Overview

For all rare disease referral, interpretation is performed using the Exomiser automated variant prioritisation framework (Next-generation diagnostics and disease-gene discovery with the Exomiser) developed by members of the Monarch initiative: principally Prof. Damian Smedley’s team at Queen Mary University London and Professor Peter Robinson’s team at Jackson Laboratory, USA, with previous contributions from staff at Charité – Universitätsmedizin, Berlin and the Sanger Institute.

Given a multi-sample VCF file, family pedigree and proband phenotypes encoded by Human Phenotype Ontology (HPO) terms, Exomiser annotates the consequence of variants (based on Ensembl transcripts) and then filters and prioritises them for how likely they are to be causative of the proband’s disease based on:

• the predicted pathogenicity and allele frequency of the variant in reference databases
• how closely the patient’s phenotypes match the known phenotypes of diseases and model organisms associated with the gene

Note

Both Genomics England and Congenica run Exomiser independently, versions and configuration may differ meaning the two systems may show different Exomiser scores and ranks.

Graphical summary of Exomiser approach: