Genetic control of mRNA splicing as a potential mechanism for incomplete penetrance of rare coding variants

Jonah Einson, Dafni Glinos, Eric Boerwinkle, Peter Castaldi, Dawood Darbar, Mariza De Andrade, Patrick Ellinor, Myriam Fornage, Stacey Gabriel, Soren Germer, Richard Gibbs, Craig P. Hersh, Jill Johnsen, Robert Kaplan, Barbara A. Konkle, Charles Kooperberg, Rami Nassir, Ruth J.F. Loos, Deborah A. Meyers, Braxton D. MitchellBruce Psaty, Ramachandran S. Vasan, Stephen S. Rich, Michael Rienstra, Jerome I. Rotter, Aabida Saferali, Moore Benjamin Shoemaker, Edwin Silverman, Albert Vernon Smith, Pejman Mohammadi, Stephane E. Castel, Ivan Iossifov, Tuuli Lappalainen

Producción científica: Articlerevisión exhaustiva

1 Cita (Scopus)


Exonic variants present some of the strongest links between genotype and phenotype. However, these variants can have significant inter-individual pathogenicity differences, known as variable penetrance. In this study, we propose a model where genetically controlled mRNA splicing modulates the pathogenicity of exonic variants. By first cataloging exonic inclusion from RNA-sequencing data in GTEx V8, we find that pathogenic alleles are depleted on highly included exons. Using a large-scale phased whole genome sequencing data from the TOPMed consortium, we observe that this effect may be driven by common splice-regulatory genetic variants, and that natural selection acts on haplotype configurations that reduce the transcript inclusion of putatively pathogenic variants, especially when limiting to haploinsufficient genes. Finally, we test if this effect may be relevant for autism risk using families from the Simons Simplex Collection, but find that splicing of pathogenic alleles has a penetrance reducing effect here as well. Overall, our results indicate that common splice-regulatory variants may play a role in reducing the damaging effects of rare exonic variants.

Idioma originalEnglish (US)
Número de artículoiyad115
EstadoPublished - ago 2023
Publicado de forma externa

ASJC Scopus subject areas

  • General Medicine


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