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Motivation: Detection of abnormal karyotypes from whole-exome sequencing has significant clinical potential, enabling a primary screen for chromosomal anomalies among samples undergoing short-read sequencing for nucleotide resolution genomic characterization. Results:We present KaryoScan, a high-throughput method for detecting chromosomal anomalies within large cohort exome sequencing studies. We detect and validate autosomal and sex chromosomal aneuploidies in a large exome sequencing cohort, and demonstrate detection of smaller and complex events (partial chromosome, mosaic, copy neutral, and complex rearrangements), representing the range of anomalies that can be uncovered from the exome.