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Specialist multidisciplinary input maximises rare disease diagnoses from whole genome sequencing

Diagnostic whole genome sequencing (WGS) is increasingly used in rare diseases. However, standard, semi-automated WGS analysis may overlook diagnoses in complex disorders. Here, we show that specialist multidisciplinary analysis of WGS, following an initial ‘no primary findings’ (NPF) report, improv...

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Autores principales: Macken, William L., Falabella, Micol, McKittrick, Caroline, Pizzamiglio, Chiara, Ellmers, Rebecca, Eggleton, Kelly, Woodward, Cathy E., Patel, Yogen, Labrum, Robyn, Phadke, Rahul, Reilly, Mary M., DeVile, Catherine, Sarkozy, Anna, Footitt, Emma, Davison, James, Rahman, Shamima, Houlden, Henry, Bugiardini, Enrico, Quinlivan, Rosaline, Hanna, Michael G., Vandrovcova, Jana, Pitceathly, Robert D. S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9640711/
https://www.ncbi.nlm.nih.gov/pubmed/36344503
http://dx.doi.org/10.1038/s41467-022-32908-7
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author Macken, William L.
Falabella, Micol
McKittrick, Caroline
Pizzamiglio, Chiara
Ellmers, Rebecca
Eggleton, Kelly
Woodward, Cathy E.
Patel, Yogen
Labrum, Robyn
Phadke, Rahul
Reilly, Mary M.
DeVile, Catherine
Sarkozy, Anna
Footitt, Emma
Davison, James
Rahman, Shamima
Houlden, Henry
Bugiardini, Enrico
Quinlivan, Rosaline
Hanna, Michael G.
Vandrovcova, Jana
Pitceathly, Robert D. S.
author_facet Macken, William L.
Falabella, Micol
McKittrick, Caroline
Pizzamiglio, Chiara
Ellmers, Rebecca
Eggleton, Kelly
Woodward, Cathy E.
Patel, Yogen
Labrum, Robyn
Phadke, Rahul
Reilly, Mary M.
DeVile, Catherine
Sarkozy, Anna
Footitt, Emma
Davison, James
Rahman, Shamima
Houlden, Henry
Bugiardini, Enrico
Quinlivan, Rosaline
Hanna, Michael G.
Vandrovcova, Jana
Pitceathly, Robert D. S.
author_sort Macken, William L.
collection PubMed
description Diagnostic whole genome sequencing (WGS) is increasingly used in rare diseases. However, standard, semi-automated WGS analysis may overlook diagnoses in complex disorders. Here, we show that specialist multidisciplinary analysis of WGS, following an initial ‘no primary findings’ (NPF) report, improves diagnostic rates and alters management. We undertook WGS in 102 adults with diagnostically challenging primary mitochondrial disease phenotypes. NPF cases were reviewed by a genomic medicine team, thus enabling bespoke informatic approaches, co-ordinated phenotypic validation, and functional work. We enhanced the diagnostic rate from 16.7% to 31.4%, with management implications for all new diagnoses, and detected strong candidate disease-causing variants in a further 3.9% of patients. This approach presents a standardised model of care that supports mainstream clinicians and enhances diagnostic equity for complex disorders, thereby facilitating access to the potential benefits of genomic healthcare. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project: http://www.genomicsengland.co.uk.
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spelling pubmed-96407112022-11-15 Specialist multidisciplinary input maximises rare disease diagnoses from whole genome sequencing Macken, William L. Falabella, Micol McKittrick, Caroline Pizzamiglio, Chiara Ellmers, Rebecca Eggleton, Kelly Woodward, Cathy E. Patel, Yogen Labrum, Robyn Phadke, Rahul Reilly, Mary M. DeVile, Catherine Sarkozy, Anna Footitt, Emma Davison, James Rahman, Shamima Houlden, Henry Bugiardini, Enrico Quinlivan, Rosaline Hanna, Michael G. Vandrovcova, Jana Pitceathly, Robert D. S. Nat Commun Article Diagnostic whole genome sequencing (WGS) is increasingly used in rare diseases. However, standard, semi-automated WGS analysis may overlook diagnoses in complex disorders. Here, we show that specialist multidisciplinary analysis of WGS, following an initial ‘no primary findings’ (NPF) report, improves diagnostic rates and alters management. We undertook WGS in 102 adults with diagnostically challenging primary mitochondrial disease phenotypes. NPF cases were reviewed by a genomic medicine team, thus enabling bespoke informatic approaches, co-ordinated phenotypic validation, and functional work. We enhanced the diagnostic rate from 16.7% to 31.4%, with management implications for all new diagnoses, and detected strong candidate disease-causing variants in a further 3.9% of patients. This approach presents a standardised model of care that supports mainstream clinicians and enhances diagnostic equity for complex disorders, thereby facilitating access to the potential benefits of genomic healthcare. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project: http://www.genomicsengland.co.uk. Nature Publishing Group UK 2022-11-07 /pmc/articles/PMC9640711/ /pubmed/36344503 http://dx.doi.org/10.1038/s41467-022-32908-7 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Macken, William L.
Falabella, Micol
McKittrick, Caroline
Pizzamiglio, Chiara
Ellmers, Rebecca
Eggleton, Kelly
Woodward, Cathy E.
Patel, Yogen
Labrum, Robyn
Phadke, Rahul
Reilly, Mary M.
DeVile, Catherine
Sarkozy, Anna
Footitt, Emma
Davison, James
Rahman, Shamima
Houlden, Henry
Bugiardini, Enrico
Quinlivan, Rosaline
Hanna, Michael G.
Vandrovcova, Jana
Pitceathly, Robert D. S.
Specialist multidisciplinary input maximises rare disease diagnoses from whole genome sequencing
title Specialist multidisciplinary input maximises rare disease diagnoses from whole genome sequencing
title_full Specialist multidisciplinary input maximises rare disease diagnoses from whole genome sequencing
title_fullStr Specialist multidisciplinary input maximises rare disease diagnoses from whole genome sequencing
title_full_unstemmed Specialist multidisciplinary input maximises rare disease diagnoses from whole genome sequencing
title_short Specialist multidisciplinary input maximises rare disease diagnoses from whole genome sequencing
title_sort specialist multidisciplinary input maximises rare disease diagnoses from whole genome sequencing
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9640711/
https://www.ncbi.nlm.nih.gov/pubmed/36344503
http://dx.doi.org/10.1038/s41467-022-32908-7
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