ArticleAmerican journal of human genetics2021
Targeted long-read sequencing identifies missing disease-causing variation.
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Article in American journal of human genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 156 papers.
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156citing papers in PubMed
30.5field-weighted citation impact, top 1% of its field
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Who cites it
156 citing papers in PubMed, 231 citations in OpenAlex.
- Detecting pathogenic structural variation in families with undiagnosed rare disease in a national genome project.European journal of human genetics : EJHG · 2026Article
- Resolving missing human polymorphic inversions and other complex variants from ultralong read data.Genome research · 2026Article
- Somatic mosaicism in the brain: linking development, ageing and neurodegeneration.Nature reviews. Neurology · 2026Review
- Nanopore Ultra-Long Sequencing for FSHD: From Molecular Diagnosis to Preimplantation Genetic Testing.Genes · 2026Review
- Cost-efficient long-read trio-barcoded adaptive sequencing improves rare disease diagnosis.Nature communications · 2026Article
- Long-Read Sequencing in CKD Diagnostics: Breaking Genomic Barriers and Expanding Global Inclusion.Kidney international reports · 2026Review
- Unraveling missing variants through target capture-based long-read sequencing in autosomal recessive disorders.European journal of human genetics : EJHG · 2026Article
- Benchmarking long-read variant sensitivity across ONT and PacBio platforms using known clinically reported variants in a cohort of critically ill newborns.medRxiv : the preprint server for health sciences · 2026Article
- Structural variant discovery and diagnostic impact in rare diseases from short-read and long-read sequencing.medRxiv : the preprint server for health sciences · 2026Article
- From fragments to full pictures: how long-read sequencing platforms are revolutionizing oncology research.Molecular biology reports · 2026Review
- Diagnosis complexity of dentinogenesis imperfecta involvingJournal of medical genetics · 2026Article
- Determinants of haplotype phasing accuracy in long-read human genome sequencing.bioRxiv : the preprint server for biology · 2026Article
- Genome-wide detection and clinical prioritization of tandem repeat outliers using long-read sequencing.medRxiv : the preprint server for health sciences · 2026Article
- Targeted long-read RNA sequencing for rare disease diagnosis and variant interpretation.Science advances · 2026Article
- Long-read analysis of tetrameric microsatellites with vmwhere supports GGAA repeat length-dependent chromatin state association in Ewing sarcoma.bioRxiv : the preprint server for biology · 2026Article
- Expanding the genetic landscape of inherited metabolic diseases using long-read sequencing and transcriptomic profiling.European journal of human genetics : EJHG · 2026Article
- Identification of de novo variants from parent-proband duos via long-read sequencing.American journal of human genetics · 2026Article
- The Tale of the Guanosine Tract in Repeat Expansion Disorders.Molecular neurobiology · 2026Review
- Long-read Sequencing in Inherited Retinal Dystrophies: A Systematic Review.Ophthalmology science · 2026Review
- Using the linear references from the pangenome to discover missing autism variants.Nature communications · 2026Article
96 more citing papers are in PubMed but not listed here.
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Authors and funding
51 authors at 6 institutions in 2 countries.
Danny E MillerDepartment of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA; Department of Pediatrics, Division of Genetic Medicine, University of Washington and Seattle Children's Hospital, Seattle, WA 98105, USA. Electronic address: danny.miller@seattlechildrens.org.
Arvis SulovariDepartment of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
Tianyun WangDepartment of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
Hailey LoucksDepartment of Pediatrics, Division of Genetic Medicine, University of Washington and Seattle Children's Hospital, Seattle, WA 98105, USA.
Kendra HoekzemaDepartment of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
Katherine M MunsonDepartment of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
Alexandra P LewisDepartment of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
Edith P Almanza FuerteDepartment of Pediatrics, Division of Genetic Medicine, University of Washington and Seattle Children's Hospital, Seattle, WA 98105, USA.
Catherine R PaschalDepartment of Laboratories, Seattle Children's Hospital, Seattle, WA 98105, USA; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA.
Tom WalshDepartment of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
Jenny ThiesDepartment of Pediatrics, Division of Genetic Medicine, University of Washington and Seattle Children's Hospital, Seattle, WA 98105, USA.
James T BennettDepartment of Pediatrics, Division of Genetic Medicine, University of Washington and Seattle Children's Hospital, Seattle, WA 98105, USA; Department of Laboratories, Seattle Children's Hospital, Seattle, WA 98105, USA; Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98101, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA.
Ian GlassDepartment of Pediatrics, Division of Genetic Medicine, University of Washington and Seattle Children's Hospital, Seattle, WA 98105, USA.
Katrina M DippleDepartment of Pediatrics, Division of Genetic Medicine, University of Washington and Seattle Children's Hospital, Seattle, WA 98105, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA; Center for Clinical and Translational Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
Karynne PattersonDepartment of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
Emily S BonkowskiDepartment of Pediatrics, Division of Genetic Medicine, University of Washington and Seattle Children's Hospital, Seattle, WA 98105, USA.
Zoe NelsonDepartment of Pediatrics, Division of Genetic Medicine, University of Washington and Seattle Children's Hospital, Seattle, WA 98105, USA.
Audrey SquireDepartment of Pediatrics, Division of Genetic Medicine, University of Washington and Seattle Children's Hospital, Seattle, WA 98105, USA.
Megan SikesDepartment of Pediatrics, Division of Genetic Medicine, University of Washington and Seattle Children's Hospital, Seattle, WA 98105, USA.
Erika BeckmanDepartment of Pediatrics, Division of Genetic Medicine, University of Washington and Seattle Children's Hospital, Seattle, WA 98105, USA.
Robin L BennettDivision of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
Dawn EarlDepartment of Pediatrics, Division of Genetic Medicine, University of Washington and Seattle Children's Hospital, Seattle, WA 98105, USA.
Winston LeeDepartment of Genetics and Development, Columbia University, New York, NY 10032, USA; Department of Ophthalmology, Columbia University, New York, NY 10032, USA.
Rando AllikmetsDepartment of Ophthalmology, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
Seth J PerlmanDepartment of Neurology, Seattle Children's Hospital, University of Washington, Seattle, WA 98105, USA.
Penny ChowDepartment of Pediatrics, Division of Craniofacial Medicine, University of Washington, Seattle, WA 98195, USA.
Anne V HingDepartment of Pediatrics, Division of Craniofacial Medicine, University of Washington, Seattle, WA 98195, USA.
Tara L WengerDepartment of Pediatrics, Division of Genetic Medicine, University of Washington and Seattle Children's Hospital, Seattle, WA 98105, USA.
Margaret P AdamDepartment of Pediatrics, Division of Genetic Medicine, University of Washington and Seattle Children's Hospital, Seattle, WA 98105, USA.
Angela SunDepartment of Pediatrics, Division of Genetic Medicine, University of Washington and Seattle Children's Hospital, Seattle, WA 98105, USA; Center for Clinical and Translational Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
Christina LamDepartment of Pediatrics, Division of Genetic Medicine, University of Washington and Seattle Children's Hospital, Seattle, WA 98105, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
Irene ChangDepartment of Pediatrics, Division of Genetic Medicine, University of Washington and Seattle Children's Hospital, Seattle, WA 98105, USA.
Xue ZouProgram in Computational Biology & Bioinformatics, Duke University, Durham, NC 27710, USA.
Stephanie L AustinDepartment of Pediatrics, Division of Medical Genetics, Duke University, Durham, NC 27708, USA.
Erin HugginsDepartment of Pediatrics, Division of Medical Genetics, Duke University, Durham, NC 27708, USA.
Alexias SafiDepartment of Pediatrics, Division of Medical Genetics, Duke University, Durham, NC 27708, USA.
Apoorva K IyengarDepartment of Biostatistics and Bioinformatics, Duke University; Durham, NC 27708, USA; University Program in Genetics and Genomics, Duke University; Durham, NC 27708, USA.
Timothy E ReddyDepartment of Biostatistics and Bioinformatics, Duke University; Durham, NC 27708, USA.
William H MajorosDepartment of Biostatistics and Bioinformatics, Duke University; Durham, NC 27708, USA.
Andrew S AllenDepartment of Biostatistics and Bioinformatics, Duke University; Durham, NC 27708, USA.
Gregory E CrawfordDepartment of Pediatrics, Division of Medical Genetics, Duke University, Durham, NC 27708, USA.
Priya S KishnaniDepartment of Pediatrics, Division of Medical Genetics, Duke University, Durham, NC 27708, USA.
University of Washington Center for Mendelian Genomics
Mary-Claire KingDepartment of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
Tim CherryCenter for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98101, USA.
Jessica X ChongDepartment of Pediatrics, Division of Genetic Medicine, University of Washington and Seattle Children's Hospital, Seattle, WA 98105, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA.
Michael J BamshadDepartment of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA; Department of Pediatrics, Division of Genetic Medicine, University of Washington and Seattle Children's Hospital, Seattle, WA 98105, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA.
Deborah A NickersonDepartment of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA.
Heather C MeffordDepartment of Pediatrics, Division of Genetic Medicine, University of Washington and Seattle Children's Hospital, Seattle, WA 98105, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA.
Dan DohertyDepartment of Pediatrics, Division of Genetic Medicine, University of Washington and Seattle Children's Hospital, Seattle, WA 98105, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA; Department of Pediatrics, Division of Developmental Medicine, University of Washington and Seattle Children's Hospital, Seattle, WA 98105, USA.
Evan E EichlerDepartment of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA. Electronic address: eee@gs.washington.edu.
Seattle Children's Hospital · USUniversity of Washington · USDuke University · USColumbia University · USHoward Hughes Medical Institute · USUniversity of Washington Medical Center · US
Funding
UW Center for Mendelian GenomicsUM1HG006493 · NHGRI · UNIVERSITY OF WASHINGTON · PI BAMSHAD, MICHAEL JOSEPH, LEAL, SUZANNE M · 2016 to 2020
$15.3MInstrumentation, Fabrication, and Design CoreP30EY019007 · NEI · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI Xin Zhang · 2010 to 2026
$12.9MMechanisms of Brain Dysmorphology in MN1 C-Terminal Truncation Syndrome, a Novel Intellectual Developmental Disability Disorder P50HD103524 · NICHD · UNIVERSITY OF WASHINGTON · PI Sandra E Juul · 2020 to 2026
$9.9MSporadic Mutations and Autism Spectrum DisordersR01MH101221 · NIMH · UNIVERSITY OF WASHINGTON · PI EICHLER, EVAN · 2013 to 2025
$9.2MGenetics Training Grant-Year 26T32GM007754 · NIGMS · DUKE UNIVERSITY · PI HAASE, STEVEN B · 1985 to 2019
$8.3MIntellectual and Developmental Disabilities Research CenterU54HD083091 · NICHD · UNIVERSITY OF WASHINGTON · PI GURALNICK, MICHAEL J · 2014 to 2019
$7.9MMosaic: post-zygotic mutations in vascular malformationsR01HL130996 · NHLBI · SEATTLE CHILDREN'S HOSPITAL · PI BENNETT, JAMES T · 2016 to 2024
$7.5MPREDOCTORAL TRAINING GRANT IN HUMAN GENETICS &DEVELOPMET32GM007088 · NIGMS · COLUMBIA UNIV NEW YORK MORNINGSIDE · PI SHEN, MICHAEL M. · 1985 to 2020
$7.1MNHGRI Genome Sequencing Program Coordinating CenterU24HG008956 · NHGRI · RUTGERS, THE STATE UNIV OF N.J. · PI BUYSKE, STEVEN G, MATISE, TARA C. · 2016 to 2020
$4.9MGenetics and Genomics Training GrantT32GM136627 · NIGMS · DUKE UNIVERSITY · PI ALLISON E ASHLEY-KOCH · 2020 to 2026
$3.1MPrecision medicine for ABCA4 disease: modifier allelesR01EY028203 · NEI · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI ALLIKMETS, RANDO L · 2018 to 2021
$2.3MDiversity Action Plan: UW GenOM ProjectR25HG007153 · NHGRI · UNIVERSITY OF WASHINGTON · PI EICHLER, EVAN · 2013 to 2020
$2.3MNEI NIH HHS P30 EY019007NEI NIH HHS R01 EY028203NEI NIH HHS R01 EY028954NEI NIH HHS R01 EY029315NHGRI NIH HHS R25 HG007153NHGRI NIH HHS U24 HG008956NHGRI NIH HHS UM1 HG006493NHLBI NIH HHS R01 HL130996NICHD NIH HHS P50 HD103524NICHD NIH HHS R01 HD100730NICHD NIH HHS U54 HD083091NIGMS NIH HHS T32 GM007754NIGMS NIH HHS T32 GM136627NIMH NIH HHS R01 MH101221
Abstract
Despite widespread clinical genetic testing, many individuals with suspected genetic conditions lack a precise diagnosis, limiting their opportunity to take advantage of state-of-the-art treatments. In some cases, testing reveals difficult-to-evaluate structural differences, candidate variants that do not fully explain the phenotype, single pathogenic variants in recessive disorders, or no variants in genes of interest. Thus, there is a need for better tools to identify a precise genetic diagnosis in individuals when conventional testing approaches have been exhausted. We performed targeted long-read sequencing (T-LRS) using adaptive sampling on the Oxford Nanopore platform on 40 individuals, 10 of whom lacked a complete molecular diagnosis. We computationally targeted up to 151 Mbp of sequence per individual and searched for pathogenic substitutions, structural variants, and methylation differences using a single data source. We detected all genomic aberrations-including single-nucleotide variants, copy number changes, repeat expansions, and methylation differences-identified by prior clinical testing. In 8/8 individuals with complex structural rearrangements, T-LRS enabled more precise resolution of the mutation, leading to changes in clinical management in one case. In ten individuals with suspected Mendelian conditions lacking a precise genetic diagnosis, T-LRS identified pathogenic or likely pathogenic variants in six and variants of uncertain significance in two others. T-LRS accurately identifies pathogenic structural variants, resolves complex rearrangements, and identifies Mendelian variants not detected by other technologies. T-LRS represents an efficient and cost-effective strategy to evaluate high-priority genes and regions or complex clinical testing results.
Indexed as
Chromosome AberrationsGenetic Predisposition to DiseaseGenome, HumanMutationCytogenetic AnalysisDNA Copy Number VariationsFemaleGenetic Diseases, InbornGenetic TestingHigh-Throughput Nucleotide SequencingHumansKaryotypingMaleSequence Analysis, DNAlong-read sequencing, adaptive sampling, nanopore sequencing, targeted long-read sequencing
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