ArticleAmerican journal of human genetics2020
De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects.
Open access · hybridAbstract read
In one paragraph
Article in American journal of human genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
0numbers the graph read from it
0cells of the map it votes in
37citing papers in PubMed
2.7field-weighted citation impact, top 9% of its field
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
37 citing papers in PubMed, 61 citations in OpenAlex.
- White matter disorders at the intersection of transcription, RNA processing and translation.Nature reviews. Neurology · 2026Review
- Therapeutic rescue of pathogenic asparaginyl-tRNA synthetase alleles.Molecular therapy. Nucleic acids · 2026Article
- Aminoacyl-tRNA Synthetases: Variant Classification, Functional Assays, and Emerging Therapeutic Strategies.Journal of inherited metabolic disease · 2026Review
- Biallelic Variants in the DARS2 Gene as a Novel Cause of Axonal Charcot-Marie-Tooth Disease.Annals of neurology · 2025Article
- Transfer RNA and small molecule therapeutics for aminoacyl-tRNA synthetase diseases.The FEBS journal · 2025Review
- Identification and enrichment of potential pathways in the buffy coat of patients with DRE using non-targeted metabolomics integrated with GEO Datasets.European journal of medical research · 2025Article
- Yeast models for Charcot-Marie-Tooth disease-causing aminoacyl-tRNA synthetase alleles reveal the cellular basis of disease.IUBMB life · 2025Review
- Setting the Stage for Treatment of Aminoacyl-tRNA Synthetase (ARS)1-Deficiencies: Phenotypic Characterization and a Review of Treatment Effects.Journal of inherited metabolic disease · 2025Review
- Purification and validation of asparaginyl-tRNA synthetase heterodimer with indistinguishable subunits.IUBMB life · 2025Article
- Brain organoids: a new paradigm for studying human neuropsychiatric disorders.Frontiers in neuroscience · 2025Review
- Aminoacyl-tRNA synthetase defects in neurological diseases.IUBMB life · 2025Review
- Simultaneous determination of cytosolic aminoacyl-tRNA synthetase activities by LC-MS/MS.Nucleic acids research · 2024Article
- Exploring the Landscape of Pre- and Post-Synaptic Pediatric Disorders with Epilepsy: A Narrative Review on Molecular Mechanisms Involved.International journal of molecular sciences · 2024Review
- Expanding the genetic spectrum of hereditary motor sensory neuropathies in Pakistan.BMC neurology · 2024Article
- Identification of diagnostic candidates in Mendelian disorders using an RNA sequencing-centric approach.Genome medicine · 2024Article
- Early-onset dysphagia and severe neurodevelopmental disorder as early signs in a patient with two novel variants in NARS1: a case report and brief review of the literature.Neurogenetics · 2024Review
- A previously unreported NARS1 variant causes dominant distal hereditary motor neuropathy in a French family.Journal of the peripheral nervous system : JPNS · 2024Article
- Allelic heterogeneity and abnormal vesicle recycling inFrontiers in molecular neuroscience · 2024Article
- DominantBrain communications · 2024Article
- Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
93 authors at 20 institutions in 10 countries.
Andreea ManoleDepartment of Neuromuscular Disorders, University College London (UCL) Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
Stephanie EfthymiouDepartment of Neuromuscular Disorders, University College London (UCL) Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
Emer O'ConnorDepartment of Neuromuscular Disorders, University College London (UCL) Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
Marisa I MendesMetabolic Unit, Department of Clinical Chemistry, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam Gastroenterology and Metabolism, Amsterdam, 1081 the Netherlands.
Matthew JenningsDepartment of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0QQ UK.
Reza MaroofianDepartment of Neuromuscular Disorders, University College London (UCL) Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
Indran DavagnanamDepartment of Brain Repair and Rehabilitation, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
Kshitij MankadDepartment of Neuroradiology, Great Ormond Street Hospital for Children, London, WC1N 3JH, UK.
Maria Rodriguez LopezInstitute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London (UCL), London, WC1E 6BT, UK.
Vincenzo SalpietroDepartment of Neuromuscular Disorders, University College London (UCL) Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
Ricardo HarripaulCampbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, ON, M5T 1R8, Canada; Institute of Medical Science and Department of Psychiatry, University of Toronto, Toronto, ON, M5T 1R8, Canada.
Lauren BadalatoDepartment of Pediatrics, Queen's University, Kingston, ON, K7L 2V7, Canada.
Jagdeep WaliaDepartment of Pediatrics, Queen's University, Kingston, ON, K7L 2V7, Canada.
Christopher S FrancklynDepartment of Biochemistry, University of Vermont College of Medicine, Burlington, VT 05405, USA.
Alkyoni Athanasiou-FragkouliDepartment of Neuromuscular Disorders, University College London (UCL) Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
Roisin SullivanDepartment of Neuromuscular Disorders, University College London (UCL) Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
Sonal DesaiDepartment of Neurology and Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
Kristin BarananoDepartment of Neurology and Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
Faisal ZafarDepartment of Pediatrics, Multan Hospital, Multan, 60000, Pakistan.
Nuzhat RanaDepartment of Pediatrics, Multan Hospital, Multan, 60000, Pakistan.
Muhammed IlyasUniversity of Islamabad, Islamabad, 45320, Pakistan.
Alejandro HorgaDepartment of Neuromuscular Disorders, University College London (UCL) Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
Majdi KaraDepartment of Pediatrics, Tripoli Children's Hospital, Tripoli, Libya.
Francesca MattioliInstitute for Genetics and Molecular and Cellular Biology (IGBMC), University of Strasbourg, CNRS UMR7104, INSERM U1258, Illkirch, 67404, France.
Alice GoldenbergDépartement de Génétique, centre de référence anomalies du développement et syndromes malformatifs, CHU de Rouen, Inserm U1245, UNIROUEN, Normandie Université, Centre Normand de Génomique et de Médecine Personnalisée, Rouen, 76031, France.
Helen GriffinDepartment of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0QQ UK.
Amelie PitonInstitute for Genetics and Molecular and Cellular Biology (IGBMC), University of Strasbourg, CNRS UMR7104, INSERM U1258, Illkirch, 67404, France.
Lindsay B HendersonGeneDx, 207 Perry Parkway Gaithersburg, MD 20877, USA.
Benyekhlef KaraBezmiâlem Vakıf Üniversitesi, Istanbul, 34093, Turkey.
Ayca Dilruba AslangerBezmiâlem Vakıf Üniversitesi, Istanbul, 34093, Turkey.
Joost RaaphorstDepartment of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500HB Nijmegen, the Netherlands; Department of Neurology, Amsterdam Neuroscience Institute, Amsterdam University Medical Center, 1105AZ Amsterdam, the Netherlands.
Rolph PfundtDepartment of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500HB Nijmegen, the Netherlands.
Ruben PortierDepartment of Neurology, Medisch Spectrum Twente, 7512KZ Enschede, the Netherlands.
Marwan ShinawiDepartment of Pediatrics, Divisions of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Amelia KirbyDivision of Medical Genetics, SSM Health Cardinal Glennon Children's Hospital, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
Katherine M ChristensenDivision of Medical Genetics, SSM Health Cardinal Glennon Children's Hospital, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
Lu WangHoward Hughes Medical Institute, University of California San Diego and Rady Children's Hospital, La Jolla, CA 92130, USA.
Rasim O RostiHoward Hughes Medical Institute, University of California San Diego and Rady Children's Hospital, La Jolla, CA 92130, USA.
Sohail A ParachaInstitute of Basic Medical Sciences, Khyber Medical University, 25100 Peshawar, Pakistan.
Muhammad T SarwarInstitute of Basic Medical Sciences, Khyber Medical University, 25100 Peshawar, Pakistan.
Dagan JenkinsInstitute of Child Health, Guilford Street and Dubowitz Neuromuscular Centre, Great Ormond Street Hospital for Children, London, WC1N 3JH, UK.
SYNAPS Study GroupSYNAPS Study Group, see Supplemental Information for the study group members who contributed clinical cases and data.
Jawad AhmedInstitute of Basic Medical Sciences, Khyber Medical University, 25100 Peshawar, Pakistan.
Federico A SantoniDepartment of Genetic Medicine and Development, University of Geneva, 1206 Geneva, Switzerland; Department of Endocrinology, Diabetes, and Metabolism, University Hospital of Lausanne, 1011 Lausanne, Switzerland.
Emmanuelle RanzaDepartment of Genetic Medicine and Development, University of Geneva, 1206 Geneva, Switzerland; Service of Genetic Medicine, University Hospitals of Geneva, 1205 Geneva, Switzerland; Medigenome, The Swiss Institute of Genomic Medicine, Geneva, CH-1207, Switzerland.
Justyna IwaszkiewiczSwiss Institute of Bioinformatics, Molecular Modeling Group, Batiment Genopode, Unil Sorge, Lausanne, CH-1015, Switzerland.
Cheryl CytrynbaumHospital for Sick Children, Division of Clinical and Metabolic Genetics, 555 University Ave., Toronto, M5G 1X8, Canada.
Rosanna WeksbergHospital for Sick Children, Division of Clinical and Metabolic Genetics, 555 University Ave., Toronto, M5G 1X8, Canada.
Ingrid M WentzensenGeneDx, 207 Perry Parkway Gaithersburg, MD 20877, USA.
Maria J Guillen SacotoGeneDx, 207 Perry Parkway Gaithersburg, MD 20877, USA.
Yue SiGeneDx, 207 Perry Parkway Gaithersburg, MD 20877, USA.
Aida TelegrafiGeneDx, 207 Perry Parkway Gaithersburg, MD 20877, USA.
Marisa V AndrewsDepartment of Pediatrics, Divisions of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Dustin BaldridgeDepartment of Pediatrics, Divisions of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Heinz GabrielCeGaT GmbH and Praxis für Humangenetik Tuebingen, Tuebingen, 72076, Germany.
Julia MohrCeGaT GmbH and Praxis für Humangenetik Tuebingen, Tuebingen, 72076, Germany.
Barbara Oehl-JaschkowitzBiomedical Centre Cardinal-Wendel-Straße 14, 66424 Hamburg, Germany.
Sylvain DebardUniversity of Strasbourg, CNRS, GMGM UMR 7156, Strasbourg, 67083, France.
Bruno SengerUniversity of Strasbourg, CNRS, GMGM UMR 7156, Strasbourg, 67083, France.
Frédéric FischerUniversity of Strasbourg, CNRS, GMGM UMR 7156, Strasbourg, 67083, France.
Conny van RavenwaaijUniversity of Groningen, University Medical Center Groningen, Department of Neurology, Groningen, 9713, the Netherlands.
Annemarie J M FockUniversity of Groningen, University Medical Center Groningen, Department of Neurology, Groningen, 9713, the Netherlands.
Servi J C StevensDepartment of Clinical Genetics, Maastricht University Medical Centre, Maastricht, 6211, the Netherlands.
Jürg BählerInstitute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London (UCL), London, WC1E 6BT, UK.
Amina NasarDepartment of Pediatrics, Queen's University, Kingston, ON, K7L 2V7, Canada.
John F MantovaniDivision of Child Neurology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Adnan ManzurInstitute of Child Health, Guilford Street and Dubowitz Neuromuscular Centre, Great Ormond Street Hospital for Children, London, WC1N 3JH, UK.
Anna SarkozyInstitute of Child Health, Guilford Street and Dubowitz Neuromuscular Centre, Great Ormond Street Hospital for Children, London, WC1N 3JH, UK.
Desirée E C SmithMetabolic Unit, Department of Clinical Chemistry, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam Gastroenterology and Metabolism, Amsterdam, 1081 the Netherlands.
Gajja S SalomonsMetabolic Unit, Department of Clinical Chemistry, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam Gastroenterology and Metabolism, Amsterdam, 1081 the Netherlands.
Zubair M AhmedDepartment of Biochemistry and Molecular Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
Shaikh RiazuddinJinnah Burn and Reconstructive Surgery Center, Allama Iqbal Medical College, University of Health Sciences, Lahore 54550, Pakistan.
Saima RiazuddinDepartment of Biochemistry and Molecular Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
Muhammad A UsmaniDepartment of Biochemistry and Molecular Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
Annette SeibtDepartment of General Pediatrics, Heinrich-Heine-University, Moorenstr. 5, 40225 Düsseldorf, Germany.
Muhammad AnsarDepartment of Genetic Medicine and Development, University of Geneva, 1206 Geneva, Switzerland; Institute of Molecular and Clinical Ophthalmology Basel, Basel Switzerland.
Stylianos E AntonarakisDepartment of Genetic Medicine and Development, University of Geneva, 1206 Geneva, Switzerland; Service of Genetic Medicine, University Hospitals of Geneva, 1205 Geneva, Switzerland; iGE3 Institute of Genetics and Genomics of Geneva, 1211 Geneva, Switzerland.
John B VincentCampbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, ON, M5T 1R8, Canada; Institute of Medical Science and Department of Psychiatry, University of Toronto, Toronto, ON, M5T 1R8, Canada.
Muhammad AyubDepartment of Pediatrics, Queen's University, Kingston, ON, K7L 2V7, Canada.
Mona GrimmelInstitute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tübingen, Germany.
Anne Marie JelsigDepartment of Clinical Genetics, University Hospital of Copenhagen, Rigshospitalet, 2100, Denmark.
Tina Duelund HjortshøjDepartment of Clinical Genetics, University Hospital of Copenhagen, Rigshospitalet, 2100, Denmark.
Helena Gásdal KarstensenDepartment of Clinical Genetics, University Hospital of Copenhagen, Rigshospitalet, 2100, Denmark.
Marybeth HummelDepartment of Pediatrics, Section of Medical Genetics, West Virginia University, Morgantown, WV 26506-9600, USA.
Tobias B HaackInstitute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tübingen, Germany; Centre for Rare Diseases, University of Tuebingen, 72076 Tübingen, Germany.
Yalda JamshidiGenetics Centre, Molecular and Clinical Sciences Institute, St George's University of London, London, SW17 0RE, UK.
Felix DistelmaierDepartment of General Pediatrics, Heinrich-Heine-University, Moorenstr. 5, 40225 Düsseldorf, Germany.
Rita HorvathDepartment of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0QQ UK.
Joseph G GleesonHoward Hughes Medical Institute, University of California San Diego and Rady Children's Hospital, La Jolla, CA 92130, USA.
Hubert BeckerUniversity of Strasbourg, CNRS, GMGM UMR 7156, Strasbourg, 67083, France.
Jean-Louis MandelInstitute for Genetics and Molecular and Cellular Biology (IGBMC), University of Strasbourg, CNRS UMR7104, INSERM U1258, Illkirch, 67404, France.
David A KoolenDepartment of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500HB Nijmegen, the Netherlands.
Henry HouldenDepartment of Neuromuscular Disorders, University College London (UCL) Institute of Neurology, Queen Square, London, WC1N 3BG, UK. Electronic address: h.houlden@ucl.ac.uk.
National Hospital for Neurology and Neurosurgery · GBCentre National de la Recherche Scientifique · FRJohns Hopkins University · USGreat Ormond Street Hospital · GBQueen's University · CAUniversity of Geneva · CHWashington University in St. Louis · USAmsterdam Neuroscience · NLHoward Hughes Medical Institute · USKhyber Medical University · PKRigshospitalet · DKUniversity of Cambridge · GBBezmiâlem Vakıf Üniversitesi · TRCardinal Glennon Children’s Medical Center · USCentre for Addiction and Mental Health · CAHeinrich Heine University Düsseldorf · DEHospital for Sick Children · CAMRC Unit for Lifelong Health and Ageing · GBPraxis für Humangenetik Tübingen · DERadboud University Nijmegen · NL
Funding
WUIDDRC Supplement-Supporting the health and well-being of children with intellectual and developmental disability during COVID-19 pandemicP50HD103525 · NICHD · WASHINGTON UNIVERSITY · PI JEFFREY D MILBRANDT · 2020 to 2026
$15.5MGenetics and Functional Studies of Autosomal Recessive Neurological DisordersR01NS107428 · NINDS · UNIVERSITY OF MARYLAND BALTIMORE · PI Saima Riazuddin · 2018 to 2026
$4.7MMedical Research Council G0601943Medical Research Council G1000848Medical Research Council MR/N010035/1Medical Research Council MR/N025431/1Medical Research Council MR/N025431/2NICHD NIH HHS P50 HD103525NINDS NIH HHS N01 NS002331NINDS NIH HHS R01 NS107428Wellcome Trust
Abstract
Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and bi-allelic mutations in NARS1 are a significant cause of neurodevelopmental disease, where the mechanism for de novo variants could be toxic gain-of-function and for recessive variants, partial loss-of-function.
Indexed as
AllelesAmino Acyl-tRNA SynthetasesAspartate-tRNA LigaseCell LineFemaleGain of Function MutationGenetic Predisposition to DiseaseHumansLoss of Function MutationMaleNeurodevelopmental DisordersPedigreeRNA, TransferRNA, Transfer, Amino AcylStem CellsAmino Acyl-tRNA Synthetasesasparaginyl-tRNA synthetaseAspartate-tRNA LigaseRNA, TransferRNA, Transfer, Amino Acylaminoacyl-tRNA synthetasedevelopmental delayepilepsyneurodevelopmentneuropathynext generation sequencing
Identifiers
What OpenQuestion holds
Textmetadata
Read underepoch 390
Registered trials
None linked
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.