Clinical interpretation of variants identified in RNU4ATAC, a non-coding spliceosomal gene.
Biallelic variants in RNU4ATAC, a non-coding gene transcribed into the minor spliceosome component U4atac snRNA, are responsible for three rare recessive developmental diseases, namely Taybi-Linder/MOPD1, Roifman and Lowry-Wood syndromes. Next-generation sequencing of clinically heterogeneous cohort...
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| Format: | Article |
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Public Library of Science (PLoS)
2020-01-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0235655&type=printable |
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| author | Clara Benoit-Pilven Alicia Besson Audrey Putoux Claire Benetollo Clément Saccaro Justine Guguin Gabriel Sala Audric Cologne Marion Delous Gaetan Lesca Richard A Padgett Anne-Louise Leutenegger Vincent Lacroix Patrick Edery Sylvie Mazoyer |
| author_facet | Clara Benoit-Pilven Alicia Besson Audrey Putoux Claire Benetollo Clément Saccaro Justine Guguin Gabriel Sala Audric Cologne Marion Delous Gaetan Lesca Richard A Padgett Anne-Louise Leutenegger Vincent Lacroix Patrick Edery Sylvie Mazoyer |
| author_sort | Clara Benoit-Pilven |
| collection | DOAJ |
| description | Biallelic variants in RNU4ATAC, a non-coding gene transcribed into the minor spliceosome component U4atac snRNA, are responsible for three rare recessive developmental diseases, namely Taybi-Linder/MOPD1, Roifman and Lowry-Wood syndromes. Next-generation sequencing of clinically heterogeneous cohorts (children with either a suspected genetic disorder or a congenital microcephaly) recently identified mutations in this gene, illustrating how profoundly these technologies are modifying genetic testing and assessment. As RNU4ATAC has a single non-coding exon, the bioinformatic prediction algorithms assessing the effect of sequence variants on splicing or protein function are irrelevant, which makes variant interpretation challenging to molecular diagnostic laboratories. In order to facilitate and improve clinical diagnostic assessment and genetic counseling, we present i) an update of the previously reported RNU4ATAC mutations and an analysis of the genetic variations affecting this gene using the Genome Aggregation Database (gnomAD) resource; ii) the pathogenicity prediction performances of scores computed based on an RNA structure prediction tool and of those produced by the Combined Annotation Dependent Depletion tool for the 285 RNU4ATAC variants identified in patients or in large-scale sequencing projects; iii) a method, based on a cellular assay, that allows to measure the effect of RNU4ATAC variants on splicing efficiency of a minor (U12-type) reporter intron. Lastly, the concordance of bioinformatic predictions and cellular assay results was investigated. |
| format | Article |
| id | doaj-art-c65c22bed0df489ab421b2e558d11852 |
| institution | OA Journals |
| issn | 1932-6203 |
| language | English |
| publishDate | 2020-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-c65c22bed0df489ab421b2e558d118522025-08-20T02:00:46ZengPublic Library of Science (PLoS)PLoS ONE1932-62032020-01-01157e023565510.1371/journal.pone.0235655Clinical interpretation of variants identified in RNU4ATAC, a non-coding spliceosomal gene.Clara Benoit-PilvenAlicia BessonAudrey PutouxClaire BenetolloClément SaccaroJustine GuguinGabriel SalaAudric CologneMarion DelousGaetan LescaRichard A PadgettAnne-Louise LeuteneggerVincent LacroixPatrick EderySylvie MazoyerBiallelic variants in RNU4ATAC, a non-coding gene transcribed into the minor spliceosome component U4atac snRNA, are responsible for three rare recessive developmental diseases, namely Taybi-Linder/MOPD1, Roifman and Lowry-Wood syndromes. Next-generation sequencing of clinically heterogeneous cohorts (children with either a suspected genetic disorder or a congenital microcephaly) recently identified mutations in this gene, illustrating how profoundly these technologies are modifying genetic testing and assessment. As RNU4ATAC has a single non-coding exon, the bioinformatic prediction algorithms assessing the effect of sequence variants on splicing or protein function are irrelevant, which makes variant interpretation challenging to molecular diagnostic laboratories. In order to facilitate and improve clinical diagnostic assessment and genetic counseling, we present i) an update of the previously reported RNU4ATAC mutations and an analysis of the genetic variations affecting this gene using the Genome Aggregation Database (gnomAD) resource; ii) the pathogenicity prediction performances of scores computed based on an RNA structure prediction tool and of those produced by the Combined Annotation Dependent Depletion tool for the 285 RNU4ATAC variants identified in patients or in large-scale sequencing projects; iii) a method, based on a cellular assay, that allows to measure the effect of RNU4ATAC variants on splicing efficiency of a minor (U12-type) reporter intron. Lastly, the concordance of bioinformatic predictions and cellular assay results was investigated.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0235655&type=printable |
| spellingShingle | Clara Benoit-Pilven Alicia Besson Audrey Putoux Claire Benetollo Clément Saccaro Justine Guguin Gabriel Sala Audric Cologne Marion Delous Gaetan Lesca Richard A Padgett Anne-Louise Leutenegger Vincent Lacroix Patrick Edery Sylvie Mazoyer Clinical interpretation of variants identified in RNU4ATAC, a non-coding spliceosomal gene. PLoS ONE |
| title | Clinical interpretation of variants identified in RNU4ATAC, a non-coding spliceosomal gene. |
| title_full | Clinical interpretation of variants identified in RNU4ATAC, a non-coding spliceosomal gene. |
| title_fullStr | Clinical interpretation of variants identified in RNU4ATAC, a non-coding spliceosomal gene. |
| title_full_unstemmed | Clinical interpretation of variants identified in RNU4ATAC, a non-coding spliceosomal gene. |
| title_short | Clinical interpretation of variants identified in RNU4ATAC, a non-coding spliceosomal gene. |
| title_sort | clinical interpretation of variants identified in rnu4atac a non coding spliceosomal gene |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0235655&type=printable |
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