Novel loss-of-function SPAG17 homozygous variant segregated in a family with severe asthenozoospermia: upgrading gene-disease validity to strong.

BACKGROUND

Severe asthenozoospermia is a significant cause of male infertility, commonly associated with genetic defects affecting sperm motility. However, the specific genetic contributors remain underexplored.

OBJECTIVE

This study aimed to identify a genetic variant responsible for severe asthenozoospermia in two siblings and to evaluate the clinical validity of the gene-disease relationship between SPAG17 and this condition.

METHODS

Whole exome sequencing (WES) was performed on two siblings diagnosed with severe asthenozoospermia. Sperm motility and morphology were assessed through standard semen analysis and transmission electron microscopy (TEM). The gene-disease validity was evaluated using the ClinGen Gene-Disease Validity SOP, incorporating both genetic and experimental evidence.

RESULTS

A novel homozygous nonsense variant in SPAG17 (NM_206996.4: c.2188C>T; p.Q730*) was identified in both affected siblings. Semen analysis revealed significantly reduced sperm motility and abnormal sperm morphology, including malformed flagella. TEM showed severe axonemal defects, such as absent central-pair microtubules and disorganized axonemal structures. The gene-disease validity between SPAG17 and severe asthenozoospermia was upgraded to "Strong", with a cumulative score of 13.4 points based on genetic (9.4 points) and experimental (4 points) evidence.

CONCLUSION

We identified a novel homozygous nonsense variant in SPAG17 in two siblings with severe asthenozoospermia, emphasizing its critical role in sperm motility and male fertility. The upgraded "Strong" gene-disease validity strengthens SPAG17's clinical utility for genetic diagnostics and counseling.