The 100,000 genomes pilot on rare disease diagnosis in healthcare – a preliminary report
<p><strong>BACKGROUND:</strong> The UK 100,000 Genomes Project is in the process of investigating the role of genome sequencing of patients with undiagnosed rare disease following usual care, and the alignment of research with healthcare implementation in the UK’s national health s...
| Những tác giả chính: | , , , , , , , , , , , , , , , , , , , |
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| Định dạng: | Journal article |
| Ngôn ngữ: | English |
| Được phát hành: |
Massachusetts Medical Society
2021
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| _version_ | 1826307622398066688 |
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| author | Smedley, D Smith, KR Rueda Martin, A Buchanan, J Wordsworth, S de Burca, A Davies, J Crichton, C Welch, J Woods, K Campbell, C Camps, C Gibson, K Lester, T Patel, S Roy, NBA Sen, A Németh, AH Taylor, J Caulfield, M |
| author2 | The 100,000 Genomes Project Pilot Investigators |
| author_facet | The 100,000 Genomes Project Pilot Investigators Smedley, D Smith, KR Rueda Martin, A Buchanan, J Wordsworth, S de Burca, A Davies, J Crichton, C Welch, J Woods, K Campbell, C Camps, C Gibson, K Lester, T Patel, S Roy, NBA Sen, A Németh, AH Taylor, J Caulfield, M |
| author_sort | Smedley, D |
| collection | OXFORD |
| description | <p><strong>BACKGROUND:</strong> The UK 100,000 Genomes Project is in the process of investigating the role of genome sequencing of patients with undiagnosed rare disease following usual care, and the alignment of research with healthcare implementation in the UK’s national health service. (Other parts of this Project focus on patients with cancer and infection.)</p>
<p><strong>METHODS:</strong> We enrolled participants, collected clinical features with human phenotype ontology terms, undertook genome sequencing and applied automated variant prioritization based on virtual gene panels (PanelApp) and phenotypes (Exomiser), alongside identification of novel pathogenic variants through research analysis. We report results on a pilot study of 4660 participants from 2183 families with 161 disorders covering a broad spectrum of rare disease.</p>
<p><strong>RESULTS:</strong> Diagnostic yields varied by family structure and were highest in trios and larger pedigrees. Likely monogenic disorders had much higher diagnostic yields (35%) with intellectual disability, hearing and vision disorders, achieving yields between 40 and 55%. Those with more complex etiologies had an overall 25% yield. Combining research and automated approaches was critical to 14% of diagnoses in which we found etiologic non-coding, structural and mitochondrial genome variants and coding variants poorly covered by exome sequencing. Cohort-wide burden testing across 57,000 genomes enabled discovery of 3 new disease genes and 19 novel associations. Of the genetic diagnoses that we made, 24% had immediate ramifications for the clinical decision-making for the patient or their relatives.</p>
<p><strong>CONCLUSION:</strong> Our pilot study of genome sequencing in a national health care system demonstrates diagnostic uplift across a range of rare diseases.</p> |
| first_indexed | 2024-03-07T07:05:52Z |
| format | Journal article |
| id | oxford-uuid:28dc6d0c-e9f1-4785-abfc-c50c134f4b58 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:05:52Z |
| publishDate | 2021 |
| publisher | Massachusetts Medical Society |
| record_format | dspace |
| spelling | oxford-uuid:28dc6d0c-e9f1-4785-abfc-c50c134f4b582022-05-11T08:45:19ZThe 100,000 genomes pilot on rare disease diagnosis in healthcare – a preliminary reportJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:28dc6d0c-e9f1-4785-abfc-c50c134f4b58EnglishSymplectic ElementsMassachusetts Medical Society2021Smedley, DSmith, KRRueda Martin, ABuchanan, JWordsworth, Sde Burca, ADavies, JCrichton, CWelch, JWoods, KCampbell, CCamps, CGibson, KLester, TPatel, SRoy, NBASen, ANémeth, AHTaylor, JCaulfield, MThe 100,000 Genomes Project Pilot Investigators<p><strong>BACKGROUND:</strong> The UK 100,000 Genomes Project is in the process of investigating the role of genome sequencing of patients with undiagnosed rare disease following usual care, and the alignment of research with healthcare implementation in the UK’s national health service. (Other parts of this Project focus on patients with cancer and infection.)</p> <p><strong>METHODS:</strong> We enrolled participants, collected clinical features with human phenotype ontology terms, undertook genome sequencing and applied automated variant prioritization based on virtual gene panels (PanelApp) and phenotypes (Exomiser), alongside identification of novel pathogenic variants through research analysis. We report results on a pilot study of 4660 participants from 2183 families with 161 disorders covering a broad spectrum of rare disease.</p> <p><strong>RESULTS:</strong> Diagnostic yields varied by family structure and were highest in trios and larger pedigrees. Likely monogenic disorders had much higher diagnostic yields (35%) with intellectual disability, hearing and vision disorders, achieving yields between 40 and 55%. Those with more complex etiologies had an overall 25% yield. Combining research and automated approaches was critical to 14% of diagnoses in which we found etiologic non-coding, structural and mitochondrial genome variants and coding variants poorly covered by exome sequencing. Cohort-wide burden testing across 57,000 genomes enabled discovery of 3 new disease genes and 19 novel associations. Of the genetic diagnoses that we made, 24% had immediate ramifications for the clinical decision-making for the patient or their relatives.</p> <p><strong>CONCLUSION:</strong> Our pilot study of genome sequencing in a national health care system demonstrates diagnostic uplift across a range of rare diseases.</p> |
| spellingShingle | Smedley, D Smith, KR Rueda Martin, A Buchanan, J Wordsworth, S de Burca, A Davies, J Crichton, C Welch, J Woods, K Campbell, C Camps, C Gibson, K Lester, T Patel, S Roy, NBA Sen, A Németh, AH Taylor, J Caulfield, M The 100,000 genomes pilot on rare disease diagnosis in healthcare – a preliminary report |
| title | The 100,000 genomes pilot on rare disease diagnosis in healthcare – a preliminary report |
| title_full | The 100,000 genomes pilot on rare disease diagnosis in healthcare – a preliminary report |
| title_fullStr | The 100,000 genomes pilot on rare disease diagnosis in healthcare – a preliminary report |
| title_full_unstemmed | The 100,000 genomes pilot on rare disease diagnosis in healthcare – a preliminary report |
| title_short | The 100,000 genomes pilot on rare disease diagnosis in healthcare – a preliminary report |
| title_sort | 100 000 genomes pilot on rare disease diagnosis in healthcare a preliminary report |
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