Computational evaluation of exome sequence data using human and model organism phenotypes improves diagnostic efficiency

Genet Med. 2016 Jun;18(6):608-17. doi: 10.1038/gim.2015.137. Epub 2015 Nov 12.


Purpose: Medical diagnosis and molecular or biochemical confirmation typically rely on the knowledge of the clinician. Although this is very difficult in extremely rare diseases, we hypothesized that the recording of patient phenotypes in Human Phenotype Ontology (HPO) terms and computationally ranking putative disease-associated sequence variants improves diagnosis, particularly for patients with atypical clinical profiles.

Methods: Using simulated exomes and the National Institutes of Health Undiagnosed Diseases Program (UDP) patient cohort and associated exome sequence, we tested our hypothesis using Exomiser. Exomiser ranks candidate variants based on patient phenotype similarity to (i) known disease-gene phenotypes, (ii) model organism phenotypes of candidate orthologs, and (iii) phenotypes of protein-protein association neighbors.

Results: Benchmarking showed Exomiser ranked the causal variant as the top hit in 97% of known disease-gene associations and ranked the correct seeded variant in up to 87% when detectable disease-gene associations were unavailable. Using UDP data, Exomiser ranked the causative variant(s) within the top 10 variants for 11 previously diagnosed variants and achieved a diagnosis for 4 of 23 cases undiagnosed by clinical evaluation.

Conclusion: Structured phenotyping of patients and computational analysis are effective adjuncts for diagnosing patients with genetic disorders.Genet Med 18 6, 608-617.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Computational Biology
  • Databases, Genetic
  • Disease Models, Animal
  • Exome / genetics*
  • Exome Sequencing / methods*
  • Genetic Association Studies
  • Genetic Variation
  • Humans
  • Mice
  • National Institutes of Health (U.S.)
  • Patients
  • Phenotype
  • Rare Diseases / diagnosis
  • Rare Diseases / epidemiology
  • Rare Diseases / genetics*
  • Rare Diseases / physiopathology*
  • United States
  • Zebrafish