{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T07:05:07Z","timestamp":1777100707368,"version":"3.51.4"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,9]],"date-time":"2022-11-09T00:00:00Z","timestamp":1667952000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p>Congenital absence of the vas deferens (CAVD) is a major cause of obstructive azoospermia. Mutations of <jats:italic>CFTR<\/jats:italic> and <jats:italic>ADGRG2<\/jats:italic> cause the majority of CAVD. Despite this, 10%\u201320% of CAVD patients remain without a clear genetic diagnosis. Herein, the <jats:italic>CFTR<\/jats:italic> and <jats:italic>ADGRG2<\/jats:italic> genes were first sequenced using Sanger sequencing in 50 CAVD patients. Whole-exome sequencing (WES) was used to further identify potential novel genetic causes in CAVD with hypospadias. In total, 29 of 50 CAVD patients carried at least one <jats:italic>CFTR<\/jats:italic> mutation, but no <jats:italic>ADGRG2<\/jats:italic> mutation was found. 5T was found to be the most frequent variant in our CAVD populations. Seven CAVD patients with hypospadias were further analyzed using WES. No homozygous or compound heterozygous mutations related to disorders of sex development (DSDs) or male infertility were identified by WES. CAVD with hypospadias presented lower testicular volume (9.71 \u00b1 2.14\u00a0ml vs. 14.45 \u00b1 2.93\u00a0ml, <jats:italic>p<\/jats:italic> &amp;lt; 0.001) and higher FSH level (FSH: 7.28 \u00b1 3.91\u00a0IU\/L vs. 4.24 \u00b1 1.96\u00a0IU\/L, <jats:italic>p<\/jats:italic> = 0.027) than CAVD without hypospadias. It is worth noting that neither <jats:italic>CFTR<\/jats:italic> or <jats:italic>ADGRG2<\/jats:italic> mutation nor homozygous or compound heterozygous gene mutations were identified in seven CAVD cases with hypospadias. However, nine heterozygous or hemizygous mutations were selected as potential pathogenic genes in CAVD with hypospadias. In conclusion, <jats:italic>CFTR<\/jats:italic> variants, especially 5T, play a major role in the Chinese CAVD population<jats:italic>.<\/jats:italic> CAVD with hypospadias shows relatively lower testicular spermatogenesis, suggesting a different genetic basis or pathogenic factor from cystic fibrosis\/CAVD or unilateral renal agenesis\/CAVD.<\/jats:p>","DOI":"10.3389\/fgene.2022.1035468","type":"journal-article","created":{"date-parts":[[2022,11,9]],"date-time":"2022-11-09T08:10:04Z","timestamp":1667981404000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Congenital absence of the vas deferens with hypospadias or without hypospadias: Phenotypic findings and genetic considerations"],"prefix":"10.3389","volume":"13","author":[{"given":"Jianzheng","family":"Fang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xueping","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yugui","family":"Cui","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feiyang","family":"Diao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyu","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1794","DOI":"10.1001\/jama.1992.03480130110034","article-title":"Congenital bilateral absence of the vas deferens. A primarily genital form of cystic fibrosis","volume":"267","author":"Anguiano","year":"1992","journal-title":"JAMA"},{"key":"B2","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1093\/humupd\/dmx021","article-title":"The diagnosis of male infertility: An analysis of the evidence to support the development of global WHO guidance-challenges and future research opportunities","volume":"23","author":"Barratt","year":"2017","journal-title":"Hum. Reprod. Update"},{"key":"B3","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1007\/s00439-020-02122-w","article-title":"Genetics of the congenital absence of the vas deferens","volume":"140","author":"Bieth","year":"2021","journal-title":"Hum. Genet."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1245","DOI":"10.1016\/j.ijom.2020.01.007","article-title":"Fraser syndrome: Review of the literature illustrated by a historical adult case","volume":"49","author":"Bouaoud","year":"2020","journal-title":"Int. J. Oral Maxillofac. Surg."},{"key":"B5","doi-asserted-by":"publisher","first-page":"826","DOI":"10.1038\/s41436-018-0262-7","article-title":"CFTR variants and renal abnormalities in males with congenital unilateral absence of the vas deferens (CUAVD): A systematic review and meta-analysis of observational studies","volume":"21","author":"Cai","year":"2019","journal-title":"Genet. Med."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1475","DOI":"10.1056\/NEJM199506013322204","article-title":"Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens","volume":"332","author":"Chillon","year":"1995","journal-title":"N. Engl. J. Med."},{"key":"B7","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1111\/andr.12450","article-title":"Congenital bilateral absence of the vas deferens as an atypical form of cystic fibrosis: Reproductive implications and genetic counseling","volume":"6","author":"de Souza","year":"2018","journal-title":"Andrology"},{"key":"B8","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1007\/s004390050518","article-title":"Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens","volume":"100","author":"Dork","year":"1997","journal-title":"Hum. Genet."},{"key":"B9","doi-asserted-by":"publisher","first-page":"689185","DOI":"10.1155\/2014\/689185","article-title":"The CFTR M470V, intron 8 poly-T, and 8 TG-repeats detection in Chinese males with congenital bilateral absence of the vas deferens","volume":"2014","author":"Du","year":"2014","journal-title":"Biomed. Res. Int."},{"key":"B10","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1016\/0140-6736(90)92066-q","article-title":"Abnormal distribution of CF delta F508 allele in azoospermic men with congenital aplasia of epididymis and vas deferens","volume":"336","author":"Dumur","year":"1990","journal-title":"Lancet"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1109","DOI":"10.1093\/hmg\/ddi123","article-title":"Mkks-null mice have a phenotype resembling Bardet-Biedl syndrome","volume":"14","author":"Fath","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1111\/and.12858","article-title":"The CFTR gene mild variants poly-T, TG repeats and M470V detection in Indian men with congenital bilateral absence of vas deferens","volume":"50","author":"Gaikwad","year":"2018","journal-title":"Andrologia"},{"key":"B13","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1186\/s13023-018-0968-2","article-title":"Clinical and genetic characteristics of cystic fibrosis in Chinese patients: A systemic review of reported cases","volume":"13","author":"Gottlieb","year":"1993","journal-title":"Orphanet J. Rare Dis."},{"key":"B33","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1186\/s13023-018-0968-2","article-title":"Clinical and genetic characteristics of cystic fibrosis in Chinese patients: A systemic review of reported cases","volume":"13","author":"Guo","year":"2018","journal-title":"Orphanet J. Rare Dis."},{"key":"B14","first-page":"15","article-title":"Congenital absence of the vasa deferentia presenting with infertility","volume":"6","author":"Jequier","year":"1985","journal-title":"J. Androl."},{"key":"B15","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1111\/j.1745-7262.2007.00243.x","article-title":"Hypospadias: An update","volume":"9","author":"Leung","year":"2007","journal-title":"Asian J. Androl."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1536","DOI":"10.1016\/j.fertnstert.2013.07.1995","article-title":"rs189037, a functional variant in ATM gene promoter, is associated with idiopathic nonobstructive azoospermia","volume":"100","author":"Li","year":"2013","journal-title":"Fertil. Steril."},{"key":"B17","doi-asserted-by":"publisher","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":"B18","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1038\/ng1217","article-title":"Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination","volume":"34","author":"Otto","year":"2003","journal-title":"Nat. Genet."},{"key":"B19","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1016\/j.ajhg.2016.06.012","article-title":"Truncating mutations in the adhesion G protein-coupled receptor G2 gene ADGRG2 cause an X-linked congenital bilateral absence of vas deferens","volume":"99","author":"Patat","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"B20","doi-asserted-by":"publisher","first-page":"554","DOI":"10.1001\/archpedi.1996.02170300108024","article-title":"Cystic fibrosis in asian Indians","volume":"150","author":"Powers","year":"1996","journal-title":"Arch. Pediatr. Adolesc. Med."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1066","DOI":"10.1126\/science.2475911","article-title":"Identification of the cystic fibrosis gene: Cloning and characterization of complementary DNA","volume":"245","author":"Riordan","year":"1989","journal-title":"Science"},{"key":"B22","doi-asserted-by":"publisher","first-page":"e1034","DOI":"10.1002\/mgg3.1034","article-title":"Identification of a novel heterozygous missense mutation of SEMA3E (c.1327G>A; p. Ala443Thr) in a labor induced fetus with CHARGE syndrome","volume":"8","author":"Song","year":"2020","journal-title":"Mol. Genet. Genomic Med."},{"key":"B23","doi-asserted-by":"publisher","first-page":"314","DOI":"10.1093\/humupd\/7.3.314","article-title":"Disorders linked to insufficient androgen action in male children","volume":"7","author":"Sultan","year":"2001","journal-title":"Hum. Reprod. Update"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1006","DOI":"10.1002\/ajmg.a.38646","article-title":"Novel RSPO1 mutation causing 46, XX testicular disorder of sex development with palmoplantar keratoderma: A review of literature and expansion of clinical phenotype","volume":"176","author":"Tallapaka","year":"2018","journal-title":"Am. J. Med. Genet. A"},{"key":"B25","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/j.beem.2010.09.002","article-title":"Noonan syndrome and clinically related disorders","volume":"25","author":"Tartaglia","year":"2011","journal-title":"Best. Pract. Res. Clin. Endocrinol. Metab."},{"key":"B26","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1007\/s00431-017-2864-5","article-title":"Hypospadias, all there is to know","volume":"176","author":"van der Horst","year":"2017","journal-title":"Eur. J. Pediatr."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1064","DOI":"10.1111\/andr.12769","article-title":"Genetic diagnosis and sperm retrieval outcomes for Chinese patients with congenital bilateral absence of vas deferens","volume":"8","author":"Wang","year":"2020","journal-title":"Andrology"},{"key":"B28","doi-asserted-by":"publisher","first-page":"e164","DOI":"10.1093\/nar\/gkq603","article-title":"Annovar: Functional annotation of genetic variants from high-throughput sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"B29","doi-asserted-by":"publisher","first-page":"e1006715","DOI":"10.1371\/journal.pgen.1006715","article-title":"Loss of SLC9A3 decreases CFTR protein and causes obstructed azoospermia in mice","volume":"13","author":"Wang","year":"2017","journal-title":"PLoS Genet."},{"key":"B30","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1111\/j.1439-0272.2000.tb02859.x","article-title":"Clinical findings in congenital absence of the vasa deferentia","volume":"32","author":"Weiske","year":"2000","journal-title":"Andrologia"},{"key":"B31","doi-asserted-by":"publisher","first-page":"544","DOI":"10.1097\/00005176-199705000-00010","article-title":"The estimated incidence of cystic fibrosis in Japan","volume":"24","author":"Yamashiro","year":"1997","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"B32","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1093\/humrep\/der377","article-title":"CFTR mutations in men with congenital bilateral absence of the vas deferens (CBAVD): A systemic review and meta-analysis","volume":"27","author":"Yu","year":"2012","journal-title":"Hum. Reprod."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.1035468\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,9]],"date-time":"2022-11-09T08:10:08Z","timestamp":1667981408000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.1035468\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,9]]},"references-count":33,"alternative-id":["10.3389\/fgene.2022.1035468"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2022.1035468","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,9]]},"article-number":"1035468"}}