Specific phenotype semantics facilitate gene prioritization in clinical exome sequencing.
Journal
European journal of human genetics : EJHG
ISSN: 1476-5438
Titre abrégé: Eur J Hum Genet
Pays: England
ID NLM: 9302235
Informations de publication
Date de publication:
09 2019
09 2019
Historique:
received:
16
05
2018
accepted:
15
04
2019
revised:
21
02
2019
pubmed:
6
5
2019
medline:
13
6
2020
entrez:
5
5
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31053788
doi: 10.1038/s41431-019-0412-7
pii: 10.1038/s41431-019-0412-7
pmc: PMC6777628
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1389-1397Références
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