Specific phenotype semantics facilitate gene prioritization in clinical exome sequencing.

Area of Science:

• Genomics
• Clinical Genetics
• Bioinformatics

Background:

• Variant analysis in clinical exome sequencing faces challenges in selecting and prioritizing phenotype-centric variants.
• Phenotype-driven gene list shortlisting is crucial for accurate diagnosis in Mendelian disorders.

Purpose of the Study:

• To evaluate the efficacy of Human Phenotype Ontology (HPO) identifiers in prioritizing Mendelian disease genes.
• To assess the impact of using partial HPO ID lists versus full lists for gene prioritization.

Main Methods:

• Analysis of 50 cases (30 in-house, 20 published) using three gene prioritization tools: OMIMExplorer, VarElect, and Phenolyzer.
• Comparison of gene prioritization accuracy using randomly selected HPO IDs versus top 10%, 30%, and 50% HPO IDs based on information content.

Main Results:

• Randomly selected HPO IDs performed poorly, ranking probe genes lower.
• Using the top 10%, 30%, or 50% of HPO IDs consistently ranked the probe gene within the top 1%, similar to using the full HPO ID list.
• The top 10% of HPO IDs, selected by information content, proved sufficient for top gene ranking.

Conclusions:

• A subset of HPO IDs, specifically the top 10% based on information content, is adequate for effective gene prioritization in Mendelian disorders.
• Structured phenotype semantics and web-based tools can significantly aid in identifying candidate genes for Mendelian disorders.