{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T06:13:47Z","timestamp":1771481627302,"version":"3.50.1"},"reference-count":23,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T00:00:00Z","timestamp":1771459200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Severe asthenozoospermia is a significant cause of male infertility, commonly associated with genetic defects affecting sperm motility. However, the specific genetic contributors remain underexplored.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic>SPAG<\/jats:italic>\n                      17 and this condition.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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\u2013Disease Validity SOP, incorporating both genetic and experimental evidence.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A novel homozygous nonsense variant in\n                      <jats:italic>SPAG<\/jats:italic>\n                      17 (NM_206996.4: c.2188C&amp;gt;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\n                      <jats:italic>SPAG<\/jats:italic>\n                      17 and severe asthenozoospermia was upgraded to \u201cStrong\u201d, with a cumulative score of 13.4 points based on genetic (9.4 points) and experimental (4 points) evidence.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      We identified a novel homozygous nonsense variant in\n                      <jats:italic>SPAG<\/jats:italic>\n                      17 in two siblings with severe asthenozoospermia, emphasizing its critical role in sperm motility and male fertility. The upgraded \u201cStrong\u201d gene-disease validity strengthens\n                      <jats:italic>SPAG<\/jats:italic>\n                      17\u2019s clinical utility for genetic diagnostics and counseling.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2026.1754106","type":"journal-article","created":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T05:22:55Z","timestamp":1771478575000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel loss-of-function SPAG17 homozygous variant segregated in a family with severe asthenozoospermia: upgrading gene-disease validity to strong"],"prefix":"10.3389","volume":"17","author":[{"given":"Li","family":"Wang","sequence":"first","affiliation":[{"name":"Gansu Provincial Maternity and Child-care Hospital(Gansu Provincial Central Hospital), The Second Reproductive Medicine Center","place":["Lanzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinli","family":"Li","sequence":"additional","affiliation":[{"name":"Reproductive Medicine Center, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University","place":["Shanghai, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ling","family":"Huang","sequence":"additional","affiliation":[{"name":"Gansu Provincial Maternity and Child-care Hospital(Gansu Provincial Central Hospital), The Second Reproductive Medicine Center","place":["Lanzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jialing","family":"Wang","sequence":"additional","affiliation":[{"name":"Gansu Provincial Maternity and Child-care Hospital(Gansu Provincial Central Hospital), The Second Reproductive Medicine Center","place":["Lanzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Zhou","sequence":"additional","affiliation":[{"name":"Gansu Provincial Maternity and Child-care Hospital(Gansu Provincial Central Hospital), The Second Reproductive Medicine Center","place":["Lanzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Ding","sequence":"additional","affiliation":[{"name":"Gansu Provincial Maternity and Child-care Hospital(Gansu Provincial Central Hospital), The Second Reproductive Medicine Center","place":["Lanzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jia","family":"Li","sequence":"additional","affiliation":[{"name":"Gansu Provincial Maternity and Child-care Hospital(Gansu Provincial Central Hospital), The Second Reproductive Medicine Center","place":["Lanzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qinghua","family":"Zhang","sequence":"additional","affiliation":[{"name":"Medical Genetics Center, Gansu Provincial Maternity and Child-care Hospital(Gansu Provincial Central Hospital)","place":["Lanzhou, Gansu, China"]},{"name":"The First Clinical Medical College of Gansu University of Chinese Medicine","place":["Lanzhou, Gansu, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Reproductive Medicine Center, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University","place":["Shanghai, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guangmei","family":"Xie","sequence":"additional","affiliation":[{"name":"Gansu Provincial Maternity and Child-care Hospital(Gansu Provincial Central Hospital), The Second Reproductive Medicine Center","place":["Lanzhou, 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