| Title: |
Clinical interpretation of variants identified in RNU4ATAC, a non-coding spliceosomal gene |
| Authors: |
Benoit-Pilven, Clara; Besson, Alicia; Putoux, Audrey; Benetollo, Claire; Saccaro, Clément; Guguin, Justine; Sala, Gabriel; Cologne, Audric; Delous, Marion; Lesca, Gaetan; Padgett, Richard, A; Leutenegger, Anne-Louise; Lacroix, Vincent; Edery, Patrick; Mazoyer, Sylvie |
| Contributors: |
Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE); Université Claude Bernard Lyon 1 (UCBL); Université de Lyon-Université de Lyon-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS); Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale (ERABLE); Centre Inria de l'Université Grenoble Alpes; Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria); Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL); Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS); Cleveland Clinic; Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)); Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité); This work was supported by CNRS, Inserm, Université Paris 7 and Université Lyon 1 through recurrent funding, the ANR Aster (no. ANR-16-CE23-0001) and U4ATAC-BRAIN (no. ANR-18CE12-0007-01) grants and an Inserm/ Hospices Civils de Lyon grant to P.E. (Contrat d’Interface pour Hospitaliers). A.C. was supported by a grant from Inria (Thèse Inria-Inserm “Médecine Numérique” - 2016) and C.B.P. by a grant from the Fondation pour la Recherche Médicale to P.E. (Financement d’un ingénieur - ING20160435660).; ANR-16-CE23-0001,ASTER,Algorithmes et outils logiciels pour le séquençage d'ARN de troisième génération(2016); ANR-18-CE12-0007,U4ATAC-BRAIN,Rôle de l'épissage mineur dans le développement cérébral(2018) |
| Source: |
ISSN: 1932-6203. |
| Publisher Information: |
CCSD; Public Library of Science |
| Publication Year: |
2020 |
| Collection: |
Université Jean Monnet – Saint-Etienne: HAL |
| Subject Terms: |
[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry; Molecular Biology/Molecular biology |
| Description: |
International audience ; 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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/32628740; PUBMED: 32628740; PUBMEDCENTRAL: PMC7337319 |
| DOI: |
10.1371/journal.pone.0235655 |
| Availability: |
https://inserm.hal.science/inserm-02915106; https://inserm.hal.science/inserm-02915106v1/document; https://inserm.hal.science/inserm-02915106v1/file/journal.pone.0235655.pdf; https://doi.org/10.1371/journal.pone.0235655 |
| Rights: |
info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.AF41A3FA |
| Database: |
BASE |