A robust approach for blind detection of balanced chromosomal rearrangements with whole-genome low-coverage sequencing.

Balanced chromosomal rearrangement (or bal- anced chromosome abnormality, BCA) is a common chromo- somal structural variation. Next-generation sequencing has been reported to detect BCA-associated breakpoints with the aid of karyotyping. However, the complications associated with this approach and the requirement for cytogenetics in- formation has limited its application. Here, we provide a whole-genome low-coverage sequencing approach to detect BCA events independent of knowing the affected regions and with low false positives. First, six samples containing BCAs were used to establish a detection protocol and assess the efficacy of different library construction approaches. By clus- tering anomalous read pairs and filtering out the false-positive results with a control cohort and the concomitant mapping in- formation, we could directly detect BCA events for each sam- ple. Through optimizing the read depth, BCAs in all samples could be blindly detected with only 120 million read pairs per sample for data from a small-insert library and 30 million per sample for data from nonsize-selected mate-pair library. This approach was further validated using another 13 samples that contained BCAs. Our approach advances the application of high-throughput whole-genome low-coverage analysis for ro- bustBCAdetection—especiallyforclinicalsamples—without the need for karyotyping. Hum Mutat 35:625-636, 2014. C