Novel mutations in ZMYND15 are associated with male infertility with oligozoospermia/azoospermia.

PURPOSE: This study aimed to identify the genetic causes of male infertility associated with oligozoospermia/azoospermia in two unrelated Chinese families. METHODS: Whole-exome sequencing (WES) and Sanger sequencing were performed on peripheral blood samples from three infertile individuals with reduced sperm counts. Semen analysis data were collected, and sperm morphology was evaluated using hematoxylin and eosin staining, along with transmission electron microscopy. Acidic aniline staining and fluorescence in situ hybridization (FISH) were employed to assess sperm nuclear maturity and chromosome aneuploidy. In vitro analyses were performed to determine the effect of the identified variants. RESULTS: We identified two novel homozygous variants in ZMYND15: a frameshift variant (NM_001136046.3:c.828-2_833dupAGAGAGCT) in family 1 and a missense variant (c.2051 T > A:p.Met684Lys) in family 2. Both variants were absent in public databases, and the missense variant was predicted to be deleterious. In vitro analyses confirmed that the frameshift variants likely impact protein function. Abnormal sperm head morphologies, characterized by reduced chromatin condensation and nuclear aneuploidy, were frequently observed in ZMYND15 mutant individual. CONCLUSION: Our findings reveal two novel ZMYND15 variants in three infertile patients with oligozoospermia/azoospermia, expanding the mutational spectrum of ZMYND15 and providing valuable insights for genetic counseling and the diagnosis in cases of male infertility.