ArticleGenetics2023
Genetic control of mRNA splicing as a potential mechanism for incomplete penetrance of rare coding variants.
Article in Genetics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
7 citing papers in PubMed, 9 citations in OpenAlex.
- Paired DNA and RNA sequencing uncovers common and rare variation regulating human retinal gene expression.Nature communications · 2026Article
- Residual allelic activity likely underlies the low rates of disease expression for predicted loss-of-function variants in population-scale biobanks.American journal of human genetics · 2025Article
- Exploring penetrance of clinically relevant variants in over 800,000 humans from the Genome Aggregation Database.Nature communications · 2025Article
- Transcriptomic and lipidomic profiling provide novel insight into the pathogenesis of monogenicJBMR plus · 2025Article
- CommonGenome research · 2025Article
- Promoter Deletion Leading to Allele Specific Expression in a Genetically Unsolved Case of Primary Ciliary Dyskinesia.American journal of medical genetics. Part A · 2025Article
- Exome sequencing in retinal dystrophy patients reveals a novel candidate gene ER membrane protein complex subunit 3.Heliyon · 2023Article
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Authors and funding
34 authors at 20 institutions in 4 countries.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.