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🧬 Exomiser

What is Exomiser?

Exomiser is a phenotype-driven variant and gene prioritization tool designed for
next-generation sequencing (NGS) analysis in Mendelian disease.
It integrates genetic variant data with Human Phenotype Ontology (HPO) annotations
to rank candidate disease genes for diagnosis or novel gene discovery.

📖 Key References

  • Robinson PN et al. (2014)
    Improved exome prioritization of disease genes through cross-species phenotype comparison.
    Genome Research 24(2):340-348.
    PMID:24162188

  • Smedley D (2015)
    Next-generation diagnostics and disease-gene discovery with the Exomiser.
    Nature Protocols 10(12):2004-2015.
    PMID:26562621

🧪 Background

Exomiser was among the first phenotype-aware prioritization tools and was released in 2014
as a freely available Java application.

It requires two primary inputs:

  1. Genomic data
  2. A VCF file containing variants from a rare-disease patient

  3. Optionally, a multi-sample VCF and a pedigree (PED) file for family analyses

  4. Phenotypic data

  5. A list of HPO terms describing the patient’s clinical features

The algorithm combines variant pathogenicity predictions with phenotype similarity scoring across human and model-organism data.

🚀 Online Demo

A demo version of Exomiser is available here:

👉 https://exomiser.monarchinitiative.org/exomiser/

🧬 Hands-On Exercise

Goal

Learn how phenotype-driven prioritization improves variant interpretation.

Download the provided example dataset containing:

  • An exome from a healthy individual
  • A causative FGFR2 variant associated with autosomal dominant Pfeiffer syndrome

Step 1 — Add Phenotypes

Add HPO terms describing Pfeiffer syndrome, similar to the workflow used in Phenomizer.

You may consult the HPO disease page:

👉 https://hpo.jax.org/app/browse/disease/OMIM:101600

Step 2 — Run Exomiser

You can:

  • Run Exomiser using default settings, or
  • Adjust parameters (see the publications above for detailed explanations).

🧾 Exercise 1

Explore the results

Examine the Exomiser output and answer the following:

  • What are the top five candidate genes?
  • What phenotypic evidence supports their ranking?
  • What genetic evidence argues for or against each candidate?

Consider:

  • Variant pathogenicity scores
  • Phenotype similarity scores
  • Mode of inheritance
  • Gene–disease associations

Next Module: Running Exomiser from command line