Selection and use of human phenotype ontology (HPO) terms: creation of virtual gene panel

The HPO currently contains over 13,000 terms. Most ontologies are structured as directed acyclic graphs, which are similar to hierarchies but differ in that a more specialized term can be related to more than one less specialized term. The HPO terms used for variant filtering in our study were selected with the goal of covering phenotypic abnormalities that explain an unexpected sudden natural death. We selected the HPO term “arrhythmia” (HP: 0011675, associated with 356 genes), which belongs to the subclass abnormality of cardiovascular system electrophysiology. We selected the HPO term “sudden cardiac death” (HP: 0001645, associated with 72 genes) for variant filtering, which belongs to the category “cardiac arrest”. Since SUD is a fatal complication of seizures without recovery [21], we selected the specific HPO term “status epilepticus” (HP: 0002133, associated with 131 genes) which belongs to the category “seizure”. Since a lack of breathing may result in SD, we selected the HPO term “apnea” (HP: 0002104, associated with 266 genes) from the category “Abnormal pattern of respiratory”. Taken together, all cases of the study were annotated with the following set of HPO terms: arrhythmia, sudden cardiac death, status epilepticus and apnea. Overall, 672 different genes were associated with the selected HPO terms, thus creating a HPO-driven “virtual gene panel”.

HPO project data are available at http://www.human-phenotype-ontology.org. (Release: August 2020).

We additionally used the recently developed HPO similarity score (HPOSimScore; Release 12-2020) included in the varvis® software (Limbus Medical Technologies GmbH). The HPOSimScore calculates the phenotype similarity based on the selected HPO terms to improve efficiency of disease diagnoses (Phenotype/gene match). HPO score and match are controlled gene annotations which will be calculated after HPO terms have been associated to the case.