Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP.
Where this comes from
- Record sourced from PubMed, PMID 31147538.
- Also identified by DOI 10.1038/s41467-019-10016-3 and PMC identifier 6542828.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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 (G2P<sup>DD</sup>; 2044 entries). VEP-G2P<sup>DD</sup> 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.
Medical subject headings
- Developmental Disabilities
- Genetic Testing
- Genome, Human
- Exome Sequencing