Saturation genome editing of BAP1 functionally classifies somatic and germline variants
Nature Genetics, vol. 56, pp. 1434–1445
Abstract
Many variants that we inherit from our parents or acquire de novo or somatically are rare, limiting the precision with which we can associate them with disease. We performed exhaustive saturation genome editing (SGE) of BAP1, the disruption of which is linked to tumorigenesis and altered neurodevelopment. We experimentally characterized 18,108 unique variants, of which 6,196 were found to have abnormal functions, and then used these data to evaluate phenotypic associations in the UK Biobank. We also characterized variants in a large population-ascertained tumor collection, in cancer pedigrees and ClinVar, and explored the behavior of cancer-associated variants compared to that of variants linked to neurodevelopmental phenotypes. Our analyses demonstrated that disruptive germline BAP1 variants were significantly associated with higher circulating levels of the mitogen IGF-1, suggesting a possible pathological mechanism and therapeutic target. Furthermore, we built a variant classifier with >98% sensitivity and specificity and quantify evidence strengths to aid precision variant interpretation.
Authors 21
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Andrew J. Waters corresponding
Affiliation as printed
Wellcome Sanger Institute, Hinxton, UK. aw28@sanger.ac.uk
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Affiliation as printed
Wellcome Sanger Institute, Hinxton, UK
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Affiliation as printed
Wellcome Sanger Institute, Hinxton, UK
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Affiliation as printed
Wellcome Sanger Institute, Hinxton, UK
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Affiliation as printed
Wellcome Sanger Institute, Hinxton, UK
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University of Cambridge · Wellcome/MRC Institute of Metabolic Science
Affiliation as printed
Metabolic Research Laboratory, Wellcome-MRC Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK
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Affiliation as printed
Wellcome Sanger Institute, Hinxton, UK
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Leiden University Medical Center
Affiliation as printed
Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Dermatology, Leiden University Medical Center, Leiden, the Netherlands
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Foundation Medicine (United States)
Affiliation as printed
Foundation Medicine Inc., Cambridge, MA, USA
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Affiliation as printed
Wellcome Sanger Institute, Hinxton, UK
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Affiliation as printed
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
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University of Exeter · Royal Devon University Healthcare NHS Foundation Trust
Affiliation as printed
Department of Clinical Genetics, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK
Faculty of Health and Life Sciences, University of Exeter, Exeter, UK
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Affiliation as printed
Wellcome Sanger Institute, Hinxton, UK
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Affiliation as printed
Wellcome Sanger Institute, Hinxton, UK
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University of Cambridge · Wellcome Sanger Institute
Affiliation as printed
Department of Paediatrics, University of Cambridge, Cambridge, UK
Wellcome Sanger Institute, Hinxton, UK
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Affiliation as printed
Wellcome Sanger Institute, Hinxton, UK
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National Health Service · Royal Marsden NHS Foundation Trust · Institute of Cancer Research · Royal Marsden Hospital · NHS England
Affiliation as printed
Cancer Genetics Unit, The Royal Marsden NHS Foundation Trust, London, UK
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
National Cancer Registration and Analysis Service, NHS England, London, UK
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University of Cambridge · Wellcome/MRC Institute of Metabolic Science
Affiliation as printed
Metabolic Research Laboratory, Wellcome-MRC Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK
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Affiliation as printed
Wellcome Sanger Institute, Hinxton, UK
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David J. Adams corresponding
Affiliation as printed
Wellcome Sanger Institute, Hinxton, UK. da1@sanger.ac.uk
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