Association of novel DNAH11 and DNAH 5 variants with oligoasthenoteratozoospermia lead to male infertility

Abstract Background Bi-allelic variants in DNAH11 and DNAH5 have been identified as causative factors in Primary Ciliary Dyskinesia, leading to abnormal respiratory cilia. Nonetheless, the specific impact of these variants on sperm flagellar and their involvement in male infertility remain elusive. Methods A collaborative effort involving two Chinese reproductive centers conducted a study with 975 unrelated infertile men. Whole-exome sequencing was employed for variant screening, and Sanger sequencing confirmed the identified variants. Morphological and ultrastructural analyses of sperm were conducted using Scanning Electron Microscopy and Transmission Electron Microscopy. Western Blot Analysis and Immunofluorescence Analysis were utilized to assess protein levels and localization. ICSI was performed to evaluate its efficacy in achieving favorable pregnancy outcomes for individuals with DNAH11 / DNAH5 variants. Results The study identified seven novel variants in the DNAH11 gene in four subjects and two novel variants in the DNAH5 gene in one individual with oligoasthenoteratozoospermia. These variants led to structural defects in sperm flagella, particularly affecting the outer dynein arms (ODAs) and adjacent structures. Two out of four individuals with DNAH11 variants achieved clinical pregnancies through ICSI. However, the patient carrying DNAH5 variants did not achieve a favorable pregnancy outcome. Conclusions The findings confirm the association between male infertility and bi-allelic deleterious variants in DNAH11 / DNAH 5, resulting in the aberrant assembly of sperm flagella and contributing to oligoasthenoteratozoospermia. Importantly, ICSI emerges as an effective intervention for overcoming reproductive challenges caused by DNAH11 gene variants.