Carrier Screening helps individuals and reproductive partners understand their reproductive risk of passing along autosomal recessive and X-linked conditions to their children, allowing them to make more informed reproductive decisions. Several carrier screening panels are now available for Next-Generation Sequencing (NGS) platforms, ranging from targeted panels for prevalent disorders to expanded panels that include hundreds of inherited conditions. As NGS offers a high-throughput and cost-effective solution, carrier screening has become a common and valuable practice within modern healthcare systems.

At Golden Helix, we’ve built VarSeq with powerful features to streamline and automate the carrier screening workflow, helping clinical labs scale their analysis to support high sample volumes with minimal hands-on time. In this post, we’ll walk through the core features and benefits of using VarSeq in conjunction with VSPipeline to automate this process, allowing your lab to perform carrier screening in a highly parallelized and economical fashion.

Designing a Carrier Screening Workflow in VarSeq

Setting up a carrier screening workflow begins with key planning steps that define the scope and behavior of your analysis pipeline:

• Define your covered gene set: Determine which genes and conditions your screening panel will evaluate based on clinical relevance and sequencing coverage. The American College of Medical Genetics (ACMG) recommends a carrier screening panel of around 100 genes with a high carrier frequency in the general population. This set of genes is used by our default Carrier Screening report template, but it can be easily modified to include additional genes.
• Establish a filtering strategy: Use built-in annotations and algorithms in VarSeq to develop a variant filtering strategy that prioritizes high-quality, rare, and clinically relevant variants. These variants can then be further prioritized using VarSeq’s shared carrier gene detection algorithm, which identifies variants in genes that have clinically relevant mutations in both partners.
• Customize your report template: Tailor your carrier screening report to include the appropriate gene-disease relationships, variant classifications, and reproductive risk summaries. Our built-in Carrier Screening Report template provides an excellent starting point for carrier analysis but it can be customized to incorporate additional genes or updated risk calculations.

Once your tertiary analysis workflow has been designed and validated, you can save it as a VarSeq project template. Our VSPipeline tool then leverages this template to create a repeatable analysis pipeline, generating comprehensive draft reports for each sample pair with minimal manual intervention required.

Stages of the Automated Carrier Screening Pipeline

Sample Collection and Primary Analysis

The pipeline begins with sample collection and primary analysis. VarSeq is platform-agnostic, supporting downstream analysis for all major NGS technologies, including Illumina, Ion Torrent, and other leading sequencing technologies.

Secondary Analysis

For secondary analysis, VarSeq seamlessly integrates with all major analysis pipelines. Through our partnership with Sentieon, we also offer robust secondary analysis capabilities, ensuring high-quality alignment and variant calling as the foundation for downstream interpretation.

Tertiary Analysis in VarSeq

Once alignment and variant calling has been performed, VarSeq takes over to handle the core of the carrier screening process. The basic outline of the process is shown in the figure below:

Import Partnered Samples

This process begins with the import of partnered samples. VarSeq’s specialized import functionality allows you to designate primary and partner samples, automatically pairing them for subsequent analysis. This pairing is crucial for identifying shared carrier status across reproductive partners.

Detect Carrier Variants

Once samples are imported, VarSeq performs standard quality filtering on called variants and prioritizes them for interpretation using our built-in ACMG scoring system, which operates in accordance with the ACMG Guidelines for germline variant interpretation. The software then uses the shared carrier gene detection algorithm to identify genes where both partners carry potentially pathogenic variants. These variants with potential compound risks are then flagged for interpretation and inclusion in the draft report.

Evaluate with VSClinical

Prioritized variants are then imported into VSClinical, our interpretation platform that guides the user though the variant interpretation process based on the ACMG guidelines for germline variant classification. VSClinical provides a streamlined, guided review process with built-in data sources, scoring, and partner-aware evaluation tools, enabling confident and consistent variant interpretation and classification.

Generate Clinical Report

Once variant interpretation is complete, you can generate a draft report using VSClinical’s customizable Carrier Screening Report template. This template automatically incorporates gene-disease reproductive risk calculations and generates a table displaying detected variants for each sample, along with their associated gene/disease pairs and corresponding risk assessments.

The entire process described above, from variant calling to report generation, is completely automated using our VSPipeline tool, with manual intervention only required for the final review and editing of the draft report.

Conclusion

By leveraging VarSeq’s automation capabilities for carrier screening analysis, laboratories can dramatically improve throughput without sacrificing quality. The initial investment in pipeline setup pays dividends through ongoing efficiency gains, allowing clinicians to focus their expertise on reviewing edge cases rather than performing repetitive manual tasks. Whether you’re running a small laboratory or a high-volume testing center, VarSeq’s carrier screening capabilities can help you meet growing demand while maintaining the highest standards of clinical care.

If you would like to learn more about how VarSeq can be used to automate carrier analysis or if you have questions related to carrier screening, please reach out to us at [email protected].