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Pathogenic variants that alter protein code often disrupt splicing.

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.

SUBMITTER: Soemedi R

PROVIDER: S-EPMC6679692 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Pathogenic variants that alter protein code often disrupt splicing.

Soemedi Rachel R Cygan Kamil J KJ Rhine Christy L CL Wang Jing J Bulacan Charlston C Yang John J Bayrak-Toydemir Pinar P McDonald Jamie J Fairbrother William G WG

Nature genetics 20170417 6

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 ...[more]

PMID: 28416821

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