Abstract
Oligozoospermia is an important cause of male infertility for which treatment options are limited. Spermatogenesis is complex, and the causes of oligozoospermia remain largely unknown. Because genetic mutations are important factors of oligozoospermia pathogenesis, our study aimed to explore the genetic causes of oligozoospermia. Whole- exome sequencing (WES) was performed on one proband from a Chinese family who was diagnosed with oligozoospermia. The pathogenic mutations were confirmed by Sanger sequencing, and a minigene assay was used to determine the effect of the identified splicing mutation. We identified a novel compound heterozygous mutation in the TDRD9 gene, comprising a splicing mutation (c.1115 + 3A > G) and a frameshift mutation (c.958delC), in the proband; neither of these mutations were found in 50 unrelated healthy people. In addition, a minigene assay demonstrated that the frameshift produced partially truncated protein, and the splicing mutation led to a frameshift mutation and premature termination due to abnormal alternative splicing of TDRD9. These findings indicate that deleterious compound heterozygous mutation in TDRD9 could lead to oligozoospermia, highlighting the crucial role of TDRD9 in spermatogenesis and further clarifying the genetic causes of male infertility resulting from oligozoospermia. Our study expands the spectrum of TDRD9-related phenotypes and provides a new specific target for future genetic counseling.