Pathogenic variants that alter protein code often disrupt splicing

Nat Genet. 2017 Jun;49(6):848-855. doi: 10.1038/ng.3837. Epub 2017 Apr 17.


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
  • RNA-Binding Proteins / metabolism
  • Spliceosomes / genetics
  • Spliceosomes / metabolism


  • Proteins
  • RNA Splice Sites
  • RNA-Binding Proteins