GermVarX: A Robust Workflow for Joint Germline Variant Exploration in whole-exome sequencing cohorts

Area of Science:

• Genomics
• Bioinformatics
• Computational Biology

Background:

• Accurate germline variant identification from whole-exome sequencing (WES) data is crucial for population genetics, disease association studies, and clinical genomics.
• Current variant calling methods across cohorts face challenges in scalability, consistency, and reproducibility.

Purpose of the Study:

• To present GermVarX, a fully automated, modular workflow for joint germline variant discovery and exploration in WES cohort studies.
• To provide a scalable, reproducible, and comprehensive solution for germline variant analysis in large WES studies.

Main Methods:

• GermVarX implements joint variant calling for simultaneous genotyping of multiple samples, producing a high-confidence multi-sample VCF.
• The workflow is developed using Nextflow DSL2 for reproducibility and portability across diverse computing environments.
• It integrates GATK HaplotypeCaller and DeepVariant, with joint genotyping via GATK or GLnexus, supporting consensus generation and quality control.

Main Results:

• GermVarX ensures efficient parallelization and integrates quality control, functional annotation (VEP), and reporting (MultiQC).
• The workflow provides PLINK-compatible outputs for seamless integration with statistical and association analyses.
• It delivers consistent and interpretable results for both research and clinical genomics.

Conclusions:

• GermVarX offers a scalable and reproducible solution for germline variant analysis in large WES studies.
• The workflow enhances the reliability and interpretability of variant data for population genetics and clinical applications.
• GermVarX supports consistent and high-confidence germline variant discovery and exploration.