nucleus. These findings underscore the importance of genetic testing for infertile men with specific morphological abnormalities.