Leman, Raphael ORCID: 0000-0003-1978-7133, Gaildrat, Pascaline ORCID: 0000-0002-6388-7628, Gac, Gerald L., Ka, Chandran, Fichou, Yann, Audrezet, Marie-Pierre, Caux-Moncoutier, Virginie, Caputo, Sandrine M., Boutry-Kryza, Nadia, Leone, Melanie, Mazoyer, Sylvie ORCID: 0000-0002-2135-0160, Bonnet-Dorion, Francoise, Sevenet, Nicolas, Guillaud-Bataille, Marine, Rouleau, Etienne, Bressac-de Paillerets, Brigitte, Wappenschmidt, Barbara, Rossing, Maria, Muller, Danielle, Bourdon, Violaine, Revillon, Francoise, Parsons, Michael T., Rousselin, Antoine, Davy, Gregoire, Castelain, Gaia, Castera, Laurent, Sokolowska, Joanna, Coulet, Florence, Delnatte, Capucine, Ferec, Claude, Spurdle, Amanda B., Martins, Alexandra ORCID: 0000-0003-4322-8497, Krieger, Sophie and Houdayer, Claude (2018). Novel diagnostic tool for prediction of variant spliceogenicity derived from a set of 395 combined in silico/in vitro studies: an international collaborative effort. Nucleic Acids Res., 46 (15). S. 7913 - 7924. OXFORD: OXFORD UNIV PRESS. ISSN 1362-4962

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Abstract

Variant interpretation is the key issue in molecular diagnosis. Spliceogenic variants exemplify this issue as each nucleotide variant can be deleterious via disruption or creation of splice site consensus sequences. Consequently, reliable in silico prediction of variant spliceogenicity would be a major improvement. Thanks to an international effort, a set of 395 variants studied at the mRNA level and occurring in 5' and 3' consensus regions (defined as the 11 and 14 bases surrounding the exon/intron junction, respectively) was collected for 11 different genes, including BRCA1, BRCA2, CFTR and RHD, and used to train and validate a new prediction protocol named Splicing Prediction in Consensus Elements (SPiCE). SPiCE combines in silico predictions fromSpliceSiteFinder-like and MaxEntScan and uses logistic regression to define optimal decision thresholds. It revealed an unprecedented sensitivity and specificity of 99.5 and 95.2%, respectively, and the impact on splicing was correctly predicted for 98.8% of variants. We therefore propose SPiCE as the new tool for predicting variant spliceogenicity. It could be easily implemented in any diagnostic laboratory as a routine decision making tool to help geneticists to face the deluge of variants in the next-generation sequencing era. SPiCE is accessible at (https://sourceforge.net/projects/spicev2-1/).

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Leman, RaphaelUNSPECIFIEDorcid.org/0000-0003-1978-7133UNSPECIFIED
Gaildrat, PascalineUNSPECIFIEDorcid.org/0000-0002-6388-7628UNSPECIFIED
Gac, Gerald L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ka, ChandranUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fichou, YannUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Audrezet, Marie-PierreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Caux-Moncoutier, VirginieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Caputo, Sandrine M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boutry-Kryza, NadiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leone, MelanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mazoyer, SylvieUNSPECIFIEDorcid.org/0000-0002-2135-0160UNSPECIFIED
Bonnet-Dorion, FrancoiseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sevenet, NicolasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guillaud-Bataille, MarineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rouleau, EtienneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bressac-de Paillerets, BrigitteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wappenschmidt, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rossing, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muller, DanielleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bourdon, ViolaineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Revillon, FrancoiseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Parsons, Michael T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rousselin, AntoineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Davy, GregoireUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Castelain, GaiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Castera, LaurentUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sokolowska, JoannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Coulet, FlorenceUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Delnatte, CapucineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ferec, ClaudeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spurdle, Amanda B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Martins, AlexandraUNSPECIFIEDorcid.org/0000-0003-4322-8497UNSPECIFIED
Krieger, SophieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Houdayer, ClaudeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-173147
DOI: 10.1093/nar/gky372
Journal or Publication Title: Nucleic Acids Res.
Volume: 46
Number: 15
Page Range: S. 7913 - 7924
Date: 2018
Publisher: OXFORD UNIV PRESS
Place of Publication: OXFORD
ISSN: 1362-4962
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
SPLICE-SITE PREDICTION; SEQUENCE VARIANTS; UNCLASSIFIED VARIANTS; MOLECULAR DIAGNOSIS; BRCA2; GUIDELINES; CLASSIFICATION; PHENOTYPE; DATABASE; DEFECTSMultiple languages
Biochemistry & Molecular BiologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/17314

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