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Validation of copy number variation analysis for next-generation sequencing diagnostics
Jamie M Ellingford1,2, Christopher Campbell1, Stephanie Barton1
1Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, St Mary's Hospital, Manchester, UK.
European Journal of Human Genetics : EJHG
|April 6, 2017
Summary
Copy number variants (CNVs) are a common cause of disease but often missed in genetic testing. ExomeDepth software accurately identifies CNVs from next-generation sequencing (NGS) data, improving diagnoses for Mendelian disorders.
Area of Science:
- Genetics
- Bioinformatics
- Clinical Diagnostics
Background:
- Copy number variants (CNVs) are a significant cause of genetic disorders.
- Routine identification of CNVs from next-generation sequencing (NGS) data in clinical settings remains challenging.
Purpose of the Study:
- To evaluate the sensitivity and specificity of ExomeDepth software for CNV detection in targeted NGS data.
- To establish quality assurance metrics for CNV surveillance using ExomeDepth.
- To assess the clinical utility of ExomeDepth for diagnosing Mendelian disorders.
Main Methods:
- Benchmarking ExomeDepth v1.1.6 against whole-genome sequencing data for 25 individuals.
- Simulating single- and multi-exon heterozygous deletion events (n=2749) to determine sensitivity.
- Applying ExomeDepth with quality assurance metrics to NGS data from 140 patients lacking molecular diagnoses.
Main Results:
- ExomeDepth demonstrated 100% sensitivity and 99.8% specificity for CNV detection when compared to whole-genome sequencing.
- Simulations indicated 97% sensitivity for detecting deletion events.
- Quality assurance metrics were defined, considering sequencing coverage and variability.
- ExomeDepth identified 17 causative CNVs in 140 patients with suspected Mendelian disorders.
Conclusions:
- ExomeDepth is a sensitive and specific tool for identifying CNVs from targeted NGS data.
- Defined quality assurance metrics are crucial for reliable CNV surveillance.
- Integrating ExomeDepth into routine diagnostic workflows significantly increases diagnostic yield for Mendelian disorders.