{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T13:35:31Z","timestamp":1793367331110,"version":"4.5.0"},"reference-count":21,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T00:00:00Z","timestamp":1741737600000},"content-version":"vor","delay-in-days":11,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82301817"],"award-info":[{"award-number":["82301817"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100017958","name":"Health Commission of Hubei Province","doi-asserted-by":"publisher","award":["WJ2023M049"],"award-info":[{"award-number":["WJ2023M049"]}],"id":[{"id":"10.13039\/100017958","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018583","name":"Wuhan Science and Technology Project","doi-asserted-by":"publisher","award":["2022020801020492"],"award-info":[{"award-number":["2022020801020492"]}],"id":[{"id":"10.13039\/501100018583","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Cellular Molecular Medi"],"published-print":{"date-parts":[[2025,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Joubert syndrome (JS) is a rare neurodevelopmental disorder associated with mutations in genes involved in ciliary function. Germline variants in <jats:italic>CPLANE1<\/jats:italic> have been implicated in JS. In this study, we investigated a family with three adverse pregnancies characterised by fetal malformations consistent with JS. Whole\u2010exome sequencing (WES) identified compound heterozygous variants in <jats:italic>CPLANE1<\/jats:italic>: c.8893C&gt;T (p.Gln2965*) and c.203C&gt;T (p.Thr68Ile). Sanger sequencing confirmed the variants in the family. Bioinformatics analysis predicted that the c.203C&gt;T variant affects mRNA splicing and protein function. Functional studies using PBMCs demonstrated that the c.203C&gt;T variant causes exon 3 skipping, resulting in a frameshift and premature termination codon, leading to potential nonsense\u2010mediated mRNA degradation (NMD). The mRNA transcription and translation inhibition experiment, by treatment with actinomycin D and puromycin, indicated that the c.203C&gt;T variant leads to accelerated mRNA degradation. Notably, the inhibition of SMG1, a key marker of the NMD pathway, partially rescued mRNA expression in mutated cells, providing further evidence of NMD activation. Based on these findings and ACMG guidelines, the c.203C&gt;T variant was reclassified from a variant of uncertain significance (VUS) to likely pathogenic. This is the first report of novel <jats:italic>CPLANE1<\/jats:italic> compound heterozygous variants contributing to JS in this family. Our study expands the known pathogenic variant spectrum of <jats:italic>CPLANE1<\/jats:italic> in JS and provides new insights into the molecular mechanisms of this ciliopathy.<\/jats:p>","DOI":"10.1111\/jcmm.70484","type":"journal-article","created":{"date-parts":[[2025,3,13]],"date-time":"2025-03-13T03:35:06Z","timestamp":1741836906000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Unveiling the Pathogenic Role of Novel <i>CPLANE1<\/i> Compound Heterozygous Variants in Joubert Syndrome: Insights Into <scp>mRNA<\/scp> Stability and <scp>NMD<\/scp> Pathway"],"prefix":"10.1111","volume":"29","author":[{"given":"Zhidan","family":"Hong","sequence":"first","affiliation":[{"name":"Center for Reproductive Medicine Zhongnan Hospital of Wuhan University  Wuhan Hubei People's Republic of China"},{"name":"Clinical Medicine Research Center of Prenatal Diagnosis and Birth Health in Hubei Province  Wuhan Hubei People's 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