{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,30]],"date-time":"2025-08-30T16:35:42Z","timestamp":1756571742944,"version":"3.37.3"},"reference-count":21,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,12,26]],"date-time":"2024-12-26T00:00:00Z","timestamp":1735171200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,12,26]],"date-time":"2024-12-26T00:00:00Z","timestamp":1735171200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100012542","name":"Sichuan Provincial Science and Technology Support Program","doi-asserted-by":"publisher","award":["2023JDKP0070"],"award-info":[{"award-number":["2023JDKP0070"]}],"id":[{"id":"10.13039\/100012542","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Chengdu Medical Research Programme","award":["2023013"],"award-info":[{"award-number":["2023013"]}]},{"DOI":"10.13039\/501100010822","name":"Chengdu Science and Technology Bureau","doi-asserted-by":"publisher","award":["2022-YF09-00002-SN"],"award-info":[{"award-number":["2022-YF09-00002-SN"]}],"id":[{"id":"10.13039\/501100010822","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Pregnancy Childbirth"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Prenatal whole exome sequencing (WES) is becoming an increasingly used diagnostic tool for fetuses with structural anomalies. However, the identification of variants of uncertain significance (VUS) in clinically relevant genes can significantly complicate prenatal diagnosis and genetic counseling.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Case presentation<\/jats:title>\n                <jats:p>A fetus conceived through in vitro fertilization at the third attempt presented with polydactyly and molar tooth sign at 24\u2009+\u20096 weeks of gestation. Trio-based WES was performed on both parents and the affected fetus, revealing a pair of compound heterozygous <jats:italic>CPLANE1<\/jats:italic> variants (c.4646\u00a0A\u2009&gt;\u2009T\/p.Glu1549Val and c.1233\u00a0C\u2009&gt;\u2009A\/p.Tyr411*) potentially associated with Joubert syndrome. According to the ACMG guidelines, one of the biallelic variants was classified as VUS, and the other as pathogenic. However, these variants had no allele frequencies in the general population. The p.Tyr411* variant was classified as deleterious, while the p.Glu1549Val variant was located in highly conserved residues, was predicted to be damaging by in silico tools, and altered hydrogen bonding. Furthermore, <jats:italic>CPLANE1<\/jats:italic> expression was highest in the brain during the embryonic and fetal stages. These findings provide additional support for the association between <jats:italic>CPLANE1<\/jats:italic> variants in this fetus and Joubert syndrome. Thus, the most likely diagnosis was Joubert syndrome, and after careful consideration, the couple decided to terminate the pregnancy.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>The expression patterns of <jats:italic>CPLANE1<\/jats:italic> and the molecular effects of the variants may provide further evidence supporting the potential for prenatal diagnosis of Joubert syndrome in the case of biallelic VUS and pathogenic variant. This study suggests that molecular insights may play a role in interpreting VUS in clinically relevant prenatal genes for prenatal diagnosis.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12884-024-07052-3","type":"journal-article","created":{"date-parts":[[2024,12,26]],"date-time":"2024-12-26T14:30:43Z","timestamp":1735223443000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Uncertain significance and molecular insights of CPLANE1 variants in prenatal diagnosis of Joubert syndrome: a case report"],"prefix":"10.1186","volume":"24","author":[{"given":"Si-Xiu","family":"Li","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leiting","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chen","family":"Deng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dongmei","family":"Tang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen-Guang","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hua","family":"Lai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,12,26]]},"reference":[{"key":"7052_CR1","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1038\/s41436-019-0731-7","volume":"22","author":"KG Monaghan","year":"2020","unstructured":"Monaghan KG, Leach NT, Pekarek D, Prasad P, Rose NC. The use of fetal exome sequencing in prenatal diagnosis: a points to consider document of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2020;22:675\u201380.","journal-title":"Genet Med"},{"key":"7052_CR2","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1002\/bdra.23240","volume":"100","author":"E Calzolari","year":"2014","unstructured":"Calzolari E, Barisic I, Loane M, Morris J, Wellesley D, Dolk H, et al. Epidemiology of multiple congenital anomalies in Europe: A EUROCAT population-based registry study. Birt Defects Res Clin Mol Teratol. 2014;100:270\u20136.","journal-title":"Birt Defects Res Clin Mol Teratol"},{"key":"7052_CR3","doi-asserted-by":"publisher","first-page":"224","DOI":"10.3390\/diagnostics11020224","volume":"11","author":"D Guadagnolo","year":"2021","unstructured":"Guadagnolo D, Mastromoro G, Di Palma F, Pizzuti A, Marchionni E. Prenatal Exome Sequencing: Background, Current Practice and Future Perspectives\u2014A. Syst Rev Diagnostics. 2021;11:224.","journal-title":"Syst Rev Diagnostics"},{"key":"7052_CR4","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1136\/jmg-2024-109878","volume":"61","author":"A Abul\u00ed","year":"2024","unstructured":"Abul\u00ed A, Antol\u00edn E, Borrell A, Garcia M, Santiago FG, Manj\u00f3n IG, et al. Guidelines for NGS procedures applied to prenatal diagnosis by the Spanish Society of Gynecology and Obstetrics and the Spanish Association of Prenatal Diagnosis. J Med Genet. 2024;61:727\u201333.","journal-title":"J Med Genet"},{"key":"7052_CR5","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1002\/pd.5102","volume":"38","author":"S Best","year":"2018","unstructured":"Best S, Wou K, Vora N, Van Der Veyver IB, Wapner R, Chitty LS. Promises, pitfalls and practicalities of prenatal whole exome sequencing. Prenat Diagn. 2018;38:10\u20139.","journal-title":"Prenat Diagn"},{"key":"7052_CR6","doi-asserted-by":"publisher","first-page":"1018","DOI":"10.3390\/jcm3031018","volume":"3","author":"L Westerfield","year":"2014","unstructured":"Westerfield L, Darilek S, Van Den Veyver I. Counseling Challenges with Variants of Uncertain Significance and Incidental Findings in Prenatal Genetic Screening and Diagnosis. J Clin Med. 2014;3:1018\u201332.","journal-title":"J Clin Med"},{"key":"7052_CR7","doi-asserted-by":"publisher","first-page":"689","DOI":"10.1080\/14737159.2018.1493924","volume":"18","author":"R Mellis","year":"2018","unstructured":"Mellis R. Next generation sequencing and the impact on prenatal diagnosis. Expert Rev Mol Diagn. 2018;18:689\u201399.","journal-title":"Expert Rev Mol Diagn"},{"key":"7052_CR8","doi-asserted-by":"publisher","first-page":"103663","DOI":"10.1016\/j.ejmg.2019.05.002","volume":"62","author":"L Ferretti","year":"2019","unstructured":"Ferretti L, Mellis R, Chitty LS. Update on the use of exome sequencing in the diagnosis of fetal abnormalities. Eur J Med Genet. 2019;62:103663.","journal-title":"Eur J Med Genet"},{"key":"7052_CR9","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1007\/s00439-013-1385-1","volume":"133","author":"E Lopez","year":"2014","unstructured":"Lopez E, Thauvin-Robinet C, Reversade B, Khartoufi NE, Devisme L, Holder M, et al. C5orf42 is the major gene responsible for OFD syndrome type VI. Hum Genet. 2014;133:367\u201377.","journal-title":"Hum Genet"},{"key":"7052_CR10","doi-asserted-by":"publisher","first-page":"652","DOI":"10.1002\/pd.5494","volume":"39","author":"C Dordoni","year":"2019","unstructured":"Dordoni C, Prefumo F, Iascone M, Pinelli L, Palumbo G, Bondioni MP, et al. Prenatal findings in oral-facial\u2010digital syndrome type VI: Report of three cases and literature review. Prenat Diagn. 2019;39:652\u20135.","journal-title":"Prenat Diagn"},{"key":"7052_CR11","doi-asserted-by":"publisher","first-page":"7202168","DOI":"10.1155\/2018\/7202168","volume":"2018","author":"J Xiang","year":"2018","unstructured":"Xiang J, Zhang L, Jiang W, Zhang Q, Wang T, Li H, et al. Prenatal Diagnosis and Genetic Analysis of a Fetus with Joubert Syndrome. BioMed Res Int. 2018;2018:7202168.","journal-title":"BioMed Res Int"},{"key":"7052_CR12","doi-asserted-by":"publisher","first-page":"15045","DOI":"10.1038\/hgv.2015.45","volume":"2","author":"IM Wentzensen","year":"2015","unstructured":"Wentzensen IM, Johnston JJ, Keppler-Noreuil K, Acrich K, David K, Johnson KD, et al. Exome sequencing identifies novel mutations in C5orf42 in patients with Joubert syndrome with oral\u2013facial\u2013digital anomalies. Hum Genome Var. 2015;2:15045.","journal-title":"Hum Genome Var"},{"key":"7052_CR13","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1016\/j.ejmg.2018.03.012","volume":"61","author":"C Bonnard","year":"2018","unstructured":"Bonnard C, Shboul M, Tonekaboni SH, Ng AYJ, Tohari S, Ghosh K, et al. Novel mutations in the ciliopathy-associated gene CPLANE1 (C5orf42) cause OFD syndrome type VI rather than Joubert syndrome. Eur J Med Genet. 2018;61:585\u201395.","journal-title":"Eur J Med Genet"},{"key":"7052_CR14","doi-asserted-by":"publisher","first-page":"104212","DOI":"10.1016\/j.ejmg.2021.104212","volume":"64","author":"H Zhu","year":"2021","unstructured":"Zhu H, Chen W, Ren H, Zhang Y, Niu Y, Wu D, et al. Non-classic splicing mutation in the CPLANE1 (C5orf42) gene cause Joubert syndrome in a fetus with severe craniocerebral dysplasia. Eur J Med Genet. 2021;64:104212.","journal-title":"Eur J Med Genet"},{"key":"7052_CR15","doi-asserted-by":"publisher","first-page":"705808","DOI":"10.3389\/fgene.2021.705808","volume":"12","author":"Y Liu","year":"2021","unstructured":"Liu Y, Wang H, Jin X, Shao Q, Pan Q. Molecular Diagnosis and Prenatal Phenotype Analysis of Eight Fetuses With Ciliopathies. Front Genet. 2021;12:705808.","journal-title":"Front Genet"},{"key":"7052_CR16","doi-asserted-by":"publisher","first-page":"3213","DOI":"10.1111\/jcmm.17326","volume":"26","author":"W Qian","year":"2022","unstructured":"Qian W, Liu X, Wang Z, Xu Y, Zhang J, Li H, et al. Whole-exome sequencing identified novel variants in CPLANE1 that causes oral\u2010facial\u2010digital syndrome VI by inducing primary cilia abnormality. J Cell Mol Med. 2022;26:3213\u201322.","journal-title":"J Cell Mol Med"},{"key":"7052_CR17","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1186\/s12920-023-01697-3","volume":"16","author":"Y Qin","year":"2023","unstructured":"Qin Y, Yao Y, Liu N, Wang B, Liu L, Li H, et al. Prenatal whole-exome sequencing for fetal structural anomalies: a retrospective analysis of 145 Chinese cases. BMC Med Genomics. 2023;16:262.","journal-title":"BMC Med Genomics"},{"key":"7052_CR18","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","volume":"17","author":"S Richards","year":"2015","unstructured":"Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405\u201324.","journal-title":"Genet Med"},{"key":"7052_CR19","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","volume":"581","author":"KJ Karczewski","year":"2020","unstructured":"Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alf\u00f6ldi J, Wang Q, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581:434\u201343.","journal-title":"Nature"},{"key":"7052_CR20","doi-asserted-by":"publisher","first-page":"e1877","DOI":"10.1002\/mgg3.1877","volume":"10","author":"H Fei","year":"2022","unstructured":"Fei H, Wu Y, Wang Y, Zhang J. Exome sequencing and RNA analysis identify two novel CPLANE1 variants causing Joubert syndrome. Mol Genet Genomic Med. 2022;10:e1877.","journal-title":"Mol Genet Genomic Med"},{"key":"7052_CR21","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1186\/s12920-018-0409-z","volume":"11","author":"GKC Leung","year":"2018","unstructured":"Leung GKC, Mak CCY, Fung JLF, Wong WHS, Tsang MHY, Yu MHC, et al. Identifying the genetic causes for prenatally diagnosed structural congenital anomalies (SCAs) by whole-exome sequencing (WES). BMC Med Genomics. 2018;11:93.","journal-title":"BMC Med Genomics"}],"container-title":["BMC Pregnancy and Childbirth"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12884-024-07052-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12884-024-07052-3\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12884-024-07052-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,26]],"date-time":"2024-12-26T15:03:03Z","timestamp":1735225383000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcpregnancychildbirth.biomedcentral.com\/articles\/10.1186\/s12884-024-07052-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,26]]},"references-count":21,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["7052"],"URL":"https:\/\/doi.org\/10.1186\/s12884-024-07052-3","relation":{},"ISSN":["1471-2393"],"issn-type":[{"type":"electronic","value":"1471-2393"}],"subject":[],"published":{"date-parts":[[2024,12,26]]},"assertion":[{"value":"21 August 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 December 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 December 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was approved by the ethics committee of the Chengdu Women\u2019s and Children\u2019s Central Hospital, approval ethics number 2024(3).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Written informed consent was obtained from the family regarding the publication of the case.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"865"}}