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Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.

Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP.

Author information

1
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK.
2
MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, EH4 2XU, UK.
3
South East Scotland Regional Genetics Services, Western General Hospital, Edinburgh, EH4 2XU, UK.
4
Centre for Genomic and Experimental Medicine, Institute of Genetics & Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, EH4 2XU, UK.
5
Usher Institute for Population Health Sciences and Informatics, The University of Edinburgh, Nine Edinburgh BioQuarter, 9 Little France Road, Edinburgh, EH16 4UX, UK.
6
Clinical Genetic Department, Addenbrooke's Hospital Cambridge University Hospitals, Cambridge, CB2 0QQ, UK.
7
Edinburgh Cancer Research Centre, Institute of Genetics & Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, EH4 2XU, UK.
8
Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.
9
University of Exeter Medical School, RILD Level 4, Royal Devon & Exeter Hospital, Barrack Road, Exeter, UK.
10
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK. fiona@ebi.ac.uk.
11
MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, EH4 2XU, UK. david.fitzpatrick@ed.ac.uk.

Abstract

We aimed to develop an efficient, flexible and scalable approach to diagnostic genome-wide sequence analysis of genetically heterogeneous clinical presentations. Here we present G2P ( www.ebi.ac.uk/gene2phenotype ) as an online system to establish, curate and distribute datasets for diagnostic variant filtering via association of allelic requirement and mutational consequence at a defined locus with phenotypic terms, confidence level and evidence links. An extension to Ensembl Variant Effect Predictor (VEP), VEP-G2P was used to filter both disease-associated and control whole exome sequence (WES) with Developmental Disorders G2P (G2PDD; 2044 entries). VEP-G2PDD shows a sensitivity/precision of 97.3%/33% for de novo and 81.6%/22.7% for inherited pathogenic genotypes respectively. Many of the missing genotypes are likely false-positive pathogenic assignments. The expected number and discriminative features of background genotypes are defined using control WES. Using only human genetic data VEP-G2P performs well compared to other freely-available diagnostic systems and future phenotypic matching capabilities should further enhance performance.

PMID:
31147538
PMCID:
PMC6542828
DOI:
10.1038/s41467-019-10016-3
[Indexed for MEDLINE]
Free PMC Article

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