Systematic identification of disease-causing promoter and untranslated region variants in 8,040 undiagnosed individuals with rare disease.
| العنوان: | Systematic identification of disease-causing promoter and untranslated region variants in 8,040 undiagnosed individuals with rare disease. |
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| المؤلفون: | Martin-Geary AC; Big Data Institute, University of Oxford, UK.; Wellcome Centre for Human Genetics, University of Oxford, UK., Blakes AJM; Manchester Centre for Genomic Medicine, Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK., Dawes R; Big Data Institute, University of Oxford, UK.; Wellcome Centre for Human Genetics, University of Oxford, UK., Findlay SD; Department of Biology, Massachusetts Institute of Technology, Cambridge, USA., Lord J; Genomics England, UK., Walker S; Genomics England, UK., Talbot-Martin J; Department of Bioengineering, Imperial College London, UK., Wieder N; Big Data Institute, University of Oxford, UK.; Wellcome Centre for Human Genetics, University of Oxford, UK., D'Souza EN; Big Data Institute, University of Oxford, UK.; Wellcome Centre for Human Genetics, University of Oxford, UK., Fernandes M; Big Data Institute, University of Oxford, UK.; Wellcome Centre for Human Genetics, University of Oxford, UK., Hilton S; Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester M13 9WL, UK., Lahiri N; St George's, University of London & St George's University Hospitals NHS Foundation Trust, Institute of Molecular and Clinical Sciences, London, SW17 0QT, UK., Campbell C; Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester M13 9WL, UK., Jenkinson S; Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester M13 9WL, UK., DeGoede CGEL; Department of Paediatric Neurology, Clinical research Facility, Lancashire Teaching Hospitals NHS Trust.; Manchester Metropolitan University., Anderson ER; Liverpool Centre for Genomic Medicine, Liverpool Women's Hospital, Liverpool, UK., Burge CB; Department of Biology, Massachusetts Institute of Technology, Cambridge, USA., Sanders SJ; Institute of Developmental and Regenerative Medicine, Department of Paediatrics, University of Oxford, Oxford, OX3 7TY, UK.; Department of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.; New York Genome Center, New York, NY, USA., Ellingford J; Manchester Centre for Genomic Medicine, Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.; Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester M13 9WL, UK., Baralle D; School of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, United Kingdom., Banka S; Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester M13 9WL, UK., Whiffin N; Big Data Institute, University of Oxford, UK.; Wellcome Centre for Human Genetics, University of Oxford, UK.; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. |
| المصدر: | MedRxiv : the preprint server for health sciences [medRxiv] 2023 Sep 12. Date of Electronic Publication: 2023 Sep 12. |
| نوع المنشور: | Preprint |
| اللغة: | English |
| بيانات الدورية: | Country of Publication: United States NLM ID: 101767986 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: medRxiv Subsets: PubMed not MEDLINE |
| مستخلص: | 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. |
| معلومات مُعتمدة: | United Kingdom WT_ Wellcome Trust; R01 MH116999 United States MH NIMH NIH HHS; U01 MH122681 United States MH NIMH NIH HHS |
| فهرسة مساهمة: | Keywords: Untranslated regions; non-coding; promoters; rare disease; regulatory regions; splicing |
| تواريخ الأحداث: | Date Created: 20230925 Latest Revision: 20231019 |
| رمز التحديث: | 20231020 |
| مُعرف محوري في PubMed: | PMC10516070 |
| DOI: | 10.1101/2023.09.12.23295416 |
| PMID: | 37745552 |
| قاعدة البيانات: | MEDLINE |
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