{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T11:46:56Z","timestamp":1784634416447,"version":"3.55.0"},"reference-count":36,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2024,8,19]],"date-time":"2024-08-19T00:00:00Z","timestamp":1724025600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Shanghai Pujiang Program","award":["2020PJD078"],"award-info":[{"award-number":["2020PJD078"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Male infertility affects approximately 7% of the male population, and about 15% of these cases are predicted to have a genetic etiology. One gene implicated in autosomal dominant male infertility, SYCP2, encodes a protein critical for the synapsis of homologous chromosomes during meiosis I, resulting in impaired spermatogenesis. However, the clinical validity of the gene\u2013disease pair was previously categorized as on the border of limited and moderate due to few reported cases. This study investigates the genetic cause of infertility for three unrelated Chinese patients with oligoasthenozoospermia. Whole exome sequencing (WES) and subsequent Sanger sequencing revealed novel heterozygous loss-of-function (LOF) variants in SYCP2 (c.89dup, c.946_947del, and c.4378_4379del). These cases, combined with the previously reported cases, provide strong genetic evidence supporting an autosomal dominant inheritance pattern. The experimental evidence also demonstrates a critical role for SYCP2 in spermatogenesis. Collectively, this updated assessment of the genetic and experimental evidence upgrades the gene\u2013disease association strength of SYCP2 and autosomal dominant male infertility from on the border of limited and moderate to strong. The reclassification improves SYCP2 variant interpretation and qualifies it for the inclusion on diagnostic male infertility gene panels and prioritization in whole exome or genome studies for related phenotypes. These findings therefore improve the clinical interpretation of SYCP2 LOF variants.<\/jats:p>","DOI":"10.3390\/genes15081092","type":"journal-article","created":{"date-parts":[[2024,8,19]],"date-time":"2024-08-19T07:37:21Z","timestamp":1724053041000},"page":"1092","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Novel Loss-of-Function SYCP2 Variants in Infertile Males Upgrade the Gene\u2013Disease Clinical Validity Classification for SYCP2 and Male Infertility to Strong"],"prefix":"10.3390","volume":"15","author":[{"given":"Jinli","family":"Li","sequence":"first","affiliation":[{"name":"Reproductive Medicine Center, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, 2699 West Gaoke Road, Shanghai 201204, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8991-6327","authenticated-orcid":false,"given":"Samantha L.P.","family":"Schilit","sequence":"additional","affiliation":[{"name":"Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanshan","family":"Liang","sequence":"additional","affiliation":[{"name":"Reproductive Medicine Center, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, 2699 West Gaoke Road, Shanghai 201204, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ningxin","family":"Qin","sequence":"additional","affiliation":[{"name":"Reproductive Medicine Center, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, 2699 West Gaoke Road, Shanghai 201204, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoming","family":"Teng","sequence":"additional","affiliation":[{"name":"Reproductive Medicine Center, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, 2699 West Gaoke Road, Shanghai 201204, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0239-6670","authenticated-orcid":false,"given":"Junyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Reproductive Medicine Center, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, 2699 West Gaoke Road, Shanghai 201204, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1038\/s41585-018-0003-3","article-title":"Genetics of Male Infertility","volume":"15","author":"Krausz","year":"2018","journal-title":"Nat. Rev. Urol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1007\/s11930-019-00225-8","article-title":"Recent Advances and Future Opportunities to Diagnose Male Infertility","volume":"11","author":"Schilit","year":"2019","journal-title":"Curr. Sex Health Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.21037\/tau-19-681","article-title":"How Do We Counsel Men with Obstructive Azoospermia Due to CF Mutations?-A Review of Treatment Options and Outcomes","volume":"10","author":"Persily","year":"2021","journal-title":"Transl. Androl. Urol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1093\/humrep\/dez022","article-title":"A Systematic Review and Standardized Clinical Validity Assessment of Male Infertility Genes","volume":"34","author":"Oud","year":"2019","journal-title":"Hum. Reprod."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"13127","DOI":"10.1038\/nature13127","article-title":"Guidelines for Investigating Causality of Sequence Variants in Human Disease","volume":"508","author":"MacArthur","year":"2014","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1016\/j.ajhg.2017.04.015","article-title":"Evaluating the Clinical Validity of Gene-Disease Associations: An Evidence-Based Framework Developed by the Clinical Genome Resource","volume":"100","author":"Strande","year":"2017","journal-title":"Am. J. Hum. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2235","DOI":"10.1056\/NEJMsr1406261","article-title":"ClinGen--the Clinical Genome Resource","volume":"372","author":"Rehm","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.ajhg.2019.11.013","article-title":"SYCP2 Translocation-Mediated Dysregulation and Frameshift Variants Cause Human Male Infertility","volume":"106","author":"Schilit","year":"2020","journal-title":"Am. J. Hum. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2572","DOI":"10.1093\/nar\/26.11.2572","article-title":"SCP2: A Major Protein Component of the Axial Elements of Synaptonemal Complexes of the Rat","volume":"26","author":"Offenberg","year":"1998","journal-title":"Nucleic Acids Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1007\/s003359901062","article-title":"Isolation and Characterization of the Human SCP2 cDNA and Chromosomal Localization of the Gene","volume":"10","author":"Schalk","year":"1999","journal-title":"Mamm. Genome"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1126\/science.1086605","article-title":"Chromosome Choreography: The Meiotic Ballet","volume":"301","author":"Page","year":"2003","journal-title":"Science"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1083\/jcb.200603063","article-title":"Mouse SYCP2 Is Required for Synaptonemal Complex Assembly and Chromosomal Synapsis during Male Meiosis","volume":"173","author":"Yang","year":"2006","journal-title":"J. Cell Biol."},{"key":"ref_13","unstructured":"World Health Organization (2010). WHO Laboratory Manual for the Examination and Processing of Human Semen."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","article-title":"Fast and Accurate Short Read Alignment with Burrows\u2013Wheeler Transform","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1101\/gr.107524.110","article-title":"The Genome Analysis Toolkit: A MapReduce Framework for Analyzing next-Generation DNA Sequencing Data","volume":"20","author":"McKenna","year":"2010","journal-title":"Genome Res."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Dahary, D., Golan, Y., Mazor, Y., Zelig, O., Barshir, R., Twik, M., Iny Stein, T., Rosner, G., Kariv, R., and Chen, F. (2019). Genome Analysis and Knowledge-Driven Variant Interpretation with TGex. BMC Med. Genom., 12.","DOI":"10.1186\/s12920-019-0647-8"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/s40001-023-01000-1","article-title":"Analysis of Euploidy Rates in Preimplantation Genetic Testing for Aneuploidy Cycles with Progestin-Primed versus GnRH Agonist\/Antagonist Protocol","volume":"28","author":"Wang","year":"2023","journal-title":"Eur. J. Med. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1016\/j.fertnstert.2010.05.042","article-title":"Standardization of Grading Embryo Morphology","volume":"94","author":"Racowsky","year":"2010","journal-title":"Fertil. Steril."},{"key":"ref_19","first-page":"581","article-title":"Clinical Predictors of Embryo Quality among Women of Advanced Age Receiving Intracytoplasmic Sperm Injection Cycles in Malaysia: A Cohort Study","volume":"20","author":"Ibrahim","year":"2022","journal-title":"Int. J. Reprod. Biomed."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1146\/annurev-genet-111212-133424","article-title":"Organizing Principles of Mammalian Nonsense-Mediated mRNA Decay","volume":"47","author":"Popp","year":"2013","journal-title":"Annu. Rev. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/nature19057","article-title":"Analysis of Protein-Coding Genetic Variation in 60,706 Humans","volume":"536","author":"Lek","year":"2016","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"S50","DOI":"10.1038\/ncb-nm-fertilityS50","article-title":"Playing for Half the Deck: The Molecular Biology of Meiosis","volume":"8","author":"Champion","year":"2002","journal-title":"Nat. Cell Biol."},{"key":"ref_23","unstructured":"(2013). GTEx Consortium The Genotype-Tissue Expression (GTEx) Project. Nat. Genet., 45, 580\u2013585."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1093\/genetics\/126.3.563","article-title":"Meiosis in Asynaptic Yeast","volume":"126","author":"Rockmill","year":"1990","journal-title":"Genetics"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Takemoto, K., Imai, Y., Saito, K., Kawasaki, T., Carlton, P.M., Ishiguro, K.-I., and Sakai, N. (2020). Sycp2 Is Essential for Synaptonemal Complex Assembly, Early Meiotic Recombination and Homologous Pairing in Zebrafish Spermatocytes. PLoS Genet., 16.","DOI":"10.1371\/journal.pgen.1008640"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1101\/gad.1613608","article-title":"Meiotic Failure in Male Mice Lacking an X-Linked Factor","volume":"22","author":"Yang","year":"2008","journal-title":"Genes Dev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1714","DOI":"10.1016\/S0140-6736(03)14845-3","article-title":"Azoospermia in Patients Heterozygous for a Mutation in SYCP3","volume":"362","author":"Miyamoto","year":"2003","journal-title":"Lancet"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2097","DOI":"10.1056\/NEJMoa1406192","article-title":"X-Linked TEX11 Mutations, Meiotic Arrest, and Azoospermia in Infertile Men","volume":"372","author":"Yatsenko","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1038\/s41436-019-0666-z","article-title":"Diagnostic Gene Sequencing Panels: From Design to Report-a Technical Standard of the American College of Medical Genetics and Genomics (ACMG)","volume":"22","author":"Bean","year":"2020","journal-title":"Genet. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1038\/s41436-020-01083-9","article-title":"DNA-Based Screening and Personal Health: A Points to Consider Statement for Individuals and Health-Care Providers from the American College of Medical Genetics and Genomics (ACMG)","volume":"23","author":"Bean","year":"2021","journal-title":"Genet. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1002\/humu.24291","article-title":"Utilizing ClinGen Gene-Disease Validity and Dosage Sensitivity Curations to Inform Variant Classification","volume":"43","author":"Thaxton","year":"2022","journal-title":"Hum. Mutat."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Okutman, \u00d6., G\u00fcrb\u00fcz, A.S., Salvarci, A., B\u00fcy\u00fck, U., Ruso, H., G\u00fcrgan, T., Tarabeux, J., Leuvrey, A.-S., Nourisson, E., and Lang, C. (2024). Evaluation of an Updated Gene Panel as a Diagnostic Tool for Both Male and Female Infertility. Reprod. Sci.","DOI":"10.1007\/s43032-024-01553-4"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1016\/S0092-8674(00)80479-1","article-title":"Classification of Introns: U2-Type or U12-Type","volume":"91","author":"Sharp","year":"1997","journal-title":"Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1111\/cge.14392","article-title":"A Homozygous Frameshift Variant in SYCP2 Caused Meiotic Arrest and Non-obstructive Azoospermia","volume":"104","author":"Xu","year":"2023","journal-title":"Clin. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1136\/jmedgenet-2019-106789","article-title":"Homozygous Variants in SYCP2L Cause Premature Ovarian Insufficiency","volume":"58","author":"He","year":"2021","journal-title":"J. Med. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"6505","DOI":"10.1093\/hmg\/ddv359","article-title":"Accelerated Reproductive Aging in Females Lacking a Novel Centromere Protein SYCP2L","volume":"24","author":"Zhou","year":"2015","journal-title":"Hum. Mol. Genet."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/8\/1092\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:39:00Z","timestamp":1760110740000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/8\/1092"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,19]]},"references-count":36,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2024,8]]}},"alternative-id":["genes15081092"],"URL":"https:\/\/doi.org\/10.3390\/genes15081092","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,19]]}}}