{"doi":"10.1002/mgg3.1877","title":"Exome sequencing and <scp>RNA</scp> analysis identify two novel <scp><i>CPLANE1</i></scp> variants causing Joubert syndrome","abstract":"<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Joubert syndrome (JS) is a genetically heterogeneous disorder; its genetic etiology involves more than 35 genes, and a limited number of studies have investigated the pathogenic mechanism of variants in patients with JS. RNA splicing analysis is critical to determine the functional significance for noncanonical splicing variants.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Whole exome sequencing was performed to screen the causative gene variants in a JS family. Sanger sequencing was used to verify the variants. cDNA PCR products were analyzed and functional experiments were performed to determine the pathogenicity of the variants.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>The clinical phenotypes and <jats:italic>CPLANE1</jats:italic> variants in the JS patient were analyzed and proved consistent. We identified two novel heterozygous variants of <jats:italic>CPLANE1</jats:italic> in the proband first, including c.4459del (frameshift variant) and c.7534‐14G &gt; A (intronic variant). We analyzed the pathogenic consequences of the 2 variants and classified the c.4459del as likely pathogenic according to the ACMG/AMP guidelines; however, the pathogenic significance of c.7534‐14G &gt; A was uncertain. Furthermore, we performed RNA splicing analysis and revealed that the noncanonical splicing variant (c.7534‐14G &gt; A) caused aberrant exon 37 skipping. It produced an aberrant transcript that was predicted to encode a C‐terminal truncated protein.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>The genetic variation spectrum of JS caused by <jats:italic>CPLANE1</jats:italic> was updated. Two novel variants further deepened our insight into the disease's molecular mechanism and confirmed the significance of diagnostic whole‐exome sequencing.</jats:p></jats:sec>","journal":"Molecular Genetics &amp; Genomic Medicine","year":2022,"id":638904,"datarank":0.3453877639491069,"base_score":2.302585092994046,"endowment":2.302585092994046,"self_citation_contribution":0.3453877639491069,"citation_network_contribution":0.0,"self_endowment_contribution":0.3453877639491069,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":546868,"name":"Yi Wu","orcid":"0000-0002-6969-4552","position":1,"is_corresponding":false},{"id":1496506,"name":"Yanlin Wang","orcid":"0009-0009-1171-1768","position":2,"is_corresponding":false},{"id":527060,"name":"Junyu Zhang","orcid":"0000-0003-0239-6670","position":3,"is_corresponding":false},{"id":1659715,"name":"Hongjun Fei","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Exome sequencing and <scp>RNA</scp> analysis identify two novel <scp><i>CPLANE1</i></scp> variants causing Joubert syndrome","abstract":"<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Joubert syndrome (JS) is a genetically heterogeneous disorder; its genetic etiology involves more than 35 genes, and a limited number of studies have investigated the pathogenic mechanism of variants in patients with JS. RNA splicing analysis is critical to determine the functional significance for noncanonical splicing variants.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Whole exome sequencing was performed to screen the causative gene variants in a JS family. Sanger sequencing was used to verify the variants. cDNA PCR products were analyzed and functional experiments were performed to determine the pathogenicity of the variants.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>The clinical phenotypes and <jats:italic>CPLANE1</jats:italic> variants in the JS patient were analyzed and proved consistent. We identified two novel heterozygous variants of <jats:italic>CPLANE1</jats:italic> in the proband first, including c.4459del (frameshift variant) and c.7534‐14G &gt; A (intronic variant). We analyzed the pathogenic consequences of the 2 variants and classified the c.4459del as likely pathogenic according to the ACMG/AMP guidelines; however, the pathogenic significance of c.7534‐14G &gt; A was uncertain. Furthermore, we performed RNA splicing analysis and revealed that the noncanonical splicing variant (c.7534‐14G &gt; A) caused aberrant exon 37 skipping. It produced an aberrant transcript that was predicted to encode a C‐terminal truncated protein.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>The genetic variation spectrum of JS caused by <jats:italic>CPLANE1</jats:italic> was updated. Two novel variants further deepened our insight into the disease's molecular mechanism and confirmed the significance of diagnostic whole‐exome sequencing.</jats:p></jats:sec>","is_dataset_classified":null,"base_score":2.302585092994046,"endowment":2.302585092994046,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"35092359","pmcid":"PMC8922956","openalex_id":"https://openalex.org/W4210695678","authors":[],"funders":[{"funder_name":"Science and Technology Commission of Shanghai Municipality","grant_id":"19YF1452200","title":null}],"total_grants":1,"fwci":1.3438,"citation_percentile":0.80579654,"influential_citations":0,"citation_trend":[{"year":2022,"count":2},{"year":2023,"count":2},{"year":2024,"count":4},{"year":2026,"count":1}],"oa_status":"gold","license":"cc-by-nc","oa_locations":[{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/mgg3.1877","host_type":"journal"},{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/mgg3.1877","host_type":"publisher"},{"url":"https://onlinelibrary.wiley.com/doi/pdf/10.1002/mgg3.1877","host_type":"publisher"},{"url":"https://onlinelibrary.wiley.com/doi/full-xml/10.1002/mgg3.1877","host_type":"publisher"},{"url":"https://doi.org/10.1002/mgg3.1877","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/35092359","host_type":"repository"},{"url":"https://doaj.org/article/376348ed523a4f88813d3019a59c3da1","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/8922956","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC8922956","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC8922956?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Genetic and Kidney Cyst Diseases","Hedgehog Signaling Pathway Studies","Congenital gastrointestinal and neural anomalies"],"mesh_terms":["Abnormalities, Multiple","Exome Sequencing","Cerebellum","Eye Abnormalities","Female","Humans","Male","Pedigree","Retina","RNA","Kidney Diseases, Cystic","Exome"],"keywords":["Genetics","Exome sequencing","Sanger sequencing","Biology","RNA splicing","Exon","Exome","Gene","Exon skipping","Frameshift mutation","RNA","Computational biology","Mutation","Joubert Syndrome","Novel Variants","Aberrant Splicing","Cplane1","Diagnostic Whole Exome Sequencing"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"omim"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-06T21:52:29.530106Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}