Detection and characterization of copy-number variants from exome sequencing in the DDD study.

PURPOSE

Structural variants such as multiexon deletions and duplications are an important cause of disease but are often overlooked in standard exome/genome sequencing analysis. We aimed to evaluate the detection of copy-number variants (CNVs) from exome sequencing (ES) in comparison with genome-wide low-resolution and exon-resolution chromosomal microarrays (CMAs) and to characterize the properties of de novo CNVs in a large clinical cohort.

METHODS

We performed CNV detection using ES of 9859 parent-offspring trios in the Deciphering Developmental Disorders (DDD) study and compared them with CNVs detected from exon-resolution array comparative genomic hybridization in 5197 probands from the DDD study.

RESULTS

Integrating calls from multiple ES-based CNV algorithms using random forest machine learning generated a higher quality data set than using individual algorithms. Both ES- and array comparative genomic hybridization-based approaches had the same sensitivity of 89% and detected the same number of unique pathogenic CNVs not called by the other approach. Of DDD probands prescreened with low-resolution CMAs, 2.6% had a pathogenic CNV detected by higher-resolution assays. De novo CNVs were strongly enriched in known DD-associated genes and exhibited no bias in parental age or sex.

CONCLUSION

ES-based CNV calling has higher sensitivity than low-resolution CMAs currently in clinical use and comparable sensitivity to exon-resolution CMA. With sufficient investment in bioinformatic analysis, exome-based CNV detection could replace low-resolution CMA for detecting pathogenic CNVs.