ArticleNature2014
Guidelines for investigating causality of sequence variants in human disease.
Registry-linked trialAbstract read
In one paragraph
Article in Nature, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT03829176 (Investigating the Feasibility and Implementation of Whole Genome Sequencing in Patients With Suspected Genetic Disorder), which is not on this map. Cited by 710 papers, 5 of them syntheses that pooled it.
0numbers the graph read from it
0cells of the map it votes in
710citing papers in PubMed, 5 pooled it
–field-weighted citation impact
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.
Investigating the Feasibility and Implementation of Whole Genome Sequencing in Patients With Suspected Genetic Disorder
Who cites it
710 citing papers in PubMed, 5 syntheses or guidelines pooled it.
- Whole-Exome Sequencing for the Identification of Genetic Factors Implicated in Severe Bacterial Infections: A Systematic Review.The Journal of infectious diseases · 2026Pooled it
- Genetic Influences on the Developing Young Brain and Risk for Neuropsychiatric Disorders.Biological psychiatry · 2023Pooled it
- Guideline
- Clinical Pharmacogenetics Implementation Consortium Guideline for the Use of Aminoglycosides Based on MT-RNR1 Genotype.Clinical pharmacology and therapeutics · 2022Guideline
- How to deal with uncertainty in prenatal genomics: A systematic review of guidelines and policies.Clinical genetics · 2021Pooled it
- Revolutionizing neonatal health: India's journey from assays to advanced genetics.Journal of applied genetics · 2026Review
- Article
- Integrating single-cell sQTL mapping with deep-learning splicing prediction identifies causal variants under influenza infection.Genome biology · 2026Article
- criTRia: A Classification System and Evidence Criteria for Tandem Repeat Locus-Disease Relationships.medRxiv : the preprint server for health sciences · 2026Article
- Exploring cell-type associations of rare disease phenotypes using non-diseased cell atlases.Briefings in bioinformatics · 2026Article
- Nephrin-IgG co-localization expression in pediatric steroid-resistant nephrotic syndrome: a case series from Indonesia.CEN case reports · 2026Article
- Historical Perspectives, Classification and Diagnostic Approaches of Inborn Errors of Metabolism: A Systematic Review and Meta-Analysis.Metabolites · 2026Review
- A Comprehensive Analysis of the Agreement and Performance of Variant Annotation Programs in Equine Genomes.Genes · 2026Article
- Identification of the ACTB p.Ser348Leu de novo variant in individuals with syndromic neonatal diabetes.EBioMedicine · 2026Article
- Benchmarking genetic birth prevalence estimates against newborn screening data.American journal of human genetics · 2026Article
- Tutorial for variant interrogation in tumor samples.PLoS computational biology · 2026Article
- An accurate cellular assay to determine pathogenicity of coding and noncoding variants in Lynch syndrome genes.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Causal splicing variants revealed by deep-learning integration of single-cell sQTL mapping under influenza infection.Research square · 2026Article
- Exploring cooperation among social pathogens: a computational perspective.FEMS microbiology reviews · 2026Review
- A Scoping Review on Genetic Mutations and Single-Nucleotide Polymorphisms Associated with Pectus Excavatum.Journal of multidisciplinary healthcare · 2026Review
650 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
27 authors.
D G MacArthur1] Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA [2] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
T A ManolioDivision of Genomic Medicine, National Human Genome Research Institute, Bethesda, Maryland 20892, USA.
D P DimmockDivision of Genetics, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
H L Rehm1] Laboratory for Molecular Medicine, Partners Healthcare Center for Personalized Genetic Medicine, Cambridge, Massachusetts 02139, USA [2] Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
J ShendureDepartment of Genome Sciences, University of Washington, Seattle, Washington 98115, USA.
G R AbecasisDepartment of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA.
D R Adams1] NIH Undiagnosed Diseases Program, National Institutes of Health Office of Rare Diseases Research and National Human Genome Research Institute, Bethesda, Maryland 20892, USA [2] Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
R B AltmanDepartments of Bioengineering & Genetics, Stanford University, Stanford, California 94305, USA.
S E Antonarakis1] Department of Genetic Medicine, University of Geneva Medical School, 1211 Geneva, Switzerland [2] iGE3 Institute of Genetics and Genomics of Geneva, 1211 Geneva, Switzerland.
E A AshleyCenter for Inherited Cardiovascular Disease, Stanford University School of Medicine, Stanford, California 94305, USA.
J C BarrettWellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
L G BieseckerGenetic Disease Research Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892, USA.
D F ConradDepartments of Genetics, Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
G M CooperHudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, Alabama 35806, USA.
N J CoxSection of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
M J Daly1] Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA [2] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
M B Gerstein1] Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut 06520, USA [2] Departments of Computer Science, Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520, USA.
D B GoldsteinCenter for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina 27708, USA.
J N Hirschhorn1] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA [2] Divisions of Genetics and Endocrinology, Children's Hospital, Boston, Massachusetts 02115, USA.
S M LealDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
L A Pennacchio1] Genomics Division, MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA [2] US Department of Energy Joint Genome Institute, Walnut Creek, California 94598, USA.
J A StamatoyannopoulosDepartment of Genome Sciences, University of Washington, 1705 Northeast Pacific Street, Seattle, Washington 98195, USA.
S R Sunyaev1] Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA [2] Harvard Medical School, Boston, Massachusetts 02115, USA.
D ValleMcKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
B F VoightDepartment of Pharmacology and Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA.
W Winckler1] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA [2] Next Generation Diagnostics, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA (W.W.); Marcus Autism Center, Children's Healthcare of Atlanta, Atlanta, Georgia 30329, USA (C.G.).
C Gunter1] HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, Alabama 35806, USA [2] Next Generation Diagnostics, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA (W.W.); Marcus Autism Center, Children's Healthcare of Atlanta, Atlanta, Georgia 30329, USA (C.G.).
Funding
Rare & Mosaic Disorders Molecular ResearchZIAHG200328 · NHGRI · NATIONAL HUMAN GENOME RESEARCH INSTITUTE · PI BIESECKER, LESLIE · 2009 to 2025
$26.8MPilot and Feasibility ProgramP30DK020595 · NIDDK · UNIVERSITY OF CHICAGO · PI Matthew J Brady · 2013 to 2026
$20.9MGenomic Ascertainment - Molecular and Genetic AspectsZIAHG200359 · NHGRI · NATIONAL HUMAN GENOME RESEARCH INSTITUTE · PI BIESECKER, LESLIE · 2009 to 2025
$19.7MGenomic Ascertainment - Clinical and Behavioral AspectsZIAHG200387 · NHGRI · NATIONAL HUMAN GENOME RESEARCH INSTITUTE · PI BIESECKER, LESLIE · 2013 to 2025
$15.5MCenter for Mammalian Regulatory GenomicsU54HG006997 · NHGRI · LUDWIG INSTITUTE FOR CANCER RES LTD · PI REN, BING · 2012 to 2016
$14.3MSouth-seq: DNA sequencing for newborn nurseries in the SouthU01HG007301 · NHGRI · HUDSON-ALPHA INSTITUTE FOR BIOTECHNOLOGY · PI BARSH, GREGORY STEFAN, COOPER, GREGORY MICHAEL · 2017 to 2021
$11.9MStudies of Rare Genetic Variation in the Isolated Population of SardiniaR01HL117626 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI ABECASIS, GONCALO · 2013 to 2016
$10.5MComputational and statistical models for human geneticsR01HG007022 · NHGRI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI ABECASIS, GONCALO · 2012 to 2016
$3.0MMODELING THE EFFECTS OF STRUCTURAL VARIATION IN GTEX DATA AND MENDELIAN DISEASER01MH101810 · NIMH · WASHINGTON UNIVERSITY · PI CONRAD, DONALD F. · 2013 to 2016
$1.3MNHGRI NIH HHS R01 HG007022NHGRI NIH HHS U01 HG007301NHGRI NIH HHS U54 HG006997NHLBI NIH HHS R01 HL117626NIDDK NIH HHS P30 DK020595NIMH NIH HHS R01 MH101810
Abstract
The discovery of rare genetic variants is accelerating, and clear guidelines for distinguishing disease-causing sequence variants from the many potentially functional variants present in any human genome are urgently needed. Without rigorous standards we risk an acceleration of false-positive reports of causality, which would impede the translation of genomic research findings into the clinical diagnostic setting and hinder biological understanding of disease. Here we discuss the key challenges of assessing sequence variants in human disease, integrating both gene-level and variant-level support for causality. We propose guidelines for summarizing confidence in variant pathogenicity and highlight several areas that require further resource development.
Indexed as
DiseaseGuidelines as TopicFalse Positive ReactionsGenesGenetic Predisposition to DiseaseGenetic VariationHumansInformation DisseminationPublishingReproducibility of ResultsResearch DesignTranslational Research, Biomedical
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LicenceCC BY-NC-SA
Read underepoch 390
Registered trials
NCT03829176ClinicalTrials.gov
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.