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September 19, 2025The American Journal of Human GeneticsOpen Access

Transcriptome-wide outlier approach identifies individuals with minor spliceopathies

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Why the study?

Current RNA sequencing analyses focus on single-gene outliers linked to cis-acting variants, overlooking causal variants with trans-acting effects on splicing transcriptome wide, such as those impacting spliceosome function.

Population

385 individuals from the GREGoR and UDN consortia

Authors

RMRodrigo MendezRURachel A. UngarDBDevon Bonner

Discussion

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Overview

RNA-seq splicing-outlier screening may aid unsolved rare-disease diagnosis; leaves open RNU6ATAC as a Mendelian gene.

Structured PICO

P
Population
385 individuals with rare diseases from the Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) and Undiagnosed Diseases Network (UDN) consortia
I
Intervention
Transcriptome-wide outlier approach using splicing outlier detection methods (FRASER and FRASER2) on whole blood RNA sequencing data
O
Outcome
Identification of individuals with minor spliceopathies (excess intron retention outliers in minor intron-containing genes)

Examining RNA-sequencing data for transcriptome-wide signatures of splicing outliers can increase the diagnostic yield for individuals with rare diseases and uncover novel gene-disease associations.

Cite This Study

Mendez et al. (2025) studied this question.

synapsesocial.com/papers/6a7fe828b70cf768065a7947https://doi.org/10.1016/j.ajhg.2025.08.018
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Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome2024 · 132 citations
  2. 2The significant other: splicing by the minor spliceosome2012 · 373 citations
  3. 3Domains of human U4atac snRNA required for U12-dependent splicing in vivo2002 · 32 citations
  4. 4Genome-wide identification of tandem repeats associated with splicing variation across 49 tissues in humans2023 · 31 citations
  5. 5Making new genetic diagnoses with old data: iterative reanalysis and reporting from genome-wide data in 1,133 families with developmental disorders2018 · 354 citations