Clinical interpretation of variants identified in RNU4ATAC, a non-coding spliceosomal gene.

Autor: Benoit-Pilven C; Equipe GENDEV, Centre de Recherche en Neurosciences de Lyon, Inserm U1028, CNRS UMR5292, Université Lyon 1, Université St Etienne, Lyon, France.; Laboratoire de Biométrie et Biologie Évolutive, CNRS UMR5558, Université Lyon 1, Villeurbanne, and EPI ERABLE - Inria Grenoble, Villeurbanne, Rhône-Alpes, France., Besson A; Equipe GENDEV, Centre de Recherche en Neurosciences de Lyon, Inserm U1028, CNRS UMR5292, Université Lyon 1, Université St Etienne, Lyon, France., Putoux A; Equipe GENDEV, Centre de Recherche en Neurosciences de Lyon, Inserm U1028, CNRS UMR5292, Université Lyon 1, Université St Etienne, Lyon, France.; Service de génétique et Centre de Référence Maladies Rares des Anomalies du Développement CLAD Sud-Est, Hospices Civils de Lyon, Lyon, France., Benetollo C; Plateau NeuroGénétique FOnctionnelle, Centre de Recherche en Neurosciences de Lyon, Inserm U1028, CNRS UMR5292, Université Lyon 1, Université St Etienne, Lyon, France., Saccaro C; Equipe GENDEV, Centre de Recherche en Neurosciences de Lyon, Inserm U1028, CNRS UMR5292, Université Lyon 1, Université St Etienne, Lyon, France., Guguin J; Equipe GENDEV, Centre de Recherche en Neurosciences de Lyon, Inserm U1028, CNRS UMR5292, Université Lyon 1, Université St Etienne, Lyon, France., Sala G; Equipe GENDEV, Centre de Recherche en Neurosciences de Lyon, Inserm U1028, CNRS UMR5292, Université Lyon 1, Université St Etienne, Lyon, France., Cologne A; Equipe GENDEV, Centre de Recherche en Neurosciences de Lyon, Inserm U1028, CNRS UMR5292, Université Lyon 1, Université St Etienne, Lyon, France.; Laboratoire de Biométrie et Biologie Évolutive, CNRS UMR5558, Université Lyon 1, Villeurbanne, and EPI ERABLE - Inria Grenoble, Villeurbanne, Rhône-Alpes, France., Delous M; Equipe GENDEV, Centre de Recherche en Neurosciences de Lyon, Inserm U1028, CNRS UMR5292, Université Lyon 1, Université St Etienne, Lyon, France., Lesca G; Equipe GENDEV, Centre de Recherche en Neurosciences de Lyon, Inserm U1028, CNRS UMR5292, Université Lyon 1, Université St Etienne, Lyon, France.; Service de génétique et Centre de Référence Maladies Rares des Anomalies du Développement CLAD Sud-Est, Hospices Civils de Lyon, Lyon, France., Padgett RA; Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States of America., Leutenegger AL; Université de Paris, NeuroDiderot, Inserm, Paris, France., Lacroix V; Laboratoire de Biométrie et Biologie Évolutive, CNRS UMR5558, Université Lyon 1, Villeurbanne, and EPI ERABLE - Inria Grenoble, Villeurbanne, Rhône-Alpes, France., Edery P; Equipe GENDEV, Centre de Recherche en Neurosciences de Lyon, Inserm U1028, CNRS UMR5292, Université Lyon 1, Université St Etienne, Lyon, France.; Service de génétique et Centre de Référence Maladies Rares des Anomalies du Développement CLAD Sud-Est, Hospices Civils de Lyon, Lyon, France., Mazoyer S; Equipe GENDEV, Centre de Recherche en Neurosciences de Lyon, Inserm U1028, CNRS UMR5292, Université Lyon 1, Université St Etienne, Lyon, France.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2020 Jul 06; Vol. 15 (7), pp. e0235655. Date of Electronic Publication: 2020 Jul 06 (Print Publication: 2020).
DOI: 10.1371/journal.pone.0235655
Abstrakt: 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.
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
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