Guidelines for investigating causality of sequence variants in human disease.
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.
1] 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.
D G
DG
MacArthur
Division of Genomic Medicine, National Human Genome Research Institute, Bethesda, Maryland 20892, USA.
T A
TA
Manolio
Division of Genetics, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
D P
DP
Dimmock
1] 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.
H L
HL
Rehm
Department of Genome Sciences, University of Washington, Seattle, Washington 98115, USA.
J
J
Shendure
Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA.
G R
GR
Abecasis
1] 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.
D R
DR
Adams
Departments of Bioengineering & Genetics, Stanford University, Stanford, California 94305, USA.
R B
RB
Altman
1] Department of Genetic Medicine, University of Geneva Medical School, 1211 Geneva, Switzerland [2] iGE3 Institute of Genetics and Genomics of Geneva, 1211 Geneva, Switzerland.
S E
SE
Antonarakis
Center for Inherited Cardiovascular Disease, Stanford University School of Medicine, Stanford, California 94305, USA.
E A
EA
Ashley
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
J C
JC
Barrett
Genetic Disease Research Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892, USA.
L G
LG
Biesecker
Departments of Genetics, Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
D F
DF
Conrad
HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, Alabama 35806, USA.
G M
GM
Cooper
Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
N J
NJ
Cox
1] 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 J
MJ
Daly
1] 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.
M B
MB
Gerstein
Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina 27708, USA.
D B
DB
Goldstein
1] 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.
J N
JN
Hirschhorn
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
S M
SM
Leal
1] 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.
L A
LA
Pennacchio
Department of Genome Sciences, University of Washington, 1705 Northeast Pacific Street, Seattle, Washington 98195, USA.
J A
JA
Stamatoyannopoulos
1] Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA [2] Harvard Medical School, Boston, Massachusetts 02115, USA.
S R
SR
Sunyaev
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
D
D
Valle
Department of Pharmacology and Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA.
B F
BF
Voight
1] 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.).
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W
Winckler
1] 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.).
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C
Gunter
D004194:Disease; D005189:False Positive Reactions; D005796:Genes / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D017408:Guidelines as Topic; D006801:Humans; D033181:Information Dissemination; D011643:Publishing; D015203:Reproducibility of Results; D012107:Research Design; D057170:Translational Research, Biomedical / Q000592:standards