Fulvio D'Abrusco, Simone Gana, Enrico Alfei, Emanuela Scarano, Francesco Nicita, Enrico Silvio Bertini, Maria Cristina Digilio, Ginevra Zanni, Domenico Barbuti, Eleonora Carlicchi, Anna Pichiecchio, Stefano D'Arrigo, Valentina Serpieri, Enza Maria Valente
{"title":"RNU4ATAC变异导致Joubert综合征伴骨骼受累的进一步证据。","authors":"Fulvio D'Abrusco, Simone Gana, Enrico Alfei, Emanuela Scarano, Francesco Nicita, Enrico Silvio Bertini, Maria Cristina Digilio, Ginevra Zanni, Domenico Barbuti, Eleonora Carlicchi, Anna Pichiecchio, Stefano D'Arrigo, Valentina Serpieri, Enza Maria Valente","doi":"10.1136/jmg-2025-110987","DOIUrl":null,"url":null,"abstract":"<p><p><i>RNU4ATAC</i> is a non-coding gene involved in the minor spliceosome, and is mutated in a spectrum of syndromic skeletal disorders with recessive inheritance. Recently, biallelic <i>RNU4ATAC</i> pathogenic variants were detected in five patients presenting a complex syndromic phenotype and a brain malformation resembling the 'molar tooth sign' (MTS). This is the hallmark of Joubert syndrome (JS), a neurodevelopmental ciliopathy with multiorgan involvement.We reanalysed exome sequencing (ES) from 53 patients with JS, who lacked coding variants in known JS-associated genes. Four <i>RNU4ATAC</i> variants (n.16G>A, n.51G>A, n.13C>T and n.30G>A) were identified in compound heterozygosity in three probands, accounting for 5.6% of negative cases. All patients displayed the MTS and clinical features overlapping those of JS and <i>RNU4ATAC</i>-related skeletal disorders.These findings expand the phenotypic spectrum of <i>RNU4ATAC</i>-related disorders to include a complex neurological-skeletal ciliopathy phenotype, and highlight the relevance of ES reanalysis to uncover non-coding variants often undetected by conventional diagnostics.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7000,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Further evidence of <i>RNU4ATAC</i> variants causing Joubert syndrome with skeletal involvement.\",\"authors\":\"Fulvio D'Abrusco, Simone Gana, Enrico Alfei, Emanuela Scarano, Francesco Nicita, Enrico Silvio Bertini, Maria Cristina Digilio, Ginevra Zanni, Domenico Barbuti, Eleonora Carlicchi, Anna Pichiecchio, Stefano D'Arrigo, Valentina Serpieri, Enza Maria Valente\",\"doi\":\"10.1136/jmg-2025-110987\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p><i>RNU4ATAC</i> is a non-coding gene involved in the minor spliceosome, and is mutated in a spectrum of syndromic skeletal disorders with recessive inheritance. Recently, biallelic <i>RNU4ATAC</i> pathogenic variants were detected in five patients presenting a complex syndromic phenotype and a brain malformation resembling the 'molar tooth sign' (MTS). This is the hallmark of Joubert syndrome (JS), a neurodevelopmental ciliopathy with multiorgan involvement.We reanalysed exome sequencing (ES) from 53 patients with JS, who lacked coding variants in known JS-associated genes. Four <i>RNU4ATAC</i> variants (n.16G>A, n.51G>A, n.13C>T and n.30G>A) were identified in compound heterozygosity in three probands, accounting for 5.6% of negative cases. All patients displayed the MTS and clinical features overlapping those of JS and <i>RNU4ATAC</i>-related skeletal disorders.These findings expand the phenotypic spectrum of <i>RNU4ATAC</i>-related disorders to include a complex neurological-skeletal ciliopathy phenotype, and highlight the relevance of ES reanalysis to uncover non-coding variants often undetected by conventional diagnostics.</p>\",\"PeriodicalId\":16237,\"journal\":{\"name\":\"Journal of Medical Genetics\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":3.7000,\"publicationDate\":\"2025-09-11\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Medical Genetics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1136/jmg-2025-110987\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"GENETICS & HEREDITY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medical Genetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1136/jmg-2025-110987","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
Further evidence of RNU4ATAC variants causing Joubert syndrome with skeletal involvement.
RNU4ATAC is a non-coding gene involved in the minor spliceosome, and is mutated in a spectrum of syndromic skeletal disorders with recessive inheritance. Recently, biallelic RNU4ATAC pathogenic variants were detected in five patients presenting a complex syndromic phenotype and a brain malformation resembling the 'molar tooth sign' (MTS). This is the hallmark of Joubert syndrome (JS), a neurodevelopmental ciliopathy with multiorgan involvement.We reanalysed exome sequencing (ES) from 53 patients with JS, who lacked coding variants in known JS-associated genes. Four RNU4ATAC variants (n.16G>A, n.51G>A, n.13C>T and n.30G>A) were identified in compound heterozygosity in three probands, accounting for 5.6% of negative cases. All patients displayed the MTS and clinical features overlapping those of JS and RNU4ATAC-related skeletal disorders.These findings expand the phenotypic spectrum of RNU4ATAC-related disorders to include a complex neurological-skeletal ciliopathy phenotype, and highlight the relevance of ES reanalysis to uncover non-coding variants often undetected by conventional diagnostics.
期刊介绍:
Journal of Medical Genetics is a leading international peer-reviewed journal covering original research in human genetics, including reviews of and opinion on the latest developments. Articles cover the molecular basis of human disease including germline cancer genetics, clinical manifestations of genetic disorders, applications of molecular genetics to medical practice and the systematic evaluation of such applications worldwide.