Show Notes
Martin‑Geary AC et al et al., Genome Medicine - A systematic framework to prioritise promoter and UTR variants in 8040 undiagnosed trios from the Genomics England 100,000 Genomes Project, yielding ten likely diagnoses and a validated annotation pipeline for clinical use. Key terms: promoters, untranslated regions, de novo variants, rare disease, Genomics England.
Study Highlights:
The authors applied a region‑specific annotation and strict filtering pipeline to de novo variants in 8040 undiagnosed trios, focusing on proximal promoters and UTRs of dominant disease genes. Eleven candidate de novo variants (twelve total) were prioritised; ten lie in genes that match the proband phenotype and six represent newly identified diagnoses. Validation included RNA‑seq and DNA methylation where available, and pipeline benchmarking against ClinVar showed high specificity. Burden testing in 7862 probands versus matched controls did not show a significant collective enrichment of prioritised promoter/UTR variants.
Conclusion:
Screening proximal promoters and UTRs can uncover additional rare disease diagnoses and the authors provide a high‑specificity framework for clinical pipelines, but routinely including these regions is unlikely to dramatically increase overall diagnostic yield.
QC:
This episode was checked against the original article PDF and publication metadata.
Scope: article metadata and core scientific claims from the narration, excluding analogies, intro/outro, and music.
Factual QC score: 10/10.
Metadata QC score: 10/10.
Supported core claims: 7.
Claims flagged for review: 0.
Metadata checks passed: 4.
Metadata issues found: 0.
QC result: Pass.
Music:
Enjoy the music based on this article at the end of the episode.
Article title:
Systematic identification of disease‑causing promoter and untranslated region variants in 8040 undiagnosed individuals with rare disease
First author:
Martin‑Geary AC et al
Journal:
Genome Medicine
DOI:
10.1186/s13073‑025‑01464‑2
Reference:
Martin‑Geary AC et al., Genome Medicine (2025) 17:40. https://doi.org/10.1186/s13073‑025‑01464‑2
License:
Creative Commons Attribution 4.0 International License (CC BY 4.0)
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