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PMID: 28416821 Published · ppublish English Journal Article

Pathogenic variants that alter protein code often disrupt splicing.

Nature genetics ·Vol. 49 ·No. 6 ·2017-06-00 ·Pages 848-855

Soemedi R, Cygan KJ, Rhine CL, Wang J, Bulacan C, Yang J, Bayrak-Toydemir P, McDonald J, Fairbrother WG

Abstract

The lack of tools to identify causative variants from sequencing data greatly limits the promise of precision medicine. Previous studies suggest that one-third of disease-associated alleles alter splicing. We discovered that the alleles causing splicing defects cluster in disease-associated genes (for example, haploinsufficient genes). We analyzed 4,964 published disease-causing exonic mutations using a massively parallel splicing assay (MaPSy), which showed an 81% concordance rate with splicing in patient tissue. Approximately 10% of exonic mutations altered splicing, mostly by disrupting multiple stages of spliceosome assembly. We present a large-scale characterization of exonic splicing mutations using a new technology that facilitates variant classification and keeps pace with variant discovery.

MeSH Terms
DNA Mutational Analysis/methods Exons Genome, Human High-Throughput Nucleotide Sequencing/methods Humans Models, Genetic Mutation Proteins/genetics RNA Splice Sites RNA Splicing RNA-Binding Proteins/genetics,metabolism Spliceosomes/genetics,metabolism
Chemicals
Proteins RNA Splice Sites RNA-Binding Proteins
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Soemedi Rachel
Center for Computational Molecular Biology, Brown University, Providence, Rhode Island, USA. | Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island, USA.
Cygan Kamil J ORCID
Center for Computational Molecular Biology, Brown University, Providence, Rhode Island, USA. | Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island, USA.
Rhine Christy L
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island, USA.
Wang Jing
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island, USA.
Bulacan Charlston
Department of Computer Engineering, Brown University, Providence, Rhode Island, USA.
Yang John
Department of Computer Science, Brown University, Providence, Rhode Island, USA.
Bayrak-Toydemir Pinar
Department of Pathology, University of Utah, School of Medicine, Salt Lake City, Utah, USA.
McDonald Jamie
Department of Pathology, University of Utah, School of Medicine, Salt Lake City, Utah, USA.
Fairbrother William G
Center for Computational Molecular Biology, Brown University, Providence, Rhode Island, USA. | Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island, USA. | Hassenfeld Child Health Innovation Institute of Brown University, Brown University, Providence, Rhode Island, USA.
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Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.3837
Published
2017-06-00
Epub
2017-00-17
Pages
848-855
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC6679692
Subset
IM
Grants
NIGMS NIH HHS · R01 GM095612 · United States
NIGMS NIH HHS · R01 GM105681 · United States
NHGRI NIH HHS · R21 HG007905 · United States
External Links
PubMed source DOI: 10.1038/ng.3837 PMC Full Text View journal details
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