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Background <p>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.</p> Methods <p>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 8040 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 7862 unrelated probands against matched unaffected controls.</p> Results <p>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.</p> Conclusions <p>Whilst screening promoters and UTRs can uncover additional diagnoses for individuals with rare disease, including these regions in diagnostic pipelines is not likely to dramatically increase diagnostic yield. Nevertheless, we provide a framework to aid identification of these variants.</p>

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Systematic identification of disease-causing promoter and untranslated region variants in 8040 undiagnosed individuals with rare disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月14日

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  • Alexandra C. Martin-Geary,
  • Alexander J.M. Blakes,
  • Ruebena Dawes,
  • Scott D. Findlay,
  • Jenny Lord,
  • Shan Dong,
  • Susan Walker,
  • Jonathan Talbot-Martin,
  • Nechama Wieder,
  • Elston N. D’Souza,
  • Maria Fernandes,
  • Sarah Hilton,
  • Nayana Lahiri,
  • Christopher Campbell,
  • Sarah Jenkinson,
  • Christian G.E.L. DeGoede,
  • Emily R. Anderson,
  • Toby Candler,
  • Helen Firth,
  • Christopher B. Burge,
  • Stephan J. Sanders,
  • Jamie Ellingford,
  • Diana Baralle,
  • Siddharth Banka,
  • Nicola Whiffin

摘要

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 8040 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 7862 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

Whilst screening promoters and UTRs can uncover additional diagnoses for individuals with rare disease, including these regions in diagnostic pipelines is not likely to dramatically increase diagnostic yield. Nevertheless, we provide a framework to aid identification of these variants.