Genome Medicine (Nov 2023)
Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases
- Alistair T. Pagnamenta,
- Carme Camps,
- Edoardo Giacopuzzi,
- John M. Taylor,
- Mona Hashim,
- Eduardo Calpena,
- Pamela J. Kaisaki,
- Akiko Hashimoto,
- Jing Yu,
- Edward Sanders,
- Ron Schwessinger,
- Jim R. Hughes,
- Gerton Lunter,
- Helene Dreau,
- Matteo Ferla,
- Lukas Lange,
- Yesim Kesim,
- Vassilis Ragoussis,
- Dimitrios V. Vavoulis,
- Holger Allroggen,
- Olaf Ansorge,
- Christian Babbs,
- Siddharth Banka,
- Benito Baños-Piñero,
- David Beeson,
- Tal Ben-Ami,
- David L. Bennett,
- Celeste Bento,
- Edward Blair,
- Charlotte Brasch-Andersen,
- Katherine R. Bull,
- Holger Cario,
- Deirdre Cilliers,
- Valerio Conti,
- E. Graham Davies,
- Fatima Dhalla,
- Beatriz Diez Dacal,
- Yin Dong,
- James E. Dunford,
- Renzo Guerrini,
- Adrian L. Harris,
- Jane Hartley,
- Georg Hollander,
- Kassim Javaid,
- Maureen Kane,
- Deirdre Kelly,
- Dominic Kelly,
- Samantha J. L. Knight,
- Alexandra Y. Kreins,
- Erika M. Kvikstad,
- Craig B. Langman,
- Tracy Lester,
- Kate E. Lines,
- Simon R. Lord,
- Xin Lu,
- Sahar Mansour,
- Adnan Manzur,
- Reza Maroofian,
- Brian Marsden,
- Joanne Mason,
- Simon J. McGowan,
- Davide Mei,
- Hana Mlcochova,
- Yoshiko Murakami,
- Andrea H. Németh,
- Steven Okoli,
- Elizabeth Ormondroyd,
- Lilian Bomme Ousager,
- Jacqueline Palace,
- Smita Y. Patel,
- Melissa M. Pentony,
- Chris Pugh,
- Aboulfazl Rad,
- Archana Ramesh,
- Simone G. Riva,
- Irene Roberts,
- Noémi Roy,
- Outi Salminen,
- Kyleen D. Schilling,
- Caroline Scott,
- Arjune Sen,
- Conrad Smith,
- Mark Stevenson,
- Rajesh V. Thakker,
- Stephen R. F. Twigg,
- Holm H. Uhlig,
- Richard van Wijk,
- Barbara Vona,
- Steven Wall,
- Jing Wang,
- Hugh Watkins,
- Jaroslav Zak,
- Anna H. Schuh,
- Usha Kini,
- Andrew O. M. Wilkie,
- Niko Popitsch,
- Jenny C. Taylor
Affiliations
- Alistair T. Pagnamenta
- Wellcome Centre for Human Genetics, University of Oxford
- Carme Camps
- Wellcome Centre for Human Genetics, University of Oxford
- Edoardo Giacopuzzi
- Wellcome Centre for Human Genetics, University of Oxford
- John M. Taylor
- NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust
- Mona Hashim
- Wellcome Centre for Human Genetics, University of Oxford
- Eduardo Calpena
- NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust
- Pamela J. Kaisaki
- Wellcome Centre for Human Genetics, University of Oxford
- Akiko Hashimoto
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital
- Jing Yu
- Wellcome Centre for Human Genetics, University of Oxford
- Edward Sanders
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital
- Ron Schwessinger
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital
- Jim R. Hughes
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital
- Gerton Lunter
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital
- Helene Dreau
- NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust
- Matteo Ferla
- Wellcome Centre for Human Genetics, University of Oxford
- Lukas Lange
- Wellcome Centre for Human Genetics, University of Oxford
- Yesim Kesim
- Wellcome Centre for Human Genetics, University of Oxford
- Vassilis Ragoussis
- Wellcome Centre for Human Genetics, University of Oxford
- Dimitrios V. Vavoulis
- Wellcome Centre for Human Genetics, University of Oxford
- Holger Allroggen
- Neurosciences Department, UHCW NHS Trust
- Olaf Ansorge
- Nuffield Department of Clinical Neurosciences, University of Oxford
- Christian Babbs
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital
- Siddharth Banka
- Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester
- Benito Baños-Piñero
- Oxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital
- David Beeson
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital
- Tal Ben-Ami
- Pediatric Hematology-Oncology Unit, Kaplan Medical Center
- David L. Bennett
- Nuffield Department of Clinical Neurosciences, University of Oxford
- Celeste Bento
- Hematology Department, Hospitais da Universidade de Coimbra
- Edward Blair
- NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust
- Charlotte Brasch-Andersen
- Department of Clinical Genetics, Odense University Hospital and Department of Clinical Research, University of Southern Denmark
- Katherine R. Bull
- Wellcome Centre for Human Genetics, University of Oxford
- Holger Cario
- Department of Pediatrics and Adolescent Medicine, University Medical Center
- Deirdre Cilliers
- Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust
- Valerio Conti
- Neuroscience Department, Meyer Children’s Hospital IRCCS
- E. Graham Davies
- Department of Immunology, Great Ormond Street Hospital for Children NHS Trust and UCL Great Ormond Street Institute of Child Health, Zayed Centre for Research
- Fatima Dhalla
- Department of Paediatrics, Institute of Developmental and Regenerative Medicine, IMS-Tetsuya Nakamura Building
- Beatriz Diez Dacal
- Oxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital
- Yin Dong
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital
- James E. Dunford
- Oxford NIHR Musculoskeletal BRC and Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Nuffield Orthopaedic Centre
- Renzo Guerrini
- Neuroscience Department, Meyer Children’s Hospital IRCCS
- Adrian L. Harris
- Department of Oncology, University of Oxford
- Jane Hartley
- Liver Unit, Birmingham Women’s & Children’s Hospital and University of Birmingham
- Georg Hollander
- Department of Paediatrics, University of Oxford, Level 2, Children’s Hospital, John Radcliffe Hospital
- Kassim Javaid
- Oxford NIHR Musculoskeletal BRC and Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Nuffield Orthopaedic Centre
- Maureen Kane
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland
- Deirdre Kelly
- Liver Unit, Birmingham Women’s & Children’s Hospital and University of Birmingham
- Dominic Kelly
- Children’s Hospital, OUH NHS Foundation Trust, NIHR Oxford BRC
- Samantha J. L. Knight
- Wellcome Centre for Human Genetics, University of Oxford
- Alexandra Y. Kreins
- Department of Immunology, Great Ormond Street Hospital for Children NHS Trust and UCL Great Ormond Street Institute of Child Health, Zayed Centre for Research
- Erika M. Kvikstad
- Wellcome Centre for Human Genetics, University of Oxford
- Craig B. Langman
- Feinberg School of Medicine, Northwestern University
- Tracy Lester
- Oxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital
- Kate E. Lines
- NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust
- Simon R. Lord
- Early Phase Clinical Trials Unit, Department of Oncology, University of Oxford, Cancer and Haematology Centre, Level 2 Administration Area, Churchill Hospital
- Xin Lu
- Nuffield Department of Clinical Medicine, Ludwig Institute for Cancer Research, University of Oxford
- Sahar Mansour
- St George’s University Hospitals NHS Foundation Trust
- Adnan Manzur
- MRC Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery
- Reza Maroofian
- Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery
- Brian Marsden
- Nuffield Department of Medicine, Kennedy Institute, University of Oxford
- Joanne Mason
- Yourgene Health Headquarters
- Simon J. McGowan
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital
- Davide Mei
- Neuroscience Department, Meyer Children’s Hospital IRCCS
- Hana Mlcochova
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital
- Yoshiko Murakami
- Research Institute for Microbial Diseases, Osaka University
- Andrea H. Németh
- Nuffield Department of Clinical Neurosciences, University of Oxford
- Steven Okoli
- Imperial College NHS Trust, Department of Haematology, Hammersmith Hospital
- Elizabeth Ormondroyd
- NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust
- Lilian Bomme Ousager
- Department of Clinical Genetics, Odense University Hospital and Department of Clinical Research, University of Southern Denmark
- Jacqueline Palace
- Nuffield Department of Clinical Neurosciences, University of Oxford
- Smita Y. Patel
- Clinical Immunology, John Radcliffe Hospital
- Melissa M. Pentony
- Wellcome Centre for Human Genetics, University of Oxford
- Chris Pugh
- Nuffield Department of Medicine, University of Oxford
- Aboulfazl Rad
- Department of Otolaryngology–Head & Neck Surgery, Tübingen Hearing Research Centre, Eberhard Karls University
- Archana Ramesh
- Wellcome Centre for Human Genetics, University of Oxford
- Simone G. Riva
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital
- Irene Roberts
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital
- Noémi Roy
- Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Level 4, Haematology, John Radcliffe Hospital
- Outi Salminen
- NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust
- Kyleen D. Schilling
- Ann & Robert H. Lurie Children’s Hospital of Chicago
- Caroline Scott
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital
- Arjune Sen
- Nuffield Department of Clinical Neurosciences, University of Oxford
- Conrad Smith
- Oxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital
- Mark Stevenson
- University of Oxford, Academic Endocrine Unit, OCDEM, Churchill Hospital
- Rajesh V. Thakker
- University of Oxford, Academic Endocrine Unit, OCDEM, Churchill Hospital
- Stephen R. F. Twigg
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital
- Holm H. Uhlig
- NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust
- Richard van Wijk
- UMC Utrecht
- Barbara Vona
- Department of Otolaryngology–Head & Neck Surgery, Tübingen Hearing Research Centre, Eberhard Karls University
- Steven Wall
- Oxford Craniofacial Unit, John Radcliffe Hospital
- Jing Wang
- Nuffield Department of Clinical Neurosciences, University of Oxford
- Hugh Watkins
- NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust
- Jaroslav Zak
- Nuffield Department of Clinical Medicine, Ludwig Institute for Cancer Research, University of Oxford
- Anna H. Schuh
- Department of Oncology, Oxford Molecular Diagnostics Centre, University of Oxford, Level 4, John Radcliffe Hospital
- Usha Kini
- NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust
- Andrew O. M. Wilkie
- NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust
- Niko Popitsch
- Wellcome Centre for Human Genetics, University of Oxford
- Jenny C. Taylor
- Wellcome Centre for Human Genetics, University of Oxford
- DOI
- https://doi.org/10.1186/s13073-023-01240-0
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 1 – 25
Abstract
Abstract 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.
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