{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T04:09:16Z","timestamp":1780632556374,"version":"3.54.1"},"reference-count":28,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T00:00:00Z","timestamp":1780531200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T00:00:00Z","timestamp":1780531200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Andrology"],"abstract":"ABSTRACT<\/jats:title>\n \n Background<\/jats:title>\n Cryptozoospermia is defined, according to WHO criteria, as the absence of spermatozoa in fresh semen preparations but the presence of rare spe matozoa after centrifugation. Identifying candidate genes and their clinical phenotypes is essential for understanding its etiology and developing targeted therapies.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n Whole\u2010exome sequencing (WES) was performed on 503 oligozoospermic and 516 azoospermic infertile patients to identify candidate variants associated with severe male infertility. Functional studies, including protein expression, subcellular localization, and interaction assays, were conducted in vitro, and assisted reproductive outcomes were analyzed.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n We identified a compound heterozygous CHTF18 variant (NM_022092: c.538G > A [p. Val180Met] and c.1434delG [p. Leu481Serfs*3]) in a cryptozoospermic patient exhibiting a high proportion of aneuploid sperm. The missense variant (c.538G > A) was rare (< 0.001% population frequency) and predicted to disrupt protein function by in silico tools. The frameshift variant (c.1434delG) was predicted to introduce premature truncation and a loss\u2010of\u2010function effect. In vitro studies suggested altered subcellular localization of mutant CHTF18 proteins and possible effects on interactions with known binding partners. Despite severe cryptozoospermia, the patient achieved a successful pregnancy and live birth via intracytoplasmic sperm injection (ICSI).<\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n These findings support\n CHTF18<\/jats:italic>\n as a candidate gene associated with cryptozoospermia and suggest that biallelic\n CHTF18<\/jats:italic>\n variants may contribute to spermatogenic failure by altering CHTF18 protein localization and interactions within the CHTF18\u2010RLC complex. Further cases and in vivo validation are required to strengthen this gene\u2013disease association.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/andr.70270","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T03:50:26Z","timestamp":1780631426000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Biallelic Variants of\n CHTF18<\/i>\n Are Associated With Male Infertility With Cryptozoospermia in Humans"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-4268-7793","authenticated-orcid":false,"given":"Yena","family":"Hu","sequence":"first","affiliation":[{"name":"Institute of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, Xiangya School of Basic Medical Science Central South University Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuze","family":"Pi","sequence":"additional","affiliation":[{"name":"Institute of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, Xiangya School of Basic Medical Science Central South University Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lanlan","family":"Meng","sequence":"additional","affiliation":[{"name":"Institute of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, Xiangya School of Basic Medical Science Central South University Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Tang","sequence":"additional","affiliation":[{"name":"Institute of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, Xiangya School of Basic Medical Science Central South University Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutong","family":"He","sequence":"additional","affiliation":[{"name":"Institute of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, Xiangya School of Basic Medical Science Central South University Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, Xiangya School of Basic Medical Science Central South University Changsha China"},{"name":"Clinical Research Center for Reproduction and Genetics in Hunan Province Reproductive and Genetic Hospital of CITIC\u2010XIANGYA Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaofeng","family":"Tu","sequence":"additional","affiliation":[{"name":"Institute of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, Xiangya School of Basic Medical Science Central South University Changsha China"},{"name":"Clinical Research Center for Reproduction and Genetics in Hunan Province Reproductive and Genetic Hospital of CITIC\u2010XIANGYA Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4906-2097","authenticated-orcid":false,"given":"Yueqiu","family":"Tan","sequence":"additional","affiliation":[{"name":"Institute of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, Xiangya School of Basic Medical Science Central South University Changsha China"},{"name":"Clinical Research Center for Reproduction and Genetics in Hunan Province Reproductive and Genetic Hospital of CITIC\u2010XIANGYA Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Hu","sequence":"additional","affiliation":[{"name":"Institute of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, Xiangya School of Basic Medical Science Central South University Changsha China"},{"name":"Clinical Research Center for Reproduction and Genetics in Hunan Province Reproductive and Genetic Hospital of CITIC\u2010XIANGYA Changsha China"},{"name":"Hunan International Scientific and Technological Cooperation Base of Development and Carcinogenesis Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,4]]},"reference":[{"key":"e_1_2_7_2_1","volume-title":"WHO Laboratory Manual for the Examination and Processing of human Semen","author":"WHO","year":"2011"},{"issue":"6","key":"e_1_2_7_3_1","doi-asserted-by":"crossref","first-page":"1506","DOI":"10.1093\/humrep\/dem046","article-title":"International Estimates of Infertility Prevalence and Treatment\u2010Seeking: Potential Need and Demand for Infertility Medical Care","volume":"22","author":"Boivin J.","year":"2007","journal-title":"Human Reproduction"},{"issue":"1","key":"e_1_2_7_4_1","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/s41572-023-00459-w","article-title":"Male Infertility","volume":"9","author":"Eisenberg M. L.","year":"2023","journal-title":"Nature Reviews Disease Primers"},{"key":"e_1_2_7_5_1","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.semcdb.2016.04.009","article-title":"Spermatogenesis in Humans and Its Affecting Factors","volume":"59","author":"Neto F. T.","year":"2016","journal-title":"Seminars in Cell & Developmental Biology"},{"issue":"1","key":"e_1_2_7_6_1","first-page":"1","article-title":"The Commitment to Meiosis","volume":"96","author":"Spermatogenesis G. M. D.","year":"2016","journal-title":"Physiological Reviews"},{"key":"e_1_2_7_7_1","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/bs.ctdb.2022.05.002","article-title":"Chromosome\u2010Specific Behaviors During Early Meiosis","volume":"151","author":"Billmyre K. K.","year":"2023","journal-title":"Current Topics in Developmental Biology"},{"issue":"6","key":"e_1_2_7_8_1","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1093\/humupd\/dmac024","article-title":"Meiotic Recombination: Insights Into Its Mechanisms and Its Role in Human Reproduction With a Special Focus on Non\u2010Obstructive Azoospermia","volume":"28","author":"Xie C.","year":"2022","journal-title":"Human Reproduction Update"},{"issue":"22","key":"e_1_2_7_9_1","doi-asserted-by":"crossref","first-page":"R873","DOI":"10.1016\/j.cub.2003.10.048","article-title":"Genome Stability: A New Member of the RFC Family","volume":"13","author":"Kim J.","year":"2003","journal-title":"Current Biology"},{"issue":"9","key":"e_1_2_7_10_1","doi-asserted-by":"crossref","first-page":"3144","DOI":"10.1128\/MCB.21.9.3144-3158.2001","article-title":"Saccharomyces cerevisiae CTF18 and CTF4 Are Required for Sister Chromatid Cohesion","volume":"21","author":"Hanna J. S.","year":"2001","journal-title":"Molecular and Cellular Biology"},{"issue":"32","key":"e_1_2_7_11_1","first-page":"30051","article-title":"Cloning and Characterization of hCTF18, hCTF8, and hDCC1. Human Homologs of a Saccharomyces cerevisiae Complex Involved in Sister Chromatid Cohesion Establishment","volume":"278","author":"Merkle C J.","year":"2003","journal-title":"Journal of Biological Chemistry"},{"issue":"7270","key":"e_1_2_7_12_1","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1038\/nature08550","article-title":"Cohesin Acetylation Speeds the Replication Fork","volume":"462","author":"Terret M. E.","year":"2009","journal-title":"Nature"},{"issue":"2","key":"e_1_2_7_13_1","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1006\/dbio.2000.0117","article-title":"Structure\u2010Specific Abnormalities Associated With Mutations in a DNA Replication Accessory Factor in Drosophila","volume":"230","author":"Jaffe A. B.","year":"2001","journal-title":"Developmental Biology"},{"issue":"11","key":"e_1_2_7_14_1","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1002996","article-title":"Disruption of CHTF18 Causes Defective Meiotic Recombination in Male Mice","volume":"8","author":"Berkowitz K. M.","year":"2012","journal-title":"PLoS Genetics"},{"issue":"1","key":"e_1_2_7_15_1","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1093\/biolre\/ioaa036","article-title":"CHTF18 Ensures the Quantity and Quality of the Ovarian Reserve","volume":"103","author":"Holton R. A.","year":"2020","journal-title":"Biology of Reproduction"},{"issue":"3","key":"e_1_2_7_16_1","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1005017","article-title":"The ATM Signaling Cascade Promotes Recombination\u2010Dependent Pachytene Arrest in Mouse Spermatocytes","volume":"11","author":"Pacheco S.","year":"2015","journal-title":"PLoS Genetics"},{"issue":"12","key":"e_1_2_7_17_1","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1038\/s41422-018-0099-2","article-title":"The Adult Human Testis Transcriptional Cell Atlas","volume":"28","author":"Guo J.","year":"2018","journal-title":"Cell Research"},{"issue":"3","key":"e_1_2_7_18_1","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1093\/molehr\/gan005","article-title":"Germline Expression of Mammalian CTF18, an Evolutionarily Conserved Protein Required for Germ Cell Proliferation in the Fly and Sister Chromatid Cohesion in Yeast","volume":"14","author":"Berkowitz K. M.","year":"2008","journal-title":"Molecular Human Reproduction"},{"issue":"7","key":"e_1_2_7_19_1","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1016\/S2213-8587(16)30043-2","article-title":"Concepts in Diagnosis and Therapy for Male Reproductive Impairment","volume":"5","author":"Tournaye H.","year":"2017","journal-title":"Lancet Diabetes & Endocrinology"},{"issue":"7","key":"e_1_2_7_20_1","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1093\/hmg\/ddab242","article-title":"The Mutation c.346\u20101G>A in SOHLH1 Impairs Sperm Production in the Homozygous but Not in the Heterozygous Condition","volume":"31","author":"Liu M.","year":"2022","journal-title":"Human Molecular Genetics"},{"issue":"1","key":"e_1_2_7_21_1","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1002\/humu.24138","article-title":"Novel Homozygous Truncating Variants in ZMYND15 Causing Severe Oligozoospermia and Their Implications for Male Infertility","volume":"42","author":"Hu T. Y.","year":"2021","journal-title":"Human Mutation"},{"key":"e_1_2_7_22_1","doi-asserted-by":"crossref","DOI":"10.3389\/fcell.2022.850052","article-title":"Homozygous Loss of Septin12, but Not Its Haploinsufficiency, Leads to Male Infertility and Fertilization Failure","volume":"10","author":"Chen H.","year":"2022","journal-title":"Frontiers in Cell and Developmental Biology"},{"issue":"12","key":"e_1_2_7_23_1","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1038\/s41431-021-00946-2","article-title":"Pathogenic Variations in Germ Cell Nuclear Acidic Peptidase (GCNA) Are Associated With human Male Infertility","volume":"29","author":"Arafat M.","year":"2021","journal-title":"European Journal of Human Genetics"},{"issue":"1","key":"e_1_2_7_24_1","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/s41421-021-00369-9","article-title":"Deficiency of X\u2010Linked TENT5D Causes Male Infertility by Disrupting the mRNA Stability During Spermatogenesis","volume":"8","author":"Cong J.","year":"2022","journal-title":"Cell Discovery"},{"issue":"4","key":"e_1_2_7_25_1","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1016\/j.fertnstert.2009.10.046","article-title":"Sperm DNA Fragmentation: Mechanisms of Origin, Impact on Reproductive Outcome, and Analysis","volume":"93","author":"Sakkas D.","year":"2010","journal-title":"Fertility and Sterility"},{"key":"e_1_2_7_26_1","doi-asserted-by":"crossref","first-page":"E221","DOI":"10.1111\/j.1365-2605.2009.00995.x","article-title":"Sperm Chromatin Structure Assay as an Independent Predictor of Fertility In Vivo: A Case\u2010Control Study","volume":"33","author":"Giwercman A.","year":"2010","journal-title":"International Journal of Andrology"},{"issue":"3","key":"e_1_2_7_27_1","doi-asserted-by":"crossref","first-page":"219","DOI":"10.2164\/jandrol.108.006908","article-title":"Are Tests of Sperm DNA Damage Clinically Useful? Pros and Cons","volume":"30","author":"Zini A.","year":"2009","journal-title":"Journal of Andrology"},{"issue":"7254","key":"e_1_2_7_28_1","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1038\/nature08162","article-title":"Distinctive Chromatin in Human Sperm Packages Genes for Embryo Development","volume":"460","author":"Hammoud S. S.","year":"2009","journal-title":"Nature"},{"issue":"1","key":"e_1_2_7_29_1","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.fertnstert.2024.08.316","article-title":"High Sperm Deoxyribonucleic Acid Fragmentation Index Is Associated With an Increased Risk of Preeclampsia Following Assisted Reproduction Treatment","volume":"123","author":"Stenqvist A.","year":"2025","journal-title":"Fertility and Sterility"}],"container-title":["Andrology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/andr.70270","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/andr.70270","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/andr.70270","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T03:50:33Z","timestamp":1780631433000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/andr.70270"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,4]]},"references-count":28,"alternative-id":["10.1111\/andr.70270"],"URL":"https:\/\/doi.org\/10.1111\/andr.70270","archive":["Portico"],"relation":{},"ISSN":["2047-2919","2047-2927"],"issn-type":[{"value":"2047-2919","type":"print"},{"value":"2047-2927","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,4]]},"assertion":[{"value":"2025-12-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-19","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-04","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"andr.70270"}}