{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T15:54:23Z","timestamp":1753890863609,"version":"3.41.2"},"reference-count":27,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,10,5]],"date-time":"2021-10-05T00:00:00Z","timestamp":1633392000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p>Human ciliopathies are hereditary conditions caused by variants in ciliary-associated genes. Ciliopathies are often characterized by multiple system defects. However, it is not easy to make a definite diagnosis in the prenatal period only based on the imageology. In this report, eight new prenatal cases from five unrelated families diagnosed with ciliopathies were systematically examined. The clinical manifestations of these fetuses showed such prenatal diagnostic features as occipital encephalocele, and polydactyly and polycystic kidneys. <jats:italic>Situs inversus<\/jats:italic> caused by <jats:italic>CPLANE1<\/jats:italic> variant was first reported. In Family 1 and Family 3, homozygous variants of <jats:italic>CPLANE1<\/jats:italic> and <jats:italic>NPHP4<\/jats:italic> caused by consanguineous marriage and uniparental disomy were detected by whole-exome sequencing, respectively. In Family 2, Family 4 and Family 5, compound heterozygotes of <jats:italic>TMEM67<\/jats:italic> and <jats:italic>DYNC2H1<\/jats:italic> including two novel missense variants and one novel nonsense variant were identified. The distribution of pathogenic missense variants along <jats:italic>TMEM67<\/jats:italic> gene mainly clustered in the extracellular cysteine rich region, extracellular area with unknown structure, and the transmembrane regions. Genotype-phenotype relationship between C<jats:italic>PLANE1<\/jats:italic> and <jats:italic>TMEM67<\/jats:italic> genes was concluded. This report describes new clinical manifestations and novel variants in <jats:italic>CPLANE1<\/jats:italic>, <jats:italic>TMEM67<\/jats:italic>, <jats:italic>NPHP4<\/jats:italic>, and <jats:italic>DYNC2H1<\/jats:italic>.<\/jats:p>","DOI":"10.3389\/fgene.2021.705808","type":"journal-article","created":{"date-parts":[[2021,10,5]],"date-time":"2021-10-05T14:33:56Z","timestamp":1633444436000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Molecular Diagnosis and Prenatal Phenotype Analysis of Eight Fetuses With Ciliopathies"],"prefix":"10.3389","volume":"12","author":[{"given":"Yuefang","family":"Liu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Jin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qixiang","family":"Shao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiong","family":"Pan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,10,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1086\/510499","article-title":"The Meckel-Gruber Syndrome Gene, MKS3, Is Mutated in Joubert Syndrome","volume":"80","author":"Baala","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"B2","doi-asserted-by":"publisher","first-page":"514","DOI":"10.1136\/jmedgenet-2015-103087","article-title":"Joubert Syndrome: a Model for Untangling Recessive Disorders with Extreme Genetic Heterogeneity","volume":"52","author":"Bachmann-Gagescu","year":"2015","journal-title":"J. Med. Genet."},{"key":"B3","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1016\/j.ejmg.2018.03.012","article-title":"Novel Mutations in the Ciliopathy-Associated Gene CPLANE1 (C5orf42) Cause OFD Syndrome Type VI rather Than Joubert Syndrome","volume":"61","author":"Bonnard","year":"2018","journal-title":"Eur. J. Med. Genet."},{"key":"B4","doi-asserted-by":"publisher","first-page":"E432","DOI":"10.1002\/humu.20924","article-title":"MKS3\/TMEM67mutations Are a Major Cause of COACH Syndrome, a Joubert Syndrome Related Disorder with Liver Involvement","volume":"30","author":"Brancati","year":"2009","journal-title":"Hum. Mutat."},{"key":"B5","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1007\/s00439-007-0341-3","article-title":"Molecular Diagnostics of Meckel-Gruber Syndrome Highlights Phenotypic Differences between MKS1 and MKS3","volume":"121","author":"Consugar","year":"2007","journal-title":"Hum. Genet."},{"key":"B6","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1016\/j.semcdb.2019.12.005","article-title":"Actin-based Regulation of Ciliogenesis - the Long and the Short of it","volume":"102","author":"Copeland","year":"2020","journal-title":"Semin. Cel Developmental Biol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"442","DOI":"10.1002\/pd.1145","article-title":"Prenatal Diagnosis in Pregnancies at Risk for Joubert Syndrome by Ultrasound and MRI","volume":"25","author":"Doherty","year":"2005","journal-title":"Prenat. Diagn."},{"key":"B8","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1136\/jmg.2009.067249","article-title":"Mutations in 3 Genes (MKS3, CC2D2A and RPGRIP1L) Cause COACH Syndrome (Joubert Syndrome with Congenital Hepatic Fibrosis)","volume":"47","author":"Doherty","year":"2010","journal-title":"J. Med. Genet."},{"key":"B9","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1136\/jmedgenet-2011-100717","article-title":"NEK1andDYNC2H1are Both Involved in Short Rib Polydactyly Majewski Type but Not in Beemer Langer Cases","volume":"49","author":"El Hokayem","year":"2012","journal-title":"J. Med. Genet."},{"key":"B10","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.cell.2006.03.002","article-title":"Nodal Flow and the Generation of Left-Right Asymmetry","volume":"125","author":"Hirokawa","year":"2006","journal-title":"Cell"},{"key":"B11","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1002\/humu.9326","article-title":"Mutational Analysis of theNPHP4 Gene in 250 Patients with Nephronophthisis","volume":"25","author":"Hoefele","year":"2005","journal-title":"Hum. Mutat."},{"key":"B12","doi-asserted-by":"publisher","first-page":"a","DOI":"10.1002\/humu.21239","article-title":"NovelTMEM67mutations and Genotype-Phenotype Correlates in Meckelin-Related Ciliopathies","volume":"31","author":"Iannicelli","year":"2010","journal-title":"Hum. Mutat."},{"key":"B13","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1002\/humu.9489","article-title":"Spectrum ofMKS1andMKS3mutations in Meckel Syndrome: a Genotype-Phenotype Correlation","volume":"28","author":"Khaddour","year":"2007","journal-title":"Hum. Mutat."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1974","DOI":"10.2215\/CJN.01280217","article-title":"Phenotypic Spectrum of Children with Nephronophthisis and Related Ciliopathies","volume":"12","author":"K\u00f6nig","year":"2017","journal-title":"Cjasn"},{"key":"B15","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1007\/s00439-013-1385-1","article-title":"C5orf42 Is the Major Gene Responsible for OFD Syndrome Type VI","volume":"133","author":"Lopez","year":"2014","journal-title":"Hum. Genet."},{"key":"B16","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1053\/j.ajkd.2020.08.012","article-title":"Ciliopathies and the Kidney: A Review","volume":"77","author":"McConnachie","year":"2021","journal-title":"Am. J. Kidney Dis."},{"key":"B17","doi-asserted-by":"publisher","first-page":"560","DOI":"10.1111\/cge.13623","article-title":"Meckel Syndrome: Clinical and Mutation Profile in Six Fetuses","volume":"96","author":"Radhakrishnan","year":"2019","journal-title":"Clin. Genet."},{"key":"B18","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1038\/nrm.2017.60","article-title":"Genes and Molecular Pathways Underpinning Ciliopathies","volume":"18","author":"Reiter","year":"2017","journal-title":"Nat. Rev. Mol. Cel Biol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1136\/jmedgenet-2012-101284","article-title":"Exome Sequencing identifiesDYNC2H1mutations as a Common Cause of Asphyxiating Thoracic Dystrophy (Jeune Syndrome) without Major Polydactyly, Renal or Retinal Involvement","volume":"50","author":"Schmidts","year":"2013","journal-title":"J. Med. Genet."},{"key":"B20","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1038\/ng1713","article-title":"The Transmembrane Protein Meckelin (MKS3) Is Mutated in Meckel-Gruber Syndrome and the Wpk Rat","volume":"38","author":"Smith","year":"2006","journal-title":"Nat. Genet."},{"key":"B21","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1016\/j.ajhg.2012.02.011","article-title":"Mutations in C5ORF42 Cause Joubert Syndrome in the French Canadian Population","volume":"90","author":"Srour","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"B22","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1111\/cge.12836","article-title":"Molecular Genetic Analysis of 30 Families with Joubert Syndrome","volume":"90","author":"Suzuki","year":"2016","journal-title":"Clin. Genet."},{"key":"B23","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1186\/2046-2530-1-18","article-title":"Founder Mutations and Genotype-Phenotype Correlations in Meckel-Gruber Syndrome and Associated Ciliopathies","volume":"1","author":"Szymanska","year":"2012","journal-title":"Cilia"},{"key":"B24","doi-asserted-by":"publisher","first-page":"875","DOI":"10.1038\/gim.2016.204","article-title":"Molecular Genetic Findings and Clinical Correlations in 100 Patients with Joubert Syndrome and Related Disorders Prospectively Evaluated at a Single center","volume":"19","author":"Vilboux","year":"2017","journal-title":"Genet. Med."},{"key":"B25","doi-asserted-by":"publisher","first-page":"559","DOI":"10.3760\/cma.j.issn.1003-9406.2020.05.016","article-title":"Ultrasonographic Manifestation and Genetic Analysis of a Fetus with Nephronophthisis Type 2","volume":"37","author":"Wu","year":"2020","journal-title":"Zhonghua Yi Xue Yi Chuan Xue Za Zhi"},{"key":"B26","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1002\/humu.23362","article-title":"Expanding the Genetic Architecture and Phenotypic Spectrum in the Skeletal Ciliopathies","volume":"39","author":"Zhang","year":"2018","journal-title":"Hum. Mutat."},{"key":"B27","doi-asserted-by":"publisher","first-page":"104212","DOI":"10.1016\/j.ejmg.2021.104212","article-title":"Non-classic Splicing Mutation in the CPLANE1 (C5orf42) Gene Cause Joubert Syndrome in a Fetus with Severe Craniocerebral Dysplasia","volume":"64","author":"Zhu","year":"2021","journal-title":"Eur. J. Med. Genet."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2021.705808\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,5]],"date-time":"2021-10-05T14:34:01Z","timestamp":1633444441000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2021.705808\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,5]]},"references-count":27,"alternative-id":["10.3389\/fgene.2021.705808"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2021.705808","relation":{},"ISSN":["1664-8021"],"issn-type":[{"type":"electronic","value":"1664-8021"}],"subject":[],"published":{"date-parts":[[2021,10,5]]},"article-number":"705808"}}