Using High-Resolution Variant Frequencies Empowers Clinical Genome Interpretation and Enables Investigation of Genetic Architecture

Nicola Whiffin¹, Angharad M Roberts², Eric Minikel³, Zach Zappala³, Roddy Walsh², Anne H O'Donnell-Luria³, Konrad J Karczewski³, Steven M Harrison⁴, Kate L Thomson⁵, Helen Sage⁶, Alexander Y Ing⁴, Paul J R Barton², Birgit Funke⁴, Stuart A Cook⁷, Daniel G MacArthur⁸, James S Ware⁹

Affiliations

¹ Cardiovascular Genetics and Genomics, National Heart and Lung Institute, Imperial College Centre for Translational and Experimental Medicine, London, W12 0NN, UK; National Institute for Health Research Royal Brompton Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, SW7 2AZ, UK; Medical Research Council London Institute of Medical Sciences, Imperial College London, London, W12 0NN, UK.
² Cardiovascular Genetics and Genomics, National Heart and Lung Institute, Imperial College Centre for Translational and Experimental Medicine, London, W12 0NN, UK; National Institute for Health Research Royal Brompton Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, SW7 2AZ, UK.
³ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of the Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
⁴ Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, Cambridge, MA 021319, USA; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
⁵ Oxford Medical Genetics Laboratory, Oxford University Hospitals National Health Service Foundation Trust, Oxford, OX3 7LJ, UK; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK.
⁶ Oxford Medical Genetics Laboratory, Oxford University Hospitals National Health Service Foundation Trust, Oxford, OX3 7LJ, UK.
⁷ Cardiovascular Genetics and Genomics, National Heart and Lung Institute, Imperial College Centre for Translational and Experimental Medicine, London, W12 0NN, UK; National Institute for Health Research Royal Brompton Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, SW7 2AZ, UK; National Heart Centre Singapore, Singapore, 169609.
⁸ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of the Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
⁹ Cardiovascular Genetics and Genomics, National Heart and Lung Institute, Imperial College Centre for Translational and Experimental Medicine, London, W12 0NN, UK; National Institute for Health Research Royal Brompton Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, SW7 2AZ, UK; Medical Research Council London Institute of Medical Sciences, Imperial College London, London, W12 0NN, UK; Program in Medical and Population Genetics, Broad Institute of the Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA. Electronic address: j.ware@imperial.ac.uk.

PMID: 30609406
PMCID: PMC6323549
DOI: 10.1016/j.ajhg.2018.11.012

Comment

Using High-Resolution Variant Frequencies Empowers Clinical Genome Interpretation and Enables Investigation of Genetic Architecture

Nicola Whiffin et al. Am J Hum Genet. 2019.

. 2019 Jan 3;104(1):187-190.

doi: 10.1016/j.ajhg.2018.11.012.

Authors

Affiliations

¹ Cardiovascular Genetics and Genomics, National Heart and Lung Institute, Imperial College Centre for Translational and Experimental Medicine, London, W12 0NN, UK; National Institute for Health Research Royal Brompton Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, SW7 2AZ, UK; Medical Research Council London Institute of Medical Sciences, Imperial College London, London, W12 0NN, UK.
² Cardiovascular Genetics and Genomics, National Heart and Lung Institute, Imperial College Centre for Translational and Experimental Medicine, London, W12 0NN, UK; National Institute for Health Research Royal Brompton Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, SW7 2AZ, UK.
³ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of the Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
⁴ Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, Cambridge, MA 021319, USA; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
⁵ Oxford Medical Genetics Laboratory, Oxford University Hospitals National Health Service Foundation Trust, Oxford, OX3 7LJ, UK; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK.
⁶ Oxford Medical Genetics Laboratory, Oxford University Hospitals National Health Service Foundation Trust, Oxford, OX3 7LJ, UK.
⁷ Cardiovascular Genetics and Genomics, National Heart and Lung Institute, Imperial College Centre for Translational and Experimental Medicine, London, W12 0NN, UK; National Institute for Health Research Royal Brompton Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, SW7 2AZ, UK; National Heart Centre Singapore, Singapore, 169609.
⁸ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of the Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
⁹ Cardiovascular Genetics and Genomics, National Heart and Lung Institute, Imperial College Centre for Translational and Experimental Medicine, London, W12 0NN, UK; National Institute for Health Research Royal Brompton Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, SW7 2AZ, UK; Medical Research Council London Institute of Medical Sciences, Imperial College London, London, W12 0NN, UK; Program in Medical and Population Genetics, Broad Institute of the Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA. Electronic address: j.ware@imperial.ac.uk.

PMID: 30609406
PMCID: PMC6323549
DOI: 10.1016/j.ajhg.2018.11.012

No abstract available

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Comment in

Response to Whiffin et al.
Shah N, Claire Hou YC, Yu HC, Sainger R, Caskey CT, Venter JC, Telenti A. Shah N, et al. Am J Hum Genet. 2019 Jan 3;104(1):186. doi: 10.1016/j.ajhg.2018.11.011. Am J Hum Genet. 2019. PMID: 30609405 Free PMC article. No abstract available.

Comment on

Identification of Misclassified ClinVar Variants via Disease Population Prevalence.
Shah N, Hou YC, Yu HC, Sainger R, Caskey CT, Venter JC, Telenti A. Shah N, et al. Am J Hum Genet. 2018 Apr 5;102(4):609-619. doi: 10.1016/j.ajhg.2018.02.019. Am J Hum Genet. 2018. PMID: 29625023 Free PMC article.

References

1. Shah N., Hou Y.-C.C., Yu H.-C., Sainger R., Caskey C.T., Venter J.C., Telenti A. Identification of misclassified ClinVar variants via disease population prevalence. Am. J. Hum. Genet. 2018;102:609–619. - PMC - PubMed
1. Landrum M.J., Lee J.M., Riley G.R., Jang W., Rubinstein W.S., Church D.M., Maglott D.R. ClinVar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res. 2014;42:D980–D985. - PMC - PubMed
1. Whiffin N., Minikel E., Walsh R., O’Donnell-Luria A.H., Karczewski K., Ing A.Y., Barton P.J.R., Funke B., Cook S.A., MacArthur D., Ware J.S. Using high-resolution variant frequencies to empower clinical genome interpretation. Genet. Med. 2017;19:1151–1158. - PMC - PubMed
1. Lek M., Karczewski K.J., Minikel E.V., Samocha K.E., Banks E., Fennell T., O’Donnell-Luria A.H., Ware J.S., Hill A.J., Cummings B.B., Exome Aggregation Consortium Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285–291. - PMC - PubMed
1. Richards S., Aziz N., Bale S., Bick D., Das S., Gastier-Foster J., Grody W.W., Hegde M., Lyon E., Spector E., ACMG Laboratory Quality Assurance Committee Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 2015;17:405–424. - PMC - PubMed

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Using High-Resolution Variant Frequencies Empowers Clinical Genome Interpretation and Enables Investigation of Genetic Architecture

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Using High-Resolution Variant Frequencies Empowers Clinical Genome Interpretation and Enables Investigation of Genetic Architecture

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