Novel loss-of-function SPAG17 homozygous variant segregated in a family with severe asthenozoospermia: upgrading gene-disease validity to strong
Abstract
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,…
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Evidence Hub reads this as a case report, done in people. Its evidence level is 5 of 5 (Very low · case / narrative / animal / in vitro / in silico). Case reports, narrative reviews, and animal, cell or computer-model studies give the weakest evidence for human health.
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