Large-scale comparative evaluation of user-friendly tools for predicting variant-induced alterations of splicing regulatory elements.
BRCA1 and MAPT
MSH2
RNA splicing
exome sequencing
functional assays
in silico predictions
increased exon skipping or inclusion
molecular diagnostics
pseudoexons
splicing regulatory elements
variant interpretation
Journal
Human mutation
ISSN: 1098-1004
Titre abrégé: Hum Mutat
Pays: United States
ID NLM: 9215429
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
revised:
11
07
2020
received:
05
02
2020
accepted:
26
07
2020
pubmed:
3
8
2020
medline:
1
4
2022
entrez:
3
8
2020
Statut:
ppublish
Résumé
Discriminating which nucleotide variants cause disease or contribute to phenotypic traits remains a major challenge in human genetics. In theory, any intragenic variant can potentially affect RNA splicing by altering splicing regulatory elements (SREs). However, these alterations are often ignored mainly because pioneer SRE predictors have proved inefficient. Here, we report the first large-scale comparative evaluation of four user-friendly SRE-dedicated algorithms (QUEPASA, HEXplorer, SPANR, and HAL) tested both as standalone tools and in multiple combined ways based on two independent benchmark datasets adding up to >1,300 exonic variants studied at the messenger RNA level and mapping to 89 different disease-causing genes. These methods display good predictive power, based on decision thresholds derived from the receiver operating characteristics curve analyses, with QUEPASA and HAL having the best accuracies either as standalone or in combination. Still, overall there was a tight race between the four predictors, suggesting that all methods may be of use. Additionally, QUEPASA and HEXplorer may be beneficial as well for predicting variant-induced creation of pseudoexons deep within introns. Our study highlights the potential of SRE predictors as filtering tools for identifying disease-causing candidates among the plethora of variants detected by high-throughput DNA sequencing and provides guidance for their use in genomic medicine settings.
Substances chimiques
RNA, Messenger
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1811-1829Informations de copyright
© 2020 Wiley Periodicals LLC.
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