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Updated: May 5, 2026
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Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
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Determinants of DNA-sequence-based Diagnostic Yield in the CSER Consortium.
Yusuph Mavura1, David Crosslin2, Kathleen Ferar3
1Department of Biomedical Data Science, Stanford University, Palo Alto, CA.
Summary
Diagnostic yield from exome and genome sequencing varies. Patient factors like sex and indications influence results, but site practices also contribute to differences in diagnostic outcomes across clinical sequencing sites.
Area of Science:
- Genomic Medicine
- Clinical Genetics
- Bioinformatics
Background:
- Diagnostic yield of exome and genome sequencing shows significant variability in current literature.
- Factors contributing to this variation, including patient demographics and site-specific practices, are not fully understood.
Purpose of the Study:
- To quantify the impact of patient-level factors versus site-level practices on diagnostic yield in clinical sequencing.
- To analyze diagnostic outcomes across five U.S. clinical sequencing sites.
Main Methods:
- Cross-sectional analysis of 3,008 cases (prenatal, neonatal, pediatric) from the NHGRI CSER consortium.
- Utilized generalized linear mixed models to assess associations between diagnostic yield and patient/site factors.
- Inferred genetic ancestry and interpreted variants using ACMG/AMP guidelines.
Main Results:
- Overall diagnostic yield was 19.0%.
- Multiple clinical indications increased yield (OR=1.47), while male sex (OR=0.80) and prenatal status (OR=0.63) decreased it.
- Site-level variance in diagnostic yield decreased from ~10% to 5.7% after adjusting for covariates, indicating unexplained site-specific variation.
Conclusions:
- Patient clinical features impact diagnostic yield, but significant site-level variation persists.
- Differences in variant interpretation or case-classification practices may explain residual variability.
- Standardizing exome and genome sequencing workflows is crucial to reduce inter-site differences.
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