LoFTK: a framework for fully automated calculation of predicted Loss-of-Function variants and genes

Loss-of-Function (LoF) variants in human genes are important due to their impact on clinical phenotypes and frequent occurrence in the genomes of healthy individuals. The association of LoF variants with complex diseases and traits may lead to the discovery and validation of novel therapeutic target...

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Bibliographic Details
Published in:BioData mining 2023-02, Vol.16 (1), p.3-10, Article 3
Main Authors: Alasiri, Abdulrahman, Karczewski, Konrad J, Cole, Brian, Loza, Bao-Li, Moore, Jason H, van der Laan, Sander W, Asselbergs, Folkert W, Keating, Brendan J, van Setten, Jessica
Format: Article
Language:English
Subjects:
Analysis
Annotations
Automation
Bioinformatics
Compound heterozygotes
Computer applications
Function
Genes
Genetic aspects
Genomes
Genomics
Genotype & phenotype
Health aspects
Heterozygotes
Human genetic
Knockout genes
Loss-of-Function variants
Offspring
Phenotypes
Software
Technology application
Therapeutic targets
Workflow
Workflow software
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Summary:Loss-of-Function (LoF) variants in human genes are important due to their impact on clinical phenotypes and frequent occurrence in the genomes of healthy individuals. The association of LoF variants with complex diseases and traits may lead to the discovery and validation of novel therapeutic targets. Current approaches predict high-confidence LoF variants without identifying the specific genes or the number of copies they affect. Moreover, there is a lack of methods for detecting knockout genes caused by compound heterozygous (CH) LoF variants. We have developed the Loss-of-Function ToolKit (LoFTK), which allows efficient and automated prediction of LoF variants from genotyped, imputed and sequenced genomes. LoFTK enables the identification of genes that are inactive in one or two copies and provides summary statistics for downstream analyses. LoFTK can identify CH LoF variants, which result in LoF genes with two copies lost. Using data from parents and offspring we show that 96% of CH LoF genes predicted by LoFTK in the offspring have the respective alleles donated by each parent. LoFTK is a command-line based tool that provides a reliable computational workflow for predicting LoF variants from genotyped and sequenced genomes, identifying genes that are inactive in 1 or 2 copies. LoFTK is an open software and is freely available to non-commercial users at https://github.com/CirculatoryHealth/LoFTK .
ISSN:1756-0381
1756-0381
DOI:10.1186/s13040-023-00321-5