Efficient identification of de novo mutations in family trios: a consensus-based informatic approach

Accurate identification of de novo variants (DNVs) remains challenging despite advances in sequencing technologies, often requiring ad hoc filters and manual inspection. Here, we explored a purely informatic, consensus-based approach for identifying DNVs in proband-parent trios using short-read genome sequencing data. We evaluated variant calls generated by three sequence analysis pipelines-GATK HaplotypeCaller, DeepTrio, and Velsera GRAF-and examined the assumption that a requirement of consensus can serve as an effective filter for high-quality DNVs. Comparison with a highly accurate DNV set, validated previously by manual inspection and Sanger sequencing, demonstrated that consensus filtering, followed by a force-calling procedure, effectively removed false-positive calls, achieving 98.0-99.4% precision. At the same time, sensitivity of the workflow based on the previously established DNVs reached 99.4%. Validation in the HG002-3-4 Genome-in-a-Bottle trio confirmed its robustness, with precision reaching 99.2% and sensitivity up to 96.6%. We believe that this consensus approach can be widely implemented as an automated bioinformatics workflow suitable for large-scale analyses without the need for manual intervention, especially when very high precision is valued over sensitivity.

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Publication Details

Journal
Life Science Alliance
Published
2025-03-28
DOI
https://doi.org/10.26508/lsa.202403039
Primary Topic
Genomics and Rare Diseases
Type
article
Field-Weighted Citation Impact
0.00

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article

Efficient identification of de novo mutations in family trios: a consensus-based informatic approach

Christine E. Seidman, Sinem Demirkaya-Budak, Deniz Turgut, Wendy K. Chung et al.
Life Science Alliance
Genomics and Rare Diseases
article

Efficient identification of de novo mutations in family trios: a consensus-based informatic approach

Christine E. Seidman, Sinem Demirkaya-Budak, Deniz Turgut, Wendy K. Chung, Mariya Shadrina, Charles A. LeDuc, Güngör Budak, Özem Kalay, Brandi N. Davis‐Dusenbery, H. Joseph Yost, Bruce D. Gelb, Vladimir Semenyuk, Anil Jain, Elif Arslan
article en

Abstract

Accurate identification of de novo variants (DNVs) remains challenging despite advances in sequencing technologies, often requiring ad hoc filters and manual inspection. Here, we explored a purely informatic, consensus-based approach for identifying DNVs in proband-parent trios using short-read genome sequencing data. We evaluated variant calls generated by three sequence analysis pipelines-GATK HaplotypeCaller, DeepTrio, and Velsera GRAF-and examined the assumption that a requirement of consensus can serve as an effective filter for high-quality DNVs. Comparison with a highly accurate DNV set, validated previously by manual inspection and Sanger sequencing, demonstrated that consensus filtering, followed by a force-calling procedure, effectively removed false-positive calls, achieving 98.0-99.4% precision. At the same time, sensitivity of the workflow based on the previously established DNVs reached 99.4%. Validation in the HG002-3-4 Genome-in-a-Bottle trio confirmed its robustness, with precision reaching 99.2% and sensitivity up to 96.6%. We believe that this consensus approach can be widely implemented as an automated bioinformatics workflow suitable for large-scale analyses without the need for manual intervention, especially when very high precision is valued over sensitivity.

Life Science AllianceVol. 8(6)
Brigham and Women's Hospital (US), Boston Children's Hospital (US), Howard Hughes Medical Institute (US), Harvard University (US), University of Utah (US), New York Proton Center (US), Child Health and Development Institute (US), Short and Associates (United States) (US), Columbia University (US), Icahn School of Medicine at Mount Sinai (US)
National Institutes of Health, National Center for Advancing Translational Sciences
Openalex Percentile: Top 92%
Genomics and Rare Diseases
DOIOpen Access PDFOpenAlex
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