ArticleAmerican journal of human genetics2024
The impact of inversions across 33,924 families with rare disease from a national genome sequencing project.
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Article in American journal of human genetics, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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23 citing papers in PubMed.
- Detecting pathogenic structural variation in families with undiagnosed rare disease in a national genome project.European journal of human genetics : EJHG · 2026Article
- Reanalysis of genomic data doubles the diagnostic yield for Welsh patients recruited to the UK 100,000 Genomes Project.European journal of human genetics : EJHG · 2026Article
- De Novo Complex Genomic Rearrangement Spanning 2q31.1 in a Proband With Congenital Malformations: Genotype-Phenotype Correlation and Development of a CGR Detection Pipeline.American journal of medical genetics. Part A · 2026Article
- Overexpression of SOX3 due to an X chromosome inversion leading to ovotesticular difference in sex development.Biology of sex differences · 2026Article
- Prime editing-based tool enables precise genomic inversions at kilobase to chromosomal scale.Nature chemical biology · 2026Article
- Long-read genome sequencing enhances diagnostics of pediatric neurological disorders.Genome medicine · 2026Article
- Palindrome-mediated 16p13.3 triplications cause a recognizable neurodegenerative disorder with ataxia.American journal of human genetics · 2026Article
- Integrating Long-Read Nanopore Sequencing for Precision Resolution of Genomic Variants in Dystonia.Movement disorders : official journal of the Movement Disorder Society · 2026Article
- Unveiling genomic rearrangements in engineered iPSC lines by optical genome mapping.Molecular therapy. Methods & clinical development · 2025Article
- Modeling the long-range effect of an inversion downstream of EFNB1 concludes a 43-year molecular diagnostic odyssey for craniofrontonasal syndrome.European journal of human genetics : EJHG · 2025Article
- Complex de novo structural variants are an underestimated cause of rare disorders.Nature communications · 2025Article
- Structural variants in the 3D genome as drivers of disease.Nature reviews. Genetics · 2025Review
- Urinary renal epithelial cells can be used for NPHP1 phenotyping and a personalized therapeutic strategy.Journal of cell science · 2025Article
- Clinical Utility of Whole-Genome Sequencing to Aid Histologic Diagnosis and to Direct Personalized Medicine in Salivary Gland Cancer.JCO precision oncology · 2025Article
- Long read whole genome sequencing-based discovery of structural variants and their role in aetiology of non-syndromic autism spectrum disorder in India.BMC medical genomics · 2025Article
- Characterisation and prevalence of inherited retinal diseases in the Finnish population reveals enrichment of population-specific phenotypes and causative variants.The British journal of ophthalmology · 2025Article
- Diversity and consequences of structural variation in the human genome.Nature reviews. Genetics · 2025Review
- Craniofrontonasal syndrome in a patient with an inv(X)(p22.2q13.1), separating EFNB1 from its enhancer.European journal of human genetics : EJHG · 2025Article
- Integrating genome and transcriptome analysis to decipher balanced structural variants in unsolved cases of neurodevelopmental disorders.Frontiers in genetics · 2025Article
- Enhanced detection and characterization of germline structural variants in cancer predisposition genes via genome sequencing.Genetics in medicine open · 2025Article
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Authors and funding
68 authors.
Alistair T PagnamentaOxford Biomedical Research Centre, Centre for Human Genetics, University of Oxford, Oxford, UK. Electronic address: alistair@well.ox.ac.uk.
Jing YuOxford Biomedical Research Centre, Centre for Human Genetics, University of Oxford, Oxford, UK; Novo Nordisk Oxford Research Centre, Oxford, UK.
Susan WalkerGenomics England, London, UK.
Alexandra J NobleTranslational Gastroenterology Unit, John Radcliffe Hospital, Oxford, UK.
Jenny LordSchool of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK; Sheffield Institute for Translational Neuroscience, The University of Sheffield, Sheffield, UK.
Prasun DuttaOxford Biomedical Research Centre, Centre for Human Genetics, University of Oxford, Oxford, UK.
Mona HashimOxford Biomedical Research Centre, Centre for Human Genetics, University of Oxford, Oxford, UK.
Carme CampsOxford Biomedical Research Centre, Centre for Human Genetics, University of Oxford, Oxford, UK.
Hannah GreenOxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Smrithi DevaiahOxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Lina NashefDepartment of Neurology, King's College Hospital, London, UK.
Jason ParrManchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Health Innovation Manchester, Manchester, UK.
Carl FratterOxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Rana Ibnouf HusseinManchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Health Innovation Manchester, Manchester, UK.
Sarah J LindsayWellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
Fiona LallooManchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Health Innovation Manchester, Manchester, UK.
Benito Banos-PineroOxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
David EvansExeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK.
Lucy MallinExeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK.
Adrian WaiteBristol Genetics Laboratory, North Bristol NHS Trust, Bristol, UK.
Julie EvansBristol Genetics Laboratory, North Bristol NHS Trust, Bristol, UK.
Andrew NewmanThe All Wales Medical Genomics Service, University Hospital of Wales, Cardiff, UK.
Zoe AllenNorth Thames Rare and Inherited Disease Laboratory, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Cristina Perez-BecerrilManchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Health Innovation Manchester, Manchester, UK.
Gavin RyanWest Midlands Regional Genetics Laboratory, Central and South Genomic Laboratory Hub, Birmingham, UK.
Rachel HartLiverpool Centre for Genomic Medicine, Liverpool Women's NHS Foundation Trust, Liverpool, UK.
John TaylorOxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Tina BedenhamOxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Emma ClementNorth East Thames Regional Genetic Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Ed BlairOxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Eleanor HayNorth East Thames Regional Genetic Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Francesca ForzanoClinical Genetics Department, Guy's and St Thomas' NHS Foundation Trust, London, UK.
Jenny HiggsLiverpool Centre for Genomic Medicine, Liverpool Women's NHS Foundation Trust, Liverpool, UK.
Natalie CanhamLiverpool Centre for Genomic Medicine, Liverpool Women's NHS Foundation Trust, Liverpool, UK.
Anirban MajumdarDepartment of Paediatric Neurology, Bristol Children's Hospital, Bristol, UK.
Meriel McEntagartSW Thames Centre for Genomic Medicine, University of London & St George's University Hospitals NHS Foundation Trust, St George's, London, UK.
Nayana LahiriSW Thames Centre for Genomic Medicine, University of London & St George's University Hospitals NHS Foundation Trust, St George's, London, UK.
Helen StewartOxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Sarah SmithsonDepartment of Clinical Genetics, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.
Eduardo CalpenaClinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK; Grupo de Investigación en Biomedicina Molecular, Celular y Genómica, Unidad CIBERER (CB06/07/1030), Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain.
Adam JacksonManchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Health Innovation Manchester, Manchester, UK; Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Siddharth BankaManchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Health Innovation Manchester, Manchester, UK; Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Hannah TitheradgeDepartment of Clinical Genetics, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.
Ruth McGowanWest of Scotland Centre for Genomic Medicine, Glasgow, UK.
Julia RankinDepartment of Clinical Genetics, Royal Devon University Healthcare NHS Trust, Exeter, UK.
Charles Shaw-SmithDepartment of Clinical Genetics, Royal Devon University Healthcare NHS Trust, Exeter, UK.
D Gareth EvansManchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Health Innovation Manchester, Manchester, UK; Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
George J BurghelManchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Health Innovation Manchester, Manchester, UK.
Miriam J SmithManchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Health Innovation Manchester, Manchester, UK.
Emily AndersonLiverpool Centre for Genomic Medicine, Liverpool Women's NHS Foundation Trust, Liverpool, UK.
Rajesh MadhuPaediatric Neurosciences Department, Alder Hey Children's Hospital NHS Foundation Trust, Liverpool, UK.
Helen FirthWellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
Sian EllardExeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK.
Paul BrennanInstitute of Genetic Medicine, Newcastle University, International Centre for Life, Newcastle University, Newcastle, UK.
Claire AndersonCanberra Clinical Genomics, Canberra Health Services and The Australian National University, Canberra, ACT, Australia.
Doug TaupinCancer Research, Canberra Hospital, Canberra, ACT, Australia.
Mark T RogersThe All Wales Medical Genomics Service, University Hospital of Wales, Cardiff, UK.
Jackie A CookDepartment of Clinical Genetics, Sheffield Children's NHS Foundation Trust, Sheffield, UK.
Miranda DurkieSheffield Diagnostic Genetics Service, Sheffield Children's NHS Foundation Trust, North East and Yorkshire Genomic Laboratory Hub, Sheffield, UK.
James E EastTranslational Gastroenterology Unit, John Radcliffe Hospital, Oxford, UK.
Darren FowlerDepartment of Cellular Pathology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Louise WilsonNorth East Thames Regional Genetic Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Rebecca IgbokweDepartment of Clinical Genetics, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.
Alice GardhamNorth East Thames Regional Genetic Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Ian TomlinsonDepartment of Oncology, University of Oxford, Oxford, UK.
Diana BaralleSchool of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK.
Holm H UhligOxford Biomedical Research Centre, Centre for Human Genetics, University of Oxford, Oxford, UK; Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, UK.
Jenny C TaylorOxford Biomedical Research Centre, Centre for Human Genetics, University of Oxford, Oxford, UK. Electronic address: jenny.taylor@well.ox.ac.uk.
Funding
Medical Research Council MR/W01761X/1Wellcome Trust
Abstract
Detection of structural variants (SVs) is currently biased toward those that alter copy number. The relative contribution of inversions toward genetic disease is unclear. In this study, we analyzed genome sequencing data for 33,924 families with rare disease from the 100,000 Genomes Project. From a database hosting >500 million SVs, we focused on 351 genes where haploinsufficiency is a confirmed disease mechanism and identified 47 ultra-rare rearrangements that included an inversion (24 bp to 36.4 Mb, 20/47 de novo). Validation utilized a number of orthogonal approaches, including retrospective exome analysis. RNA-seq data supported the respective diagnoses for six participants. Phenotypic blending was apparent in four probands. Diagnostic odysseys were a common theme (>50 years for one individual), and targeted analysis for the specific gene had already been performed for 30% of these individuals but with no findings. We provide formal confirmation of a European founder origin for an intragenic MSH2 inversion. For two individuals with complex SVs involving the MECP2 mutational hotspot, ambiguous SV structures were resolved using long-read sequencing, influencing clinical interpretation. A de novo inversion of HOXD11-13 was uncovered in a family with Kantaputra-type mesomelic dysplasia. Lastly, a complex translocation disrupting APC and involving nine rearranged segments confirmed a clinical diagnosis for three family members and resolved a conundrum for a sibling with a single polyp. Overall, inversions play a small but notable role in rare disease, likely explaining the etiology in around 1/750 families across heterogeneous clinical cohorts.
Indexed as
Chromosome InversionRare DiseasesFemaleGenome, HumanHomeodomain ProteinsHumansMaleMethyl-CpG-Binding Protein 2Middle AgedMutationPedigreeWhole Genome SequencingHomeodomain ProteinsMECP2 protein, humanMethyl-CpG-Binding Protein 2APCcomplex rearrangementfounder mutationgenome sequencingHOXD clusterinversionMECP2MSH2PacBioRNA-seq
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