Journal
NATURE COMMUNICATIONS
Volume 11, Issue 1, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-020-14284-2
Keywords
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Categories
Funding
- NIH [U54 HG006370, U54706HG006364]
- Government of Canada through Genome Canada [OGI-051]
- Government of Canada through Ontario Genomics [OGI-051]
- National Institutes of Health
- OD [U42 OD011175, UM1OD023221]
- NCRR [U42 OD011175, UM1OD023221]
- NIDDK [U42 OD011175, UM1OD023221]
- NHLBI [U42 OD011175, UM1OD023221]
- Infrafrontier grant [01KX1012]
- EU Horizon2020: IPAD-MD [653961]
- Wellcome Trust [WT098051, WT206194]
- French National Centre for Scientific Research (CNRS)
- French National Institute of Health and Medical Research (INSERM)
- University of Strasbourg
- Centre Europeen de Recherche en Biomedecine
- French state funds through the Agence Nationale de la Recherche under the frame programme Investissements d'Avenir [ANR-10-IDEX-0002-02, ANR-10-LABX-0030-INRT, ANR-10-INBS-07 PHENOMIN]
- National Institute for Health Research
- NHS England
- Cancer Research UK
- Medical Research Council
- Wellcome [HICF-1009003]
- Department of Health [HICF-1009003]
- Wellcome Sanger Institute [WT098051]
- National Institute for Health Research, through the Comprehensive Clinical Research Network
- National Human Genome Research Institute
- National Heart, Lung, and Blood Institute
- National Eye Institute
- Broad Institute [UM1 HG008900]
- Johns Hopkins University School of Medicine/Baylor College of Medicine [UM1 HG006542]
- University of Washington [UM1 HG006493]
- Yale University [UM1 HG006504]
- [EUCOMM: LSHM-CT-2005-018931]
- [EUCOMMTOOLS: FP7-HEALTH-F4-2010-261492]
- [UM1 HG006348]
- [U42 OD011174]
- [U54 HG005348]
- MRC [MC_U142684172, MC_U142684171, MC_UP_1502/1, MR/S006753/1] Funding Source: UKRI
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The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery. Discovery of causal variants for monogenic disorders has been facilitated by whole exome and genome sequencing, but does not provide a diagnosis for all patients. Here, the authors propose a Full Spectrum of Intolerance to Loss-of-Function (FUSIL) categorization that integrates gene essentiality information to aid disease gene discovery.
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