{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T23:45:05Z","timestamp":1783467905359,"version":"3.55.0"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2022,9,1]],"date-time":"2022-09-01T00:00:00Z","timestamp":1661990400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100001412","name":"Council of Scientific and Industrial Research, India","doi-asserted-by":"publisher","award":["BSC0101"],"award-info":[{"award-number":["BSC0101"]}],"id":[{"id":"10.13039\/501100001412","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001412","name":"Council of Scientific and Industrial Research, India","doi-asserted-by":"publisher","award":["MLP0113"],"award-info":[{"award-number":["MLP0113"]}],"id":[{"id":"10.13039\/501100001412","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001412","name":"Council of Scientific and Industrial Research, India","doi-asserted-by":"publisher","award":["JCB\/2019\/000027"],"award-info":[{"award-number":["JCB\/2019\/000027"]}],"id":[{"id":"10.13039\/501100001412","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,1,27]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Human spermatogenesis requires an orchestrated expression of numerous genes in various germ cell subtypes. Therefore, the genetic landscape of male infertility is highly complex. Known genetic factors alone account for at least 15% of male infertility. However, ~40% of infertile men remain undiagnosed and are classified as idiopathic infertile men. We performed exome sequencing in 47 idiopathic infertile men (discovery cohort), followed by replication study (40 variants in 33 genes) in 844 infertile men and 709 controls using Sequenom MassARRAY\u00ae based genotyping. We report 17 variants in twelve genes that comprise both previously reported (DNAH8, DNAH17, FISP2 and SPEF2) and novel candidate genes (BRDT, CETN1, CATSPERD, GMCL1, SPATA6, TSSK4, TSKS and ZNF318) for male infertility. The latter have a strong biological nexus to human spermatogenesis and their respective mouse knockouts are concordant with human phenotypes. One candidate gene CETN1, identified in this study, was sequenced in another independent cohort of 840 infertile and 689 fertile men. Further, CETN1 variants were functionally characterized using biophysical and cell biology approaches. We demonstrate that CETN1 variant- p.Met72Thr leads to multipolar cells, fragmented nuclei during mitosis leading to cell death and show significantly perturbed ciliary disassembly dynamics. Whereas CETN1\u20135\u2032 UTR variant; rs367716858 leads to loss of a methylation site and increased reporter gene expression in vitro. We report a total of eight novel candidate genes identified by exome sequencing, which may have diagnostic relevance and can contribute to improved diagnostic workup and clinical management of male infertility.<\/jats:p>","DOI":"10.1093\/hmg\/ddac216","type":"journal-article","created":{"date-parts":[[2022,9,1]],"date-time":"2022-09-01T17:41:29Z","timestamp":1662054089000},"page":"533-542","source":"Crossref","is-referenced-by-count":15,"title":["Exome sequencing and functional analyses revealed<i>CETN1<\/i>variants leads to impaired cell division and male fertility"],"prefix":"10.1093","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3373-8592","authenticated-orcid":false,"given":"Digumarthi V S","family":"Sudhakar","sequence":"first","affiliation":[{"name":"CSIR\u2014Centre for Cellular and Molecular Biology (CCMB) , Hyderabad, 500007 , India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Regur","family":"Phanindranath","sequence":"additional","affiliation":[{"name":"CSIR\u2014Centre for Cellular and Molecular Biology (CCMB) , Hyderabad, 500007 , India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shveta","family":"Jaishankar","sequence":"additional","affiliation":[{"name":"Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR) , Bengaluru , India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anand","family":"Ramani","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Hospital D\u00fcsseldorf, Heinrich-Heine-Universit\u00e4t , D\u00fcsseldorf 40225 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaustubh P","family":"Kalamkar","sequence":"additional","affiliation":[{"name":"Institute for Neurophysiology, University of Cologne , Cologne D-50931 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Umesh","family":"Kumar","sequence":"additional","affiliation":[{"name":"CSIR\u2014Centre for Cellular and Molecular Biology (CCMB) , Hyderabad, 500007 , India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asmita D","family":"Pawar","sequence":"additional","affiliation":[{"name":"CSIR\u2014Centre for Cellular and Molecular Biology (CCMB) , Hyderabad, 500007 , India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rima","family":"Dada","sequence":"additional","affiliation":[{"name":"All India Institute of Medical Sciences , New Delhi, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajender","family":"Singh","sequence":"additional","affiliation":[{"name":"CSIR\u2014Central Drug Research Institute Division of Endocrinology, , Lucknow, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nalini J","family":"Gupta","sequence":"additional","affiliation":[{"name":"Institute of Reproductive Medicine , Kolkata, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mamata","family":"Deenadayal","sequence":"additional","affiliation":[{"name":"Mamata Fertility Hospital , Secunderabad, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aarti Deenadayal","family":"Tolani","sequence":"additional","affiliation":[{"name":"Mamata Fertility Hospital , Secunderabad, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yogendra","family":"Sharma","sequence":"additional","affiliation":[{"name":"CSIR\u2014Centre for Cellular and Molecular Biology (CCMB) , Hyderabad, 500007 , India"},{"name":"Indian Institute of Science Education and Research (IISER) Berhampur , Odisha, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anuranjan","family":"Anand","sequence":"additional","affiliation":[{"name":"Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR) , Bengaluru, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay","family":"Gopalakrishnan","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Hospital D\u00fcsseldorf, Heinrich-Heine-Universit\u00e4t , D\u00fcsseldorf 40225 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0075-0106","authenticated-orcid":false,"given":"Kumarasamy","family":"Thangaraj","sequence":"additional","affiliation":[{"name":"CSIR\u2014Centre for Cellular and Molecular Biology (CCMB) , Hyderabad, 500007 , India"},{"name":"Centre for DNA Fingerprinting and Diagnostics (CDFD) , Hyderabad, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,9,1]]},"reference":[{"key":"2023020311001424400_ref1","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/j.ajhg.2010.09.009","article-title":"Human male infertility associated with mutations in NR5A1 encoding steroidogenic factor 1","volume":"87","author":"Bashamboo","year":"2010","journal-title":"Am. 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