TRAPD

TRAPD performs gene-based burden testing of rare variants from exome sequencing by comparing case allele counts to public control datasets such as the Genome Aggregation Database (gnomAD) to identify genes associated with Mendelian disorders affected by locus heterogeneity and incomplete penetrance.

Key Features:

• Utilization of Public Databases: Uses large-scale public sequencing databases like the Genome Aggregation Database (gnomAD) as control cohorts by leveraging their allele counts for burden comparisons.
• Adaptable Variant Quality Filtering: Implements an adaptable variant quality filtering strategy to calibrate tests and mitigate artifacts arising from differences in ancestry, sequencing platforms, or variant calling between cases and public controls.
• Calibration Using Synonymous Variants: Employs synonymous (presumably benign) variants to calibrate variant filters and ensure well-calibrated burden test statistics.
• Iterative Artifact Mitigation: Performs iterative analyses to identify and correct sources of artifact when using public control data.

Scientific Applications:

• Idiopathic hypogonadotropic hypogonadism (IHH) exome analysis: Applied to whole-exome sequencing data from IHH cases with comparisons to gnomAD controls.
• Gene discovery and replication: Rediscovered previously implicated genes FGFR1, TACR3, and GNRHR and identified a significant burden in TYRO3.

Methodology:

Comparison of case allele counts to public control allele counts (gnomAD), adaptable variant quality filtering, calibration using synonymous variants, and iterative analyses to overcome artifacts.