Specific phenotype semantics facilitate gene prioritization in clinical exome sequencing.

Selection and prioritization of phenotype-centric variants remains a challenging part of variant analysis and interpretation in clinical exome sequencing. Phenotype-driven shortlisting of patient-specific gene lists can avoid missed diagnosis. Here, we analyzed the relevance of using primary Human Phenotype Ontology identifiers (HPO IDs) in prioritizing Mendelian disease genes across 30 in-house, 10 previously reported, and 10 recently published cases using three popular web-based gene prioritization tools (OMIMExplorer, VarElect & Phenolyzer). We assessed partial HPO-based gene prioritization using randomly chosen and top 10%, 30%, and 50% HPO IDs based on information content and found high variance within rank ratios across the former vs the latter. This signified that randomly selected less-specific HPO IDs for a given disease phenotype performed poorly by ranking probe gene farther away from the top rank. In contrast, the use of top 10%, 30%, and 50% HPO IDs individually could rank the probe gene among the top 1% in the ranked list of genes that was equivalent to the results when the full list of HPO IDs were used. Hence, we conclude that use of just the top 10% of HPO IDs chosen based on information content is sufficient for ranking the probe gene at top position. Our findings provide practical guidance for utilizing structured phenotype semantics and web-based gene-ranking tools to aid in identifying known as well unknown candidate gene associations in Mendelian disorders.