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Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases
BACKGROUND: Whole genome sequencing is increasingly being used for the diagnosis of patients with rare diseases. However, the diagnostic yields of many studies, particularly those conducted in a healthcare setting, are often disappointingly low, at 25–30%. This is in part because although entire gen...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10636885/ https://www.ncbi.nlm.nih.gov/pubmed/37946251 http://dx.doi.org/10.1186/s13073-023-01240-0 |
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author | Pagnamenta, Alistair T. Camps, Carme Giacopuzzi, Edoardo Taylor, John M. Hashim, Mona Calpena, Eduardo Kaisaki, Pamela J. Hashimoto, Akiko Yu, Jing Sanders, Edward Schwessinger, Ron Hughes, Jim R. Lunter, Gerton Dreau, Helene Ferla, Matteo Lange, Lukas Kesim, Yesim Ragoussis, Vassilis Vavoulis, Dimitrios V. Allroggen, Holger Ansorge, Olaf Babbs, Christian Banka, Siddharth Baños-Piñero, Benito Beeson, David Ben-Ami, Tal Bennett, David L. Bento, Celeste Blair, Edward Brasch-Andersen, Charlotte Bull, Katherine R. Cario, Holger Cilliers, Deirdre Conti, Valerio Davies, E. Graham Dhalla, Fatima Dacal, Beatriz Diez Dong, Yin Dunford, James E. Guerrini, Renzo Harris, Adrian L. Hartley, Jane Hollander, Georg Javaid, Kassim Kane, Maureen Kelly, Deirdre Kelly, Dominic Knight, Samantha J. L. Kreins, Alexandra Y. Kvikstad, Erika M. Langman, Craig B. Lester, Tracy Lines, Kate E. Lord, Simon R. Lu, Xin Mansour, Sahar Manzur, Adnan Maroofian, Reza Marsden, Brian Mason, Joanne McGowan, Simon J. Mei, Davide Mlcochova, Hana Murakami, Yoshiko Németh, Andrea H. Okoli, Steven Ormondroyd, Elizabeth Ousager, Lilian Bomme Palace, Jacqueline Patel, Smita Y. Pentony, Melissa M. Pugh, Chris Rad, Aboulfazl Ramesh, Archana Riva, Simone G. Roberts, Irene Roy, Noémi Salminen, Outi Schilling, Kyleen D. Scott, Caroline Sen, Arjune Smith, Conrad Stevenson, Mark Thakker, Rajesh V. Twigg, Stephen R. F. Uhlig, Holm H. van Wijk, Richard Vona, Barbara Wall, Steven Wang, Jing Watkins, Hugh Zak, Jaroslav Schuh, Anna H. Kini, Usha Wilkie, Andrew O. M. Popitsch, Niko Taylor, Jenny C. |
author_facet | Pagnamenta, Alistair T. Camps, Carme Giacopuzzi, Edoardo Taylor, John M. Hashim, Mona Calpena, Eduardo Kaisaki, Pamela J. Hashimoto, Akiko Yu, Jing Sanders, Edward Schwessinger, Ron Hughes, Jim R. Lunter, Gerton Dreau, Helene Ferla, Matteo Lange, Lukas Kesim, Yesim Ragoussis, Vassilis Vavoulis, Dimitrios V. Allroggen, Holger Ansorge, Olaf Babbs, Christian Banka, Siddharth Baños-Piñero, Benito Beeson, David Ben-Ami, Tal Bennett, David L. Bento, Celeste Blair, Edward Brasch-Andersen, Charlotte Bull, Katherine R. Cario, Holger Cilliers, Deirdre Conti, Valerio Davies, E. Graham Dhalla, Fatima Dacal, Beatriz Diez Dong, Yin Dunford, James E. Guerrini, Renzo Harris, Adrian L. Hartley, Jane Hollander, Georg Javaid, Kassim Kane, Maureen Kelly, Deirdre Kelly, Dominic Knight, Samantha J. L. Kreins, Alexandra Y. Kvikstad, Erika M. Langman, Craig B. Lester, Tracy Lines, Kate E. Lord, Simon R. Lu, Xin Mansour, Sahar Manzur, Adnan Maroofian, Reza Marsden, Brian Mason, Joanne McGowan, Simon J. Mei, Davide Mlcochova, Hana Murakami, Yoshiko Németh, Andrea H. Okoli, Steven Ormondroyd, Elizabeth Ousager, Lilian Bomme Palace, Jacqueline Patel, Smita Y. Pentony, Melissa M. Pugh, Chris Rad, Aboulfazl Ramesh, Archana Riva, Simone G. Roberts, Irene Roy, Noémi Salminen, Outi Schilling, Kyleen D. Scott, Caroline Sen, Arjune Smith, Conrad Stevenson, Mark Thakker, Rajesh V. Twigg, Stephen R. F. Uhlig, Holm H. van Wijk, Richard Vona, Barbara Wall, Steven Wang, Jing Watkins, Hugh Zak, Jaroslav Schuh, Anna H. Kini, Usha Wilkie, Andrew O. M. Popitsch, Niko Taylor, Jenny C. |
author_sort | Pagnamenta, Alistair T. |
collection | PubMed |
description | BACKGROUND: Whole genome sequencing is increasingly being used for the diagnosis of patients with rare diseases. However, the diagnostic yields of many studies, particularly those conducted in a healthcare setting, are often disappointingly low, at 25–30%. This is in part because although entire genomes are sequenced, analysis is often confined to in silico gene panels or coding regions of the genome. METHODS: We undertook WGS on a cohort of 122 unrelated rare disease patients and their relatives (300 genomes) who had been pre-screened by gene panels or arrays. Patients were recruited from a broad spectrum of clinical specialties. We applied a bioinformatics pipeline that would allow comprehensive analysis of all variant types. We combined established bioinformatics tools for phenotypic and genomic analysis with our novel algorithms (SVRare, ALTSPLICE and GREEN-DB) to detect and annotate structural, splice site and non-coding variants. RESULTS: Our diagnostic yield was 43/122 cases (35%), although 47/122 cases (39%) were considered solved when considering novel candidate genes with supporting functional data into account. Structural, splice site and deep intronic variants contributed to 20/47 (43%) of our solved cases. Five genes that are novel, or were novel at the time of discovery, were identified, whilst a further three genes are putative novel disease genes with evidence of causality. We identified variants of uncertain significance in a further fourteen candidate genes. The phenotypic spectrum associated with RMND1 was expanded to include polymicrogyria. Two patients with secondary findings in FBN1 and KCNQ1 were confirmed to have previously unidentified Marfan and long QT syndromes, respectively, and were referred for further clinical interventions. Clinical diagnoses were changed in six patients and treatment adjustments made for eight individuals, which for five patients was considered life-saving. CONCLUSIONS: Genome sequencing is increasingly being considered as a first-line genetic test in routine clinical settings and can make a substantial contribution to rapidly identifying a causal aetiology for many patients, shortening their diagnostic odyssey. We have demonstrated that structural, splice site and intronic variants make a significant contribution to diagnostic yield and that comprehensive analysis of the entire genome is essential to maximise the value of clinical genome sequencing. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13073-023-01240-0. |
format | Online Article Text |
id | pubmed-10636885 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-106368852023-11-11 Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases Pagnamenta, Alistair T. Camps, Carme Giacopuzzi, Edoardo Taylor, John M. Hashim, Mona Calpena, Eduardo Kaisaki, Pamela J. Hashimoto, Akiko Yu, Jing Sanders, Edward Schwessinger, Ron Hughes, Jim R. Lunter, Gerton Dreau, Helene Ferla, Matteo Lange, Lukas Kesim, Yesim Ragoussis, Vassilis Vavoulis, Dimitrios V. Allroggen, Holger Ansorge, Olaf Babbs, Christian Banka, Siddharth Baños-Piñero, Benito Beeson, David Ben-Ami, Tal Bennett, David L. Bento, Celeste Blair, Edward Brasch-Andersen, Charlotte Bull, Katherine R. Cario, Holger Cilliers, Deirdre Conti, Valerio Davies, E. Graham Dhalla, Fatima Dacal, Beatriz Diez Dong, Yin Dunford, James E. Guerrini, Renzo Harris, Adrian L. Hartley, Jane Hollander, Georg Javaid, Kassim Kane, Maureen Kelly, Deirdre Kelly, Dominic Knight, Samantha J. L. Kreins, Alexandra Y. Kvikstad, Erika M. Langman, Craig B. Lester, Tracy Lines, Kate E. Lord, Simon R. Lu, Xin Mansour, Sahar Manzur, Adnan Maroofian, Reza Marsden, Brian Mason, Joanne McGowan, Simon J. Mei, Davide Mlcochova, Hana Murakami, Yoshiko Németh, Andrea H. Okoli, Steven Ormondroyd, Elizabeth Ousager, Lilian Bomme Palace, Jacqueline Patel, Smita Y. Pentony, Melissa M. Pugh, Chris Rad, Aboulfazl Ramesh, Archana Riva, Simone G. Roberts, Irene Roy, Noémi Salminen, Outi Schilling, Kyleen D. Scott, Caroline Sen, Arjune Smith, Conrad Stevenson, Mark Thakker, Rajesh V. Twigg, Stephen R. F. Uhlig, Holm H. van Wijk, Richard Vona, Barbara Wall, Steven Wang, Jing Watkins, Hugh Zak, Jaroslav Schuh, Anna H. Kini, Usha Wilkie, Andrew O. M. Popitsch, Niko Taylor, Jenny C. Genome Med Research BACKGROUND: Whole genome sequencing is increasingly being used for the diagnosis of patients with rare diseases. However, the diagnostic yields of many studies, particularly those conducted in a healthcare setting, are often disappointingly low, at 25–30%. This is in part because although entire genomes are sequenced, analysis is often confined to in silico gene panels or coding regions of the genome. METHODS: We undertook WGS on a cohort of 122 unrelated rare disease patients and their relatives (300 genomes) who had been pre-screened by gene panels or arrays. Patients were recruited from a broad spectrum of clinical specialties. We applied a bioinformatics pipeline that would allow comprehensive analysis of all variant types. We combined established bioinformatics tools for phenotypic and genomic analysis with our novel algorithms (SVRare, ALTSPLICE and GREEN-DB) to detect and annotate structural, splice site and non-coding variants. RESULTS: Our diagnostic yield was 43/122 cases (35%), although 47/122 cases (39%) were considered solved when considering novel candidate genes with supporting functional data into account. Structural, splice site and deep intronic variants contributed to 20/47 (43%) of our solved cases. Five genes that are novel, or were novel at the time of discovery, were identified, whilst a further three genes are putative novel disease genes with evidence of causality. We identified variants of uncertain significance in a further fourteen candidate genes. The phenotypic spectrum associated with RMND1 was expanded to include polymicrogyria. Two patients with secondary findings in FBN1 and KCNQ1 were confirmed to have previously unidentified Marfan and long QT syndromes, respectively, and were referred for further clinical interventions. Clinical diagnoses were changed in six patients and treatment adjustments made for eight individuals, which for five patients was considered life-saving. CONCLUSIONS: Genome sequencing is increasingly being considered as a first-line genetic test in routine clinical settings and can make a substantial contribution to rapidly identifying a causal aetiology for many patients, shortening their diagnostic odyssey. We have demonstrated that structural, splice site and intronic variants make a significant contribution to diagnostic yield and that comprehensive analysis of the entire genome is essential to maximise the value of clinical genome sequencing. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13073-023-01240-0. BioMed Central 2023-11-09 /pmc/articles/PMC10636885/ /pubmed/37946251 http://dx.doi.org/10.1186/s13073-023-01240-0 Text en © Crown 2023 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Pagnamenta, Alistair T. Camps, Carme Giacopuzzi, Edoardo Taylor, John M. Hashim, Mona Calpena, Eduardo Kaisaki, Pamela J. Hashimoto, Akiko Yu, Jing Sanders, Edward Schwessinger, Ron Hughes, Jim R. Lunter, Gerton Dreau, Helene Ferla, Matteo Lange, Lukas Kesim, Yesim Ragoussis, Vassilis Vavoulis, Dimitrios V. Allroggen, Holger Ansorge, Olaf Babbs, Christian Banka, Siddharth Baños-Piñero, Benito Beeson, David Ben-Ami, Tal Bennett, David L. Bento, Celeste Blair, Edward Brasch-Andersen, Charlotte Bull, Katherine R. Cario, Holger Cilliers, Deirdre Conti, Valerio Davies, E. Graham Dhalla, Fatima Dacal, Beatriz Diez Dong, Yin Dunford, James E. Guerrini, Renzo Harris, Adrian L. Hartley, Jane Hollander, Georg Javaid, Kassim Kane, Maureen Kelly, Deirdre Kelly, Dominic Knight, Samantha J. L. Kreins, Alexandra Y. Kvikstad, Erika M. Langman, Craig B. Lester, Tracy Lines, Kate E. Lord, Simon R. Lu, Xin Mansour, Sahar Manzur, Adnan Maroofian, Reza Marsden, Brian Mason, Joanne McGowan, Simon J. Mei, Davide Mlcochova, Hana Murakami, Yoshiko Németh, Andrea H. Okoli, Steven Ormondroyd, Elizabeth Ousager, Lilian Bomme Palace, Jacqueline Patel, Smita Y. Pentony, Melissa M. Pugh, Chris Rad, Aboulfazl Ramesh, Archana Riva, Simone G. Roberts, Irene Roy, Noémi Salminen, Outi Schilling, Kyleen D. Scott, Caroline Sen, Arjune Smith, Conrad Stevenson, Mark Thakker, Rajesh V. Twigg, Stephen R. F. Uhlig, Holm H. van Wijk, Richard Vona, Barbara Wall, Steven Wang, Jing Watkins, Hugh Zak, Jaroslav Schuh, Anna H. Kini, Usha Wilkie, Andrew O. M. Popitsch, Niko Taylor, Jenny C. Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases |
title | Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases |
title_full | Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases |
title_fullStr | Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases |
title_full_unstemmed | Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases |
title_short | Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases |
title_sort | structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10636885/ https://www.ncbi.nlm.nih.gov/pubmed/37946251 http://dx.doi.org/10.1186/s13073-023-01240-0 |
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structuralandnoncodingvariantsincreasethediagnosticyieldofclinicalwholegenomesequencingforrarediseases |