Patients with mutations in DNAH2, DNAH6 and DNAH10 causing multiple morphological abnormalities of human sperm flagella achieve good ICSI outcomes.

RESEARCH QUESTIONS

What additional genetic mutations in DNAH2, DNAH6 and DNAH10 are linked to multiple morphological abnormalities of sperm flagella (MMAF), and what are the assisted reproductive outcomes in couples affected by these mutations?

DESIGN

A cohort of 75 infertile males with MMAF underwent whole-exome sequencing and Sanger sequencing to identify pathogenic mutations. Papanicolaou staining and electron microscopy were employed to evaluate sperm morphology and ultrastructure. Immunofluorescence was performed to characterize ultrastructural abnormalities at the molecular level, and explore the underlying molecular mechanisms by which mutations in DNAH2, DNAH6 and DNAH10 genes lead to MMAF.

RESULTS

Ten mutations were identified in six unrelated infertile males and were predicted to be pathogenic by bioinformatic tools. Papanicolaou staining and scanning electron microscopy showed that all the male patients harbouring mutations in the DNAH2, DNAH6 and DNAH10 loci displayed severe sperm morphological defects, predominantly characterized by the absence and reduced length of sperm flagella. Transmission electron microscopy (TEM) revealed substantial loss of inner dynein arms and mitochondrial damage, and immunofluorescence data further supported the findings of TEM and indicated a possible interaction between DNAH2 and DNAH10. Moreover, five out of six affected couples achieved a live birth via intracytoplasmic sperm injection (ICSI).

CONCLUSIONS

The data suggest that patients with DNAH2, DNAH6 and DNAH10 mutations causing severe asthenoteratozoospermia can achieve favourable outcomes through ICSI. These findings broaden the spectrum of DNAH2, DNAH6 and DNAH10 mutations, and provide valuable insights for future genetic counselling of infertile males with MMAF.