Guidelines for investigating causality of sequence variants in human disease

doi:10.1038/nature13127

. 2014 Apr 24;508(7497):469-76.

doi: 10.1038/nature13127.

Guidelines for investigating causality of sequence variants in human disease

D G MacArthur¹, T A Manolio², D P Dimmock³, H L Rehm⁴, J Shendure⁵, G R Abecasis⁶, D R Adams⁷, R B Altman⁸, S E Antonarakis⁹, E A Ashley¹⁰, J C Barrett¹¹, L G Biesecker¹², D F Conrad¹³, G M Cooper¹⁴, N J Cox¹⁵, M J Daly¹, M B Gerstein¹⁶, D B Goldstein¹⁷, J N Hirschhorn¹⁸, S M Leal¹⁹, L A Pennacchio²⁰, J A Stamatoyannopoulos²¹, S R Sunyaev²², D Valle²³, B F Voight²⁴, W Winckler²⁵, C Gunter²⁶

Affiliations

¹ 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.
² Division of Genomic Medicine, National Human Genome Research Institute, Bethesda, Maryland 20892, USA.
³ Division of Genetics, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
⁴ 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.
⁵ Department of Genome Sciences, University of Washington, Seattle, Washington 98115, USA.
⁶ Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA.
⁷ 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.
⁸ Departments of Bioengineering & Genetics, Stanford University, Stanford, California 94305, USA.
⁹ 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.
¹⁰ Center for Inherited Cardiovascular Disease, Stanford University School of Medicine, Stanford, California 94305, USA.
¹¹ Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
¹² Genetic Disease Research Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892, USA.
¹³ Departments of Genetics, Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
¹⁴ HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, Alabama 35806, USA.
¹⁵ Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
¹⁶ 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.
¹⁷ Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina 27708, USA.
¹⁸ 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.
¹⁹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
²⁰ 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.
²¹ Department of Genome Sciences, University of Washington, 1705 Northeast Pacific Street, Seattle, Washington 98195, USA.
²² 1] Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA [2] Harvard Medical School, Boston, Massachusetts 02115, USA.
²³ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
²⁴ Department of Pharmacology and Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA.
²⁵ 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.).
²⁶ 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.).

PMID: 24759409
PMCID: PMC4180223
DOI: 10.1038/nature13127

Guidelines for investigating causality of sequence variants in human disease

D G MacArthur et al. Nature. 2014.

. 2014 Apr 24;508(7497):469-76.

doi: 10.1038/nature13127.

Authors

Affiliations

¹ 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.
² Division of Genomic Medicine, National Human Genome Research Institute, Bethesda, Maryland 20892, USA.
³ Division of Genetics, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
⁴ 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.
⁵ Department of Genome Sciences, University of Washington, Seattle, Washington 98115, USA.
⁶ Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA.
⁷ 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.
⁸ Departments of Bioengineering & Genetics, Stanford University, Stanford, California 94305, USA.
⁹ 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.
¹⁰ Center for Inherited Cardiovascular Disease, Stanford University School of Medicine, Stanford, California 94305, USA.
¹¹ Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
¹² Genetic Disease Research Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892, USA.
¹³ Departments of Genetics, Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
¹⁴ HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, Alabama 35806, USA.
¹⁵ Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
¹⁶ 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.
¹⁷ Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina 27708, USA.
¹⁸ 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.
¹⁹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
²⁰ 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.
²¹ Department of Genome Sciences, University of Washington, 1705 Northeast Pacific Street, Seattle, Washington 98195, USA.
²² 1] Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA [2] Harvard Medical School, Boston, Massachusetts 02115, USA.
²³ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
²⁴ Department of Pharmacology and Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA.
²⁵ 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.).
²⁶ 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.).

PMID: 24759409
PMCID: PMC4180223
DOI: 10.1038/nature13127

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.

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References

1. Bell CJ, et al. Carrier testing for severe childhood recessive diseases by next-generation sequencing. Sci. Transl. Med. 2011;3:65ra4. - PMC - PubMed
1. Xue Y, et al. Deleterious- and disease-allele prevalence in healthy individuals: insights from current predictions, mutation databases, and population-scale resequencing. Am. J. Hum. Genet. 2012;91:1022–1032. - PMC - PubMed
1. Norton N, et al. Evaluating pathogenicity of rare variants from dilated cardiomyopathy in the exome era. Circ Cardiovasc Genet. 2012;5:167–174. - PMC - PubMed
1. Weng L, et al. Lack of MEF2A mutations in coronary artery disease. J. Clin. Invest. 2005;115:1016–1020. - PMC - PubMed
1. Hunt KA, et al. Rare and functional SIAE variants are not associated with autoimmune disease risk in up to 66,924 individuals of European ancestry. Nature Genet. 2012;44:3–5. - PMC - PubMed

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[1] Bell CJ, et al. Carrier testing for severe childhood recessive diseases by next-generation sequencing. Sci. Transl. Med. 2011;3:65ra4. - PMC - PubMed

[2] Bell CJ, et al. Carrier testing for severe childhood recessive diseases by next-generation sequencing. Sci. Transl. Med. 2011;3:65ra4. - PMC - PubMed

[3] Xue Y, et al. Deleterious- and disease-allele prevalence in healthy individuals: insights from current predictions, mutation databases, and population-scale resequencing. Am. J. Hum. Genet. 2012;91:1022–1032. - PMC - PubMed

[4] Xue Y, et al. Deleterious- and disease-allele prevalence in healthy individuals: insights from current predictions, mutation databases, and population-scale resequencing. Am. J. Hum. Genet. 2012;91:1022–1032. - PMC - PubMed

[5] Norton N, et al. Evaluating pathogenicity of rare variants from dilated cardiomyopathy in the exome era. Circ Cardiovasc Genet. 2012;5:167–174. - PMC - PubMed

[6] Norton N, et al. Evaluating pathogenicity of rare variants from dilated cardiomyopathy in the exome era. Circ Cardiovasc Genet. 2012;5:167–174. - PMC - PubMed

[7] Weng L, et al. Lack of MEF2A mutations in coronary artery disease. J. Clin. Invest. 2005;115:1016–1020. - PMC - PubMed

[8] Weng L, et al. Lack of MEF2A mutations in coronary artery disease. J. Clin. Invest. 2005;115:1016–1020. - PMC - PubMed

[9] Hunt KA, et al. Rare and functional SIAE variants are not associated with autoimmune disease risk in up to 66,924 individuals of European ancestry. Nature Genet. 2012;44:3–5. - PMC - PubMed

[10] Hunt KA, et al. Rare and functional SIAE variants are not associated with autoimmune disease risk in up to 66,924 individuals of European ancestry. Nature Genet. 2012;44:3–5. - PMC - PubMed

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Guidelines for investigating causality of sequence variants in human disease

Affiliations

Guidelines for investigating causality of sequence variants in human disease

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