Individualised human phenotype ontology gene panels improve clinical whole exome and genome sequencing analytical efficacy in a cohort of developmental and epileptic encephalopathies

Mol Genet Genomic Med. 2023 Jul;11(7):e2167. doi: 10.1002/mgg3.2167. Epub 2023 Mar 26.


Background: The majority of genetic epilepsies remain unsolved in terms of specific genotype. Phenotype-based genomic analyses have shown potential to strengthen genomic analysis in various ways, including improving analytical efficacy.

Methods: We have tested a standardised phenotyping method termed 'Phenomodels' for integrating deep-phenotyping information with our in-house developed clinical whole exome/genome sequencing analytical pipeline. Phenomodels includes a user-friendly epilepsy phenotyping template and an objective measure for selecting which template terms to include in individualised Human Phenotype Ontology (HPO) gene panels. In a pilot study of 38 previously solved cases of developmental and epileptic encephalopathies, we compared the sensitivity and specificity of the individualised HPO gene panels with the clinical epilepsy gene panel.

Results: The Phenomodels template showed high sensitivity for capturing relevant phenotypic information, where 37/38 individuals' HPO gene panels included the causative gene. The HPO gene panels also had far fewer variants to assess than the epilepsy gene panel.

Conclusion: We have demonstrated a viable approach for incorporating standardised phenotype information into clinical genomic analyses, which may enable more efficient analysis.

Keywords: deep phenotyping; epilepsy; human phenotype ontology; precision medicine; whole exome sequencing; whole genome sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Epilepsy* / genetics
  • Epilepsy, Generalized* / genetics
  • Exome
  • Humans
  • Phenotype
  • Pilot Projects