HPO prioritization pipeline

Based on HPO profiles and input files provided this pipeline run GADO and/or Exomiser

Before you run

Before you can use the pipeline you need to install Exomiser, GADO and some supporting files

Exomiser

You can download the latest version of Exomiser from the Monarch initiative FTP

1. Update exomiser_cli params in the nextflow.config to point to the .jar file of exomiser CLI.
2. Update the config/application.properties file to point to your exomiser data folder.
3. Note that the current configuration also use CADD score, so you need to have CADD score files installed as well and you need to configure the corresponding file location in config/application.properties (or remove CADD from the template files in config)

GADO

1. Download the GADO cli 1.0.1 from the official release
2. Download dataset files. You can find the links in the GADO github wiki
3. Uncompress the prediction matrix .zip file and rename files so that you have a folder (let say GADO_resources containing the following files:
   • hpo_predictions_info.txt
   • hpo_predictions_genes.txt
   • hpo_predictions_matrix_spiked.cols.txt
   • hpo_predictions_matrix_spiked.rows.txt
   • hpo_predictions_matrix_spiked.dat
4. Download the HPO ontology .obo file from GADO wiki or directly from HPO ontology

Then you need to update the following params in the nextflow.config

• GADO_cli: path to your GADO cli .jar file
• GADO_datafolder: path to folder containing GADO files (GADO_resources in this example)
• HPO_obofile: path to your .obo files

Usage

When everything is properly configured in nextflow.config you can run the pipeline using

nextflow main.nf --GADO --exomiser \
    --HPO HPO_profiles.tsv \
    --exomiser_input exomiser_input.tsv \
    --exomiser_template config/template_GRCh38.yml \
    --out results

NB There are current profiles for sge and slurm in the config file, but you need to configure the queue names for your system

Input files

Only HPO profiles file is required for GADO, while also exomiser input is required for exomiser.

HPO profiles

This is a tab-separated file without header containing 1 case per line, with case ID in column 1 and then 1 HPO term per column

case1   HP:00001   HP:000002
case2   HP:00003   HP:000004    HP:000006

Exomiser input

This is a tab-separated file without header containing 1 case per line, with case ID, proband id, vcf file and ped file. NB case ID must match case ID from the HPO profiles and proband id must match the id of proband sample in the VCF file.

case1   proband1    case1_family.vcf.gz case1.ped
case2   proband2    case2_family.vcf.gz case2.ped

Change exomiser settings

The exomiser annotation and filter settings are store in the .yml templated in the config folder. The provided files will filter for protein-changing variants with population AF < 1% and use CADD, PP2 and SIFT scores for variant scoring. All possible segregation models are evaluated and hiPhive is used for HPO-based prioritization. You can change these template to change analysis settings for the Exomiser. Please refer to the exomiser documentation.