MirTrios

MirTrios identifies de novo mutations (DNMs) and rare inherited mutations from next-generation sequencing (NGS) data using an Expectation-Maximization (EM) model applied to GATK-derived variant calls to improve detection accuracy for studies of sporadic disease.

Key Features:

• EM-based DNM detection: Uses an Expectation-Maximization model to enhance identification of de novo mutations.
• GATK integration: Operates on Genome Analysis Toolkit (GATK)-generated variant call files (VCF) and leverages GATK result metrics PL, PRT, and PART.
• Iterative threshold refinement: Iteratively refines DNM detection thresholds based on the integrated genotype metrics.
• Training data from WGS trios: Constructs training sets of true and false positive DNMs from whole genome sequencing of 64 trios.
• Validation on WES trios: Validated on in-house whole exome sequencing data from 20 trios, identifying 27 coding-region DNMs with 92.6% validation (25/27).
• Rare inherited mutation detection: Detects and reports rare inherited mutations in addition to DNMs.
• Annotation resources: Provides comprehensive annotation for detected DNMs and rare inherited variants.
• Variant and gene prioritization: Supports interpretation and prioritization of diagnostic variants and candidate causative genes.

Scientific Applications:

• Sporadic disease genetics: Detection of de novo mutations implicated in sporadic and rare genetic disorders.
• Inherited variant analysis: Identification and annotation of rare inherited mutations for diagnostic and research use.
• Diagnostic variant prioritization: Prioritization of known diagnostic variants within coding regions.
• Causative gene discovery: Prioritization of novel candidate genes for follow-up in genetic studies.

Methodology:

Applies an Expectation-Maximization (EM) model to GATK-generated VCFs using PL, PRT, and PART metrics, iteratively refining DNM detection thresholds; training sets were derived from 64 whole genome sequencing trios and validation was performed on 20 whole exome sequencing trios.