ArticleScience translational medicine2017
Improving genetic diagnosis in Mendelian disease with transcriptome sequencing.
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Article in Science translational medicine, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 434 papers, 2 of them syntheses that pooled it.
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434citing papers in PubMed, 2 pooled it
71.6field-weighted citation impact, top 1% of its field
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Who cites it
434 citing papers in PubMed, 2 syntheses or guidelines pooled it, 790 citations in OpenAlex.
- EAN 2024 Guideline on the Diagnostic Approach to Oligo/Asymptomatic HyperCKemia.European journal of neurology · 2026Guideline
- Diagnostic yield of long-read sequencing for rare diseases: a systematic review.Frontiers in genetics · 2026Pooled it
- RNA sequencing significantly improves HYDIN diagnosis and defines the effects of common deletions in primary ciliary dyskinesia.European journal of human genetics : EJHG · 2026Article
- Optimized RNA-seq workflow for routine diagnosis of mitochondrial diseases using aberrant expression analysis and phenotype-driven prioritization.European journal of human genetics : EJHG · 2026Article
- Kidney Transcriptome Sequencing Improves Molecular Diagnosis and Reveals Splicing Complexity Across the Alport Spectrum.Kidney international reports · 2026Article
- Splice-site variants in neurology: from molecular mechanisms to clinical interpretation - a focused review.Neurogenetics · 2026Review
- Review
- Targeted gene editing ofMolecular therapy. Nucleic acids · 2026Article
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- Genomic Strategies in Pediatric Care: Addressing Rare Diseases in Children.Children (Basel, Switzerland) · 2026Review
- Long-read transcriptome analysis using IsoRanker for identifying pathogenic variants in Mendelian conditions.American journal of human genetics · 2026Article
- Technical Considerations for Blood RNA Sequencing in Genetic Testing: Evaluation of Globin Depletion Methods, Batch Effects, and Sample Types.Annals of laboratory medicine · 2026Article
- Long-read proteogenomic atlas of human neuronal differentiation reveals isoform diversity informing neurodevelopmental risk mechanisms.Nature communications · 2026Article
- Tools and tactics for studying alternative splicing.Nature reviews. Genetics · 2026Review
- Uncultured Amniocytes Enable Rapid and Clinically Informative Prenatal RNA Sequencing for Genetic Diagnosis.International journal of molecular sciences · 2026Article
- Integrative analysis of drug-gene signatures in human pluripotent stem cells reveals prazosin as a novel SQSTM1 regulator for ALS therapeutics.Stem cell reports · 2026Article
- The globin depletion paradox: when short-read optimisation does not transfer to long-read RNA sequencing.European journal of human genetics : EJHG · 2026Article
- Evaluating the Utility of RNAseq in Prenatal Diagnostics: Expression Profiles of Cultured Chorionic Villus and Amniotic Fluid Samples.Prenatal diagnosis · 2026Article
- A Synonymous DLG4 Variant (c.771G>A) Causes Exon 9 Skipping via Paternal Germline Mosaicism in DLG4-Related Synaptopathy.Molecular genetics & genomic medicine · 2026Article
- Review
374 more citing papers are in PubMed but not listed here.
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Authors and funding
39 authors at 13 institutions in 6 countries.
Beryl B CummingsAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.ORCID 0000-0001-6346-1646
Jamie L MarshallAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
Taru TukiainenAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.ORCID 0000-0002-5404-8398
Monkol LekAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
Sandra DonkervoortNeuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
A Reghan FoleyNeuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Veronique BolducNeuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.ORCID 0000-0003-1690-9270
Leigh B WaddellSchool of Paediatrics and Child Health, University of Sydney, Sydney, New South Wales 2006, Australia.
Sarah A SandaraduraSchool of Paediatrics and Child Health, University of Sydney, Sydney, New South Wales 2006, Australia.
Gina L O'GradySchool of Paediatrics and Child Health, University of Sydney, Sydney, New South Wales 2006, Australia.
Elicia EstrellaDivision of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.ORCID 0000-0001-6983-1070
Hemakumar M ReddyDivision of Pediatric Neurology, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL 32610, USA.ORCID 0000-0002-3769-6609
Fengmei ZhaoAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.ORCID 0000-0002-9711-0753
Ben WeisburdAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
Konrad J KarczewskiAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.ORCID 0000-0003-2878-4671
Anne H O'Donnell-LuriaAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.ORCID 0000-0001-6418-9592
Daniel BirnbaumAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
Anna SarkozyDubowitz Neuromuscular Centre, University College London Institute of Child Health, London WC1N 1EH, U.K.ORCID 0000-0002-1353-0583
Ying HuNeuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.ORCID 0000-0001-6393-540X
Hernan GonorazkyDivision of Neurology, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.ORCID 0000-0001-8084-8324
Kristl ClaeysDepartment of Neurology, University Hospitals Leuven and University of Leuven (Katholieke Universiteit Leuven), Leuven 3000, Belgium.
Himanshu JoshiInstitute for Neuroscience and Muscle Research, Kids Research Institute, The Children's Hospital at Westmead, Sydney, New South Wales 2145, Australia.ORCID 0000-0003-1510-8826
Adam BournazosSchool of Paediatrics and Child Health, University of Sydney, Sydney, New South Wales 2006, Australia.ORCID 0000-0002-6464-4548
Emily C OatesSchool of Paediatrics and Child Health, University of Sydney, Sydney, New South Wales 2006, Australia.ORCID 0000-0002-8836-1681
Roula GhaouiSchool of Paediatrics and Child Health, University of Sydney, Sydney, New South Wales 2006, Australia.
Mark R DavisDepartment of Diagnostic Genomics, PathWest Laboratory Medicine, Perth, Western Australia 6009, Australia.ORCID 0000-0002-0626-9030
Nigel G LaingDepartment of Diagnostic Genomics, PathWest Laboratory Medicine, Perth, Western Australia 6009, Australia.ORCID 0000-0001-5111-3732
Ana TopfJohn Walton Muscular Dystrophy Research Centre, MRC (Medical Research Council) Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, U.K.
Genotype-Tissue Expression Consortium
Peter B KangDivision of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Alan H BeggsDivision of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.ORCID 0000-0001-8818-0568
Kathryn N NorthMurdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Melbourne, Victoria 3052, Australia.ORCID 0000-0003-0841-8009
Volker StraubJohn Walton Muscular Dystrophy Research Centre, MRC (Medical Research Council) Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, U.K.ORCID 0000-0001-9046-3540
James J DowlingDivision of Neurology, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
Francesco MuntoniDubowitz Neuromuscular Centre, University College London Institute of Child Health, London WC1N 1EH, U.K.
Nigel F ClarkeSchool of Paediatrics and Child Health, University of Sydney, Sydney, New South Wales 2006, Australia.
Sandra T CooperSchool of Paediatrics and Child Health, University of Sydney, Sydney, New South Wales 2006, Australia.ORCID 0000-0002-7314-5097
Carsten G BönnemannNeuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.ORCID 0000-0002-5930-2324
Daniel G MacArthurAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA. danmac@broadinstitute.org.ORCID 0000-0002-5771-2290
Broad Institute · USThe University of Sydney · AUNational Institute of Neurological Disorders and Stroke · USBoston Children's Hospital · USHospital for Sick Children · CAInstitute of Child Health · INMuscular Dystrophy UK · GBChildren's Hospital at Westmead · AUHarry Perkins Institute of Medical Research · AUKU Leuven · BEPathwest Laboratory Medicine · AURoyal Children's Hospital · AUUniversity of Florida · US
Funding
Molecular and Clinical Manifestations of Matrix and Aggregate MyopathiesZIANS003129 · NINDS · NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE · PI BÖNNEMANN, CARSTEN · 2011 to 2025
$52.8MJoint Center for Mendelian GenomicsUM1HG008900 · NHGRI · BROAD INSTITUTE, INC. · PI O'DONNELL-LURIA, ANNE, REHM, HEIDI L · 2016 to 2020
$16.5MTRAINING GRANT IN GENETICST32GM007748 · NIGMS · HARVARD UNIVERSITY (MEDICAL SCHOOL) · PI Anne O'Donnell-Luria, Louise Wilkins-Haug · 1985 to 2026
$12.0MSARCOMERIC PROTEINS IN NORMAL AND DISEASED MUSCLER01AR044345 · NIAMS · CHILDREN'S HOSPITAL BOSTON · PI BEGGS, ALAN H. · 1997 to 2017
$5.3MMouse Neurodevelopmental Behavior CoreU54HD090255 · NICHD · BOSTON CHILDREN'S HOSPITAL · PI POMEROY, SCOTT LOREN · 2016 to 2020
$5.2MLIMBIC &MEDULLARY MECH. IN COCAINE-RELATED SUDDEN DEATHR01DA006227 · NIDA · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · PI MASH, DEBORAH C. · 1990 to 2012
$3.7MGenetics and Genomics PhD Training GrantT32GM096911 · NIGMS · HARVARD MEDICAL SCHOOL · PI KENNEDY, SCOTT G · 2011 to 2020
$2.5MGenetic screening and therapies for nemaline myopathiesR01HD075802 · NICHD · BOSTON CHILDREN'S HOSPITAL · PI BEGGS, ALAN H. · 2014 to 2018
$1.8MGene Discovery in Muscular DystrophyR01NS080929 · NINDS · UNIVERSITY OF FLORIDA · PI KANG, PETER B. · 2013 to 2017
$1.8MAnnotation and interpretation of loss-of-function polymorphisms in human genomesR01GM104371 · NIGMS · MASSACHUSETTS GENERAL HOSPITAL · PI MACARTHUR, DANIEL G · 2013 to 2016
$1.3MThe Human Knockout Project: systematic discovery of loss-of-function variants in humansF32GM115208 · NIGMS · MASSACHUSETTS GENERAL HOSPITAL · PI KARCZEWSKI, KONRAD · 2015 to 2016
$109kCCR NIH HHS HHSN261200800001CNCI NIH HHS HHSN261200800001ENHGRI NIH HHS UM1 HG008900NHLBI NIH HHS HHSN268201000029CNIAMS NIH HHS R01 AR044345NICHD NIH HHS R01 HD075802NICHD NIH HHS U54 HD090255NIDA NIH HHS R01 DA006227NIGMS NIH HHS F32 GM115208NIGMS NIH HHS R01 GM104371NIGMS NIH HHS T32 GM007748NIGMS NIH HHS T32 GM096911NIMHD NIH HHS L60 MD010032NINDS NIH HHS R01 NS080929Wellcome Trust
Abstract
Exome and whole-genome sequencing are becoming increasingly routine approaches in Mendelian disease diagnosis. Despite their success, the current diagnostic rate for genomic analyses across a variety of rare diseases is approximately 25 to 50%. We explore the utility of transcriptome sequencing [RNA sequencing (RNA-seq)] as a complementary diagnostic tool in a cohort of 50 patients with genetically undiagnosed rare muscle disorders. We describe an integrated approach to analyze patient muscle RNA-seq, leveraging an analysis framework focused on the detection of transcript-level changes that are unique to the patient compared to more than 180 control skeletal muscle samples. We demonstrate the power of RNA-seq to validate candidate splice-disrupting mutations and to identify splice-altering variants in both exonic and deep intronic regions, yielding an overall diagnosis rate of 35%. We also report the discovery of a highly recurrent de novo intronic mutation in
Indexed as
Collagen Type VIHigh-Throughput Nucleotide SequencingHumansMuscular DiseasesMutationTranscriptomeCollagen Type VI
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.