Phenotype-driven gene target definition in clinical genome-wide sequencing data interpretation

Area of Science:

• Genomics
• Medical Genetics
• Bioinformatics

Background:

• Genome-wide sequencing offers broad genetic insights but presents analytical challenges.
• Increased gene targets in genome-wide sequencing can lead to a higher rate of incidental findings.
• Current methods may struggle with analyzing complex or poorly defined clinical presentations.

Purpose of the Study:

• To develop and validate a novel phenotype-driven approach for analyzing genome-wide sequencing data.
• To improve the diagnostic yield of exome sequencing by utilizing phenotype-gene associations.
• To reduce the rate of incidental findings in genomic analyses.

Main Methods:

• Design of individualized phenotype gene panels based on observed signs and symptoms.
• Selection of relevant genes using known phenotype-gene associations.
• Retrospective analysis of diagnostic exome sequencing data from 405 cases.

Main Results:

• The phenotype gene panel approach increased the diagnostic yield of masked exome analysis from 25.4% to 29.7%.
• This strategy facilitates masked analysis of genome-wide sequencing data for complex clinical presentations.
• The incidental findings rate was effectively controlled at 0.25% using phenotype gene panels.

Conclusions:

• A novel phenotype-driven strategy enhances the diagnostic utility of genome-scale sequencing.
• This approach balances high sensitivity with a focused analysis relevant to the patient's clinical presentation.
• A web tool for creating customized phenotype panels is available to aid clinical application.