ArticleGenome medicine2023
Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases.
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Article in Genome medicine, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 61 papers, 1 of them a synthesis that pooled it.
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61 citing papers in PubMed, 1 synthesis or guideline pooled it, 66 citations in OpenAlex.
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- CRISPR-Cas9 and precision editing technologies linking functional genomics to clinical translation in genetic diseases.Clinical and translational medicine · 2026Review
- [Genetic diagnostics].Pathologie (Heidelberg, Germany) · 2026Review
- Optical mapping reveals a higher level of large-scale structural variants in a family with paternally transmitted myotonic dystrophy and independent Parkinson's disease.The Journal of pathology · 2026Article
- Incremental yield of genome sequencing after exome sequencing for nonimmune hydrops fetalis spectrum.American journal of obstetrics & gynecology MFM · 2026Article
- Best practice recommendations for bioinformatics approaches applied to high-throughput sequencing for rare disease and cancer diagnosis within the UK National Health Service.Journal of medical genetics · 2026Article
- Whole-genome sequencing implicates rare, low-frequency and structural non-coding variation at themedRxiv : the preprint server for health sciences · 2026Article
- UK Biobank whole-genome sequencing reveals robust contributions of rare variants to complex-trait heritability.Genome biology · 2026Article
- The importance and clinical utility of reanalysis of exome and genome sequencing data.Kidney research and clinical practice · 2026Article
- Genetic Testing in Inherited Retinal Disease: Current Strategies and Future Directions.Journal of personalized medicine · 2026Review
- Wilson disease is a single gene disorder - comprehensive analysis of patients with prior negative genetic testing.JHEP reports : innovation in hepatology · 2026Article
- Genetic analysis of neurodegenerative diseases.The Journal of clinical investigation · 2026Review
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- Accelerating rare disease diagnostics by linking DNA and RNA through an explainable and interactive RNA-guided workflow.NAR genomics and bioinformatics · 2026Article
- Osteogenesis Imperfecta with a gross deletion including theBone reports · 2026Article
- Breakpoint-resolved balanced t(2;12)(q35;q24.31) disruptingMetabolism open · 2026Article
- Bi-allelic TPP1 variants in neuronal ceroid lipofuscinosis 2: clinical findings from an Iranian cohort of 20 patients, founder effect, and in silico analyses.Human genetics · 2026Article
1 more citing papers are in PubMed but not listed here.
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Authors and funding
97 authors at 20 institutions in 10 countries.
Alistair T Pagnamenta *Wellcome Centre for Human Genetics, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, OX3 7BN, UK.
Carme Camps *Wellcome Centre for Human Genetics, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, OX3 7BN, UK.
Edoardo Giacopuzzi *Wellcome Centre for Human Genetics, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, OX3 7BN, UK.
John M Taylor *NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, OX3 9DU, UK.
Mona HashimWellcome Centre for Human Genetics, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, OX3 7BN, UK.
Eduardo CalpenaNIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, OX3 9DU, UK.
Pamela J KaisakiWellcome Centre for Human Genetics, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, OX3 7BN, UK.
Akiko HashimotoMRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
Jing YuWellcome Centre for Human Genetics, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, OX3 7BN, UK.
Edward SandersMRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
Ron SchwessingerMRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
Jim R HughesMRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
Gerton LunterMRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
Helene DreauNIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, OX3 9DU, UK.
Matteo FerlaWellcome Centre for Human Genetics, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, OX3 7BN, UK.
Lukas LangeWellcome Centre for Human Genetics, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, OX3 7BN, UK.
Yesim KesimWellcome Centre for Human Genetics, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, OX3 7BN, UK.
Vassilis RagoussisWellcome Centre for Human Genetics, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, OX3 7BN, UK.
Dimitrios V VavoulisWellcome Centre for Human Genetics, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, OX3 7BN, UK.
Holger AllroggenNeurosciences Department, UHCW NHS Trust, Clifford Bridge Road, Coventry, CV2 2DX, UK.
Olaf AnsorgeNuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX3 9DU, UK.
Christian BabbsMRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
Siddharth BankaDivision of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Benito Baños-PiñeroOxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Old Road, Oxford, OX3 7LE, UK.
David BeesonMRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
Tal Ben-AmiPediatric Hematology-Oncology Unit, Kaplan Medical Center, Rehovot, Israel.
David L BennettNuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX3 9DU, UK.
Celeste BentoHematology Department, Hospitais da Universidade de Coimbra, Coimbra, Portugal.
Edward BlairNIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, OX3 9DU, UK.
Charlotte Brasch-AndersenDepartment of Clinical Genetics, Odense University Hospital and Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
Katherine R BullWellcome Centre for Human Genetics, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, OX3 7BN, UK.
Holger CarioDepartment of Pediatrics and Adolescent Medicine, University Medical Center, Eythstrasse 24, 89075, Ulm, Germany.
Deirdre CilliersOxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, OX3 7LE, UK.
Valerio ContiNeuroscience Department, Meyer Children's Hospital IRCCS, Viale Pieraccini 24, 50139, Florence, Italy.
E Graham DaviesDepartment of Immunology, Great Ormond Street Hospital for Children NHS Trust and UCL Great Ormond Street Institute of Child Health, Zayed Centre for Research, 2Nd Floor, 20C Guilford Street, London, WC1N 1DZ, UK.
Fatima DhallaDepartment of Paediatrics, Institute of Developmental and Regenerative Medicine, IMS-Tetsuya Nakamura Building, Old Road Campus, Roosevelt Drive, Oxford, OX3 7TY, UK.
Beatriz Diez DacalOxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Old Road, Oxford, OX3 7LE, UK.
Yin DongMRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
James E DunfordOxford NIHR Musculoskeletal BRC and Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Nuffield Orthopaedic Centre, Old Road, Oxford, OX3 7HE, UK.
Renzo GuerriniNeuroscience Department, Meyer Children's Hospital IRCCS, Viale Pieraccini 24, 50139, Florence, Italy.
Adrian L HarrisDepartment of Oncology, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK.
Jane HartleyLiver Unit, Birmingham Women's & Children's Hospital and University of Birmingham, Steelhouse Lane, Birmingham, B4 6NH, UK.
Georg HollanderDepartment of Paediatrics, University of Oxford, Level 2, Children's Hospital, John Radcliffe Hospital, Oxford, OX3 9DU, UK.
Kassim JavaidOxford NIHR Musculoskeletal BRC and Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Nuffield Orthopaedic Centre, Old Road, Oxford, OX3 7HE, UK.
Maureen KaneDepartment of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Pharmacy Hall North, Room 731, 20 N. Pine Street, Baltimore, MD, 21201, USA.
Deirdre KellyLiver Unit, Birmingham Women's & Children's Hospital and University of Birmingham, Steelhouse Lane, Birmingham, B4 6NH, UK.
Dominic KellyChildren's Hospital, OUH NHS Foundation Trust, NIHR Oxford BRC, Headley Way, Oxford, OX3 9DU, UK.
Samantha J L KnightWellcome Centre for Human Genetics, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, OX3 7BN, UK.
Alexandra Y KreinsDepartment of Immunology, Great Ormond Street Hospital for Children NHS Trust and UCL Great Ormond Street Institute of Child Health, Zayed Centre for Research, 2Nd Floor, 20C Guilford Street, London, WC1N 1DZ, UK.
Erika M KvikstadWellcome Centre for Human Genetics, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, OX3 7BN, UK.
Craig B LangmanFeinberg School of Medicine, Northwestern University, 211 E Chicago Avenue, Chicago, IL, MS37, USA.
Tracy LesterOxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Old Road, Oxford, OX3 7LE, UK.
Kate E LinesNIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, OX3 9DU, UK.
Simon R LordEarly Phase Clinical Trials Unit, Department of Oncology, University of Oxford, Cancer and Haematology Centre, Level 2 Administration Area, Churchill Hospital, Oxford, OX3 7LJ, UK.
Xin LuNuffield Department of Clinical Medicine, Ludwig Institute for Cancer Research, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK.
Sahar MansourSt George's University Hospitals NHS Foundation Trust, Blackshore Road, Tooting, London, SW17 0QT, UK.
Adnan ManzurMRC Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK.
Reza MaroofianDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, WC1N 3BG, UK.
Brian MarsdenNuffield Department of Medicine, Kennedy Institute, University of Oxford, Oxford, OX3 7BN, UK.
Joanne MasonYourgene Health Headquarters, Skelton House, Lloyd Street North, Manchester Science Park, Manchester, M15 6SH, UK.
Simon J McGowanMRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
Davide MeiNeuroscience Department, Meyer Children's Hospital IRCCS, Viale Pieraccini 24, 50139, Florence, Italy.
Hana MlcochovaMRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
Yoshiko MurakamiResearch Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Andrea H NémethNuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX3 9DU, UK.
Steven OkoliImperial College NHS Trust, Department of Haematology, Hammersmith Hospital, Du Cane Road, London, W12 0HS, UK.
Elizabeth OrmondroydNIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, OX3 9DU, UK.
Lilian Bomme OusagerDepartment of Clinical Genetics, Odense University Hospital and Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
Jacqueline PalaceNuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX3 9DU, UK.
Smita Y PatelClinical Immunology, John Radcliffe Hospital, Level 4A, Oxford, OX3 9DU, UK.
Melissa M PentonyWellcome Centre for Human Genetics, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, OX3 7BN, UK.
Chris PughNuffield Department of Medicine, University of Oxford, Oxford, OX3 7BN, UK.
Aboulfazl RadDepartment of Otolaryngology-Head & Neck Surgery, Tübingen Hearing Research Centre, Eberhard Karls University, Elfriede-Aulhorn-Str. 5, 72076, Tübingen, Germany.
Archana RameshWellcome Centre for Human Genetics, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, OX3 7BN, UK.
Simone G RivaMRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
Irene RobertsMRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
Noémi RoyDepartment of Haematology, Oxford University Hospitals NHS Foundation Trust, Level 4, Haematology, John Radcliffe Hospital, Oxford, OX3 9DU, UK.
Outi SalminenNIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, OX3 9DU, UK.
Kyleen D SchillingAnn & Robert H. Lurie Children's Hospital of Chicago, 225 E Chicago Avenue, Chicago, IL, 60611, USA.
Caroline ScottMRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
Arjune SenNuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX3 9DU, UK.
Conrad SmithOxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Old Road, Oxford, OX3 7LE, UK.
Mark StevensonUniversity of Oxford, Academic Endocrine Unit, OCDEM, Churchill Hospital, Oxford, OX3 7LJ, UK.
Rajesh V ThakkerUniversity of Oxford, Academic Endocrine Unit, OCDEM, Churchill Hospital, Oxford, OX3 7LJ, UK.
Stephen R F TwiggMRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
Holm H UhligNIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, OX3 9DU, UK.
Richard van WijkUMC Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
Barbara VonaDepartment of Otolaryngology-Head & Neck Surgery, Tübingen Hearing Research Centre, Eberhard Karls University, Elfriede-Aulhorn-Str. 5, 72076, Tübingen, Germany.
Steven WallOxford Craniofacial Unit, John Radcliffe Hospital, Level LG1, West Wing, Oxford, OX3 9DU, UK.
Jing WangNuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX3 9DU, UK.
Hugh WatkinsNIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, OX3 9DU, UK.
Jaroslav ZakNuffield Department of Clinical Medicine, Ludwig Institute for Cancer Research, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK.
Anna H SchuhDepartment of Oncology, Oxford Molecular Diagnostics Centre, University of Oxford, Level 4, John Radcliffe Hospital, Headley Way, Oxford, OX3 9DU, UK.
Usha KiniNIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, OX3 9DU, UK.
Andrew O M WilkieNIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, OX3 9DU, UK.
Niko PopitschWellcome Centre for Human Genetics, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, OX3 7BN, UK.
Jenny C TaylorWellcome Centre for Human Genetics, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, OX3 7BN, UK. jenny.taylor@well.ox.ac.uk.ORCID 0000-0003-3602-5704
John Radcliffe Hospital · GBCentre for Human Genetics · GBUniversity of Oxford · GBChurchill Hospital · GBMeyer Children's Hospital · ITGreat Ormond Street Hospital · GBNational Hospital for Neurology and Neurosurgery · GBNuffield Orthopaedic Centre · GBOxford Health NHS Foundation Trust · GBUniversity of Southern Denmark · DKHammersmith Hospital · GBHospitais da Universidade de Coimbra · PTKaplan Medical Center · ILLurie Children's Hospital · USNorthwestern University · USOxford University Hospitals NHS Trust · GBScripps Research Institute · USSt George’s University Hospitals NHS Foundation Trust · GBThe University of Osaka · JPUniversitätsmedizin Göttingen · DE
Funding
British Heart Foundation CH/1992001/6764Department of HealthMedical Research Council G0902418Medical Research Council MC_PC_21044Medical Research Council MC_UU_00008Medical Research Council MC_UU_00008/6Medical Research Council MC_UU_00016/1Medical Research Council MC_UU_00016/14Medical Research Council MC_UU_00029/ 01-09Medical Research Council MC_UU_00029/3Medical Research Council MR/M006824/1Medical Research Council MR/R007748/1Medical Research Council MR/S007180/1Medical Research Council MR/T014067/1Medical Research Council MR/T031670/1Medical Research Council MR/W01761X/1Medical Research Council MR/WO1761X/1Medical Research Council MR/X001210/1Wellcome Trust 102731Wellcome Trust 102731/Z/13/ZWellcome Trust 106,130/Z/14/ZWellcome Trust 203141/Z/16/ZWellcome Trust 222096/Z/20/ZWellcome Trust 223,149/Z/21/ZWellcome Trust R6-388 / WT 100127
Abstract
backgroundWhole 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.
methodsWe 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.
resultsOur 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.
conclusionsGenome 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.
Indexed as
Genetic VariationRare DiseasesCell Cycle ProteinsGenetic TestingHumansMutationWhole Genome SequencingCell Cycle ProteinsRMND1 protein, humanBioinformatics pipeline developmentClinical impactDiagnostic yieldGenome sequencingNon-codingPipeline optimisationRare diseasesSplice site variantStructural variant
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