Systematic identification of disease-causing promoter and untranslated region variants in 8,040 undiagnosed individuals with rare disease
Systematic identification of disease-causing promoter and untranslated region variants in 8,040 undiagnosed individuals with rare disease
Background: both promoters and untranslated regions (UTRs) have critical regulatory roles, yet variants in these regions are largely excluded from clinical genetic testing due to difficulty in interpreting pathogenicity. The extent to which these regions may harbour diagnoses for individuals with rare disease is currently unknown.
Methods: we present a framework for the identification and annotation of potentially deleterious proximal promoter and UTR variants in known dominant disease genes. We use this framework to annotate de novo variants (DNVs) in 8,040 undiagnosed individuals in the Genomics England 100,000 genomes project, which were subject to strict region-based filtering, clinical review, and validation studies where possible. In addition, we performed region and variant annotation-based burden testing in 7,862 unrelated probands against matched unaffected controls.
Results: we prioritised eleven DNVs and identified an additional variant overlapping one of the eleven. Ten of these twelve variants (82%) are in genes that are a strong match to the individual's phenotype and six had not previously been identified. Through burden testing, we did not observe a significant enrichment of potentially deleterious promoter and/or UTR variants in individuals with rare disease collectively across any of our region or variant annotations.
Conclusions: overall, we demonstrate the value of screening promoters and UTRs to uncover additional diagnoses for previously undiagnosed individuals with rare disease and provide a framework for doing so without dramatically increasing interpretation burden.
Untranslated region, promoters, splicing, rare disease, non-coding, regulatory regions
Martin-Geary, Alexandra C .
53241751-72cf-4c09-a21b-9d5ef44cdcb2
Blakes, Alexander J.M.
dfefed45-fab2-4980-8667-7e46ce0a14f5
Dawes, Ruebena
62350073-493b-4686-83ca-2b495125b7bd
Findlay, Scott D.
fe794e0a-1e7d-4975-bfd9-e71ccd4d48eb
Lord, Jenny
e1909780-36cd-4705-b21e-4580038d4ec6
Baralle, Diana
faac16e5-7928-4801-9811-8b3a9ea4bb91
Martin-Geary, Alexandra C .
53241751-72cf-4c09-a21b-9d5ef44cdcb2
Blakes, Alexander J.M.
dfefed45-fab2-4980-8667-7e46ce0a14f5
Dawes, Ruebena
62350073-493b-4686-83ca-2b495125b7bd
Findlay, Scott D.
fe794e0a-1e7d-4975-bfd9-e71ccd4d48eb
Lord, Jenny
e1909780-36cd-4705-b21e-4580038d4ec6
Baralle, Diana
faac16e5-7928-4801-9811-8b3a9ea4bb91
Martin-Geary, Alexandra C ., Blakes, Alexander J.M. and Dawes, Ruebena
,
et al.
(2025)
Systematic identification of disease-causing promoter and untranslated region variants in 8,040 undiagnosed individuals with rare disease.
Genome Medicine, 17, [40].
(doi:10.1101/2023.09.12.23295416).
Abstract
Background: both promoters and untranslated regions (UTRs) have critical regulatory roles, yet variants in these regions are largely excluded from clinical genetic testing due to difficulty in interpreting pathogenicity. The extent to which these regions may harbour diagnoses for individuals with rare disease is currently unknown.
Methods: we present a framework for the identification and annotation of potentially deleterious proximal promoter and UTR variants in known dominant disease genes. We use this framework to annotate de novo variants (DNVs) in 8,040 undiagnosed individuals in the Genomics England 100,000 genomes project, which were subject to strict region-based filtering, clinical review, and validation studies where possible. In addition, we performed region and variant annotation-based burden testing in 7,862 unrelated probands against matched unaffected controls.
Results: we prioritised eleven DNVs and identified an additional variant overlapping one of the eleven. Ten of these twelve variants (82%) are in genes that are a strong match to the individual's phenotype and six had not previously been identified. Through burden testing, we did not observe a significant enrichment of potentially deleterious promoter and/or UTR variants in individuals with rare disease collectively across any of our region or variant annotations.
Conclusions: overall, we demonstrate the value of screening promoters and UTRs to uncover additional diagnoses for previously undiagnosed individuals with rare disease and provide a framework for doing so without dramatically increasing interpretation burden.
Text
GenomeMed_manuscript_GELdeNovo_resubmission_manuscript2
- Accepted Manuscript
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Accepted/In Press date: 27 March 2025
e-pub ahead of print date: 14 April 2025
Keywords:
Untranslated region, promoters, splicing, rare disease, non-coding, regulatory regions
Identifiers
Local EPrints ID: 501071
URI: http://eprints.soton.ac.uk/id/eprint/501071
ISSN: 1756-994X
PURE UUID: 40f982d4-18a4-4e49-b0de-2a3a8b0d01d8
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Date deposited: 22 May 2025 16:40
Last modified: 12 Dec 2025 02:54
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Contributors
Author:
Alexandra C . Martin-Geary
Author:
Alexander J.M. Blakes
Author:
Ruebena Dawes
Author:
Scott D. Findlay
Author:
Jenny Lord
Corporate Author: et al.
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