{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T22:42:17Z","timestamp":1790808137274,"version":"4.1.0"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,3,14]],"date-time":"2022-03-14T00:00:00Z","timestamp":1647216000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005230","name":"Natural Science Foundation of Chongqing","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005230","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p>\n                    Meckel syndrome (MKS), also known as the Meckel\u2013Gruber syndrome, is a severe pleiotropic autosomal recessive developmental disorder caused by dysfunction of the primary cilia during early embryogenesis. The diagnostic criteria are based on clinical variability and genetic heterogeneity. Mutations in the\n                    <jats:italic>MKS1<\/jats:italic>\n                    gene constitute approximately 7% of all MKS cases. Herein, we present a non-consanguineous couple with three abnormal pregnancies as the fetuses showed MKS-related phenotypes of the central nervous system malformation and postaxial polydactyly. Whole-exome sequencing identified two novel heterozygous mutations of\n                    <jats:italic>MKS1<\/jats:italic>\n                    : c.350C&amp;gt;A and c.1408-14A&amp;gt;G. The nonsense mutation c.350C&amp;gt;A produced a premature stop codon and induced the truncation of the MKS1 protein (p.S117*). Reverse-transcription polymerase chain reaction (RT-PCR) showed that c.1408-14A&amp;gt;G skipped exon 16 and encoded the mutant MKS1 p.E471Lfs*92. Functional studies showed that these two mutations disrupted the B9\u2013C2 domain of the MKS1 protein and attenuated the interactions with B9D2, the essential component of the ciliary transition zone. The couple finally got a healthy baby through preimplantation genetic testing for monogenic disorder (PGT-M) with haplotype linkage analysis. Thus, this study expanded the mutation spectrum of\n                    <jats:italic>MKS1<\/jats:italic>\n                    and elucidated the genetic heterogeneity of\n                    <jats:italic>MKS1<\/jats:italic>\n                    in clinical cases.\n                  <\/jats:p>","DOI":"10.3389\/fgene.2022.843931","type":"journal-article","created":{"date-parts":[[2022,3,14]],"date-time":"2022-03-14T00:34:41Z","timestamp":1647218081000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Case Report: Preimplantation Genetic Testing for Meckel Syndrome Induced by Novel Compound Heterozygous Mutations of MKS1"],"prefix":"10.3389","volume":"13","author":[{"given":"Tingting","family":"Lin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongyi","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danni","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liwei","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yezhou","family":"Xiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keya","family":"Tong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaoli","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kean","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongyun","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoning","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,3,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"105236","DOI":"10.1016\/j.nbd.2020.105236","article-title":"Cilia, Ciliopathies and Hedgehog-Related Forebrain Developmental Disorders","volume":"150","author":"Andreu-Cervera","year":"2021","journal-title":"Neurobiol. Dis."},{"key":"B2","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1038\/s41581-019-0116-9","article-title":"Cellular Signalling by Primary Cilia in Development, Organ Function and Disease","volume":"15","author":"Anvarian","year":"2019","journal-title":"Nat. Rev. Nephrol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1111\/j.1399-0004.2007.00880.x","article-title":"A Disease Causing Deletion of 29 Base Pairs in Intron 15 in the MKS1 Gene Is Highly Associated with the Campomelic Variant of the Meckel-Gruber Syndrome","volume":"72","author":"Auber","year":"2007","journal-title":"Clin. Genet."},{"key":"B4","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1016\/j.ejmg.2016.06.007","article-title":"MKS1 Mutations Cause Joubert Syndrome with Agenesis of the Corpus Callosum","volume":"59","author":"Bader","year":"2016","journal-title":"Eur. J. Med. Genet."},{"key":"B5","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1038\/ejhg.2016.33","article-title":"Clinical Utility Gene Card for: Meckel Syndrome - Update 2016","volume":"24","author":"Bergmann","year":"2016","journal-title":"Eur. J. Hum. Genet."},{"key":"B6","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1242\/jcs.028621","article-title":"Functional Interactions between the Ciliopathy-Associated Meckel Syndrome 1 (MKS1) Protein and Two Novel MKS1-Related (MKSR) Proteins","volume":"122","author":"Bialas","year":"2009","journal-title":"J. Cel Sci."},{"key":"B7","doi-asserted-by":"publisher","first-page":"871","DOI":"10.3390\/genes11080871","article-title":"Preimplantation Genetic Testing for Monogenic Disorders","volume":"11","author":"De Rycke","year":"2020","journal-title":"Genes (Basel)"},{"key":"B8","doi-asserted-by":"publisher","first-page":"E5135","DOI":"10.1073\/pnas.1604258113","article-title":"Cilium Transition Zone Proteome Reveals Compartmentalization and Differential Dynamics of Ciliopathy Complexes","volume":"113","author":"Dean","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"B9","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1016\/j.ajhg.2011.06.003","article-title":"Disruption of a Ciliary B9 Protein Complex Causes Meckel Syndrome","volume":"89","author":"Dowdle","year":"2011","journal-title":"Am. J. Hum. Genet."},{"key":"B10","doi-asserted-by":"publisher","first-page":"638","DOI":"10.1002\/humu.9496","article-title":"Aberrant Splicing Is a Common Mutational Mechanism inMKS1, a Key Player in Meckel-Gruber Syndrome","volume":"28","author":"Frank","year":"2007","journal-title":"Hum. Mutat."},{"key":"B11","doi-asserted-by":"publisher","first-page":"776","DOI":"10.1038\/ng.891","article-title":"A Transition Zone Complex Regulates Mammalian Ciliogenesis and Ciliary Membrane Composition","volume":"43","author":"Garcia-Gonzalo","year":"2011","journal-title":"Nat. Genet."},{"key":"B12","doi-asserted-by":"publisher","first-page":"e3000640","DOI":"10.1371\/journal.pbio.3000640","article-title":"MKS-NPHP Module Proteins Control Ciliary Shedding at the Transition Zone","volume":"18","author":"Gogendeau","year":"2020","journal-title":"Plos Biol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"243","DOI":"10.14348\/molcells.2017.0054","article-title":"The Ciliary Transition Zone: Finding the Pieces and Assembling the Gate","volume":"40","author":"Gon\u00e7alves","year":"2017","journal-title":"Mol. Cell"},{"key":"B14","doi-asserted-by":"publisher","first-page":"244","DOI":"10.3389\/fped.2017.00244","article-title":"Meckel-Gruber Syndrome: An Update on Diagnosis, Clinical Management, and Research Advances","volume":"5","author":"Hartill","year":"2017","journal-title":"Front. Pediatr."},{"key":"B15","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1146\/annurev-genom-090413-025352","article-title":"Single-Cell Whole-Genome Amplification and Sequencing: Methodology and Applications","volume":"16","author":"Huang","year":"2015","journal-title":"Annu. Rev. Genom. Hum. Genet."},{"key":"B16","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1038\/ng1714","article-title":"MKS1, Encoding a Component of the Flagellar Apparatus Basal Body Proteome, Is Mutated in Meckel Syndrome","volume":"38","author":"Kytt\u00e4l\u00e4","year":"2006","journal-title":"Nat. Genet."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","article-title":"Fast and Accurate Short Read Alignment with Burrows-Wheeler Transform","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"B18","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1007\/s12035-010-8154-0","article-title":"Molecular Genetics and Pathogenic Mechanisms for the Severe Ciliopathies: Insights into Neurodevelopment and Pathogenesis of Neural Tube Defects","volume":"43","author":"Logan","year":"2011","journal-title":"Mol. Neurobiol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"576235","DOI":"10.3389\/fgene.2020.576235","article-title":"Novel Compound Heterozygous Variants in MKS1 Leading to Joubert Syndrome","volume":"11","author":"Luo","year":"2020","journal-title":"Front. Genet."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1041","DOI":"10.1038\/s41436-021-01106-z","article-title":"Disrupted Intraflagellar Transport Due to IFT74 Variants Causes Joubert Syndrome","volume":"23","author":"Luo","year":"2021","journal-title":"Genet. Med."},{"key":"B21","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1186\/s13059-016-0974-4","article-title":"The Ensembl Variant Effect Predictor","volume":"17","author":"McLaren","year":"2016","journal-title":"Genome Biol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1002\/path.4843","article-title":"Motile and Non-motile Cilia in Human Pathology: from Function to Phenotypes","volume":"241","author":"Mitchison","year":"2017","journal-title":"J. Pathol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1016\/s0968-0004(98)01208-0","article-title":"A Rule for Termination-Codon Position within Intron-Containing Genes: when Nonsense Affects RNA Abundance","volume":"23","author":"Nagy","year":"1998","journal-title":"Trends Biochem. Sci."},{"key":"B24","doi-asserted-by":"publisher","first-page":"2259","DOI":"10.1091\/mbc.e20-03-0208","article-title":"Formation of the B9-Domain Protein Complex MKS1-B9D2-B9D1 Is Essential as a Diffusion Barrier for Ciliary Membrane Proteins","volume":"31","author":"Okazaki","year":"2020","journal-title":"MBoC"},{"key":"B25","doi-asserted-by":"publisher","first-page":"25","DOI":"10.3233\/TRD-190041","article-title":"The Molecular Genetics of Joubert Syndrome and Related Ciliopathies: The Challenges of Genetic and Phenotypic Heterogeneity","volume":"4","author":"Parisi","year":"2019","journal-title":"Transl. Sci. Rare Dis."},{"key":"B26","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":"B27","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"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","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"B28","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1186\/1750-1172-9-72","article-title":"Mutations in B9D1 and MKS1 Cause Mild Joubert Syndrome: Expanding the Genetic Overlap with the Lethal Ciliopathy Meckel Syndrome","volume":"9","author":"Romani","year":"2014","journal-title":"Orphanet J. Rare Dis."},{"key":"B29","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1002\/ajmg.1320180414","article-title":"The Meckel Syndrome: Clinicopathological Findings in 67 Patients","volume":"18","author":"Salonen","year":"","journal-title":"Am. J. Med. Genet."},{"key":"B30","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1002\/ajmg.1320180415","article-title":"The Meckel Syndrome in Finland: Epidemiologic and Genetic Aspects","volume":"18","author":"Salonen","year":"","journal-title":"Am. J. Med. Genet."},{"key":"B31","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1136\/jmedgenet-2015-103250","article-title":"MKS1 Regulates Ciliary INPP5E Levels in Joubert Syndrome","volume":"53","author":"Slaats","year":"2016","journal-title":"J. Med. Genet."},{"key":"B32","doi-asserted-by":"publisher","first-page":"e3001034","DOI":"10.1371\/journal.pbio.3001034","article-title":"CEP290 Is Essential for the Initiation of Ciliary Transition Zone Assembly","volume":"18","author":"Wu","year":"2020","journal-title":"Plos Biol."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.843931\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,14]],"date-time":"2022-03-14T00:34:46Z","timestamp":1647218086000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.843931\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,14]]},"references-count":32,"alternative-id":["10.3389\/fgene.2022.843931"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2022.843931","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,14]]},"article-number":"843931"}}