Whole exome sequencing reveals copy number variants in individuals with disorders of sex development

Complete androgen insensitivity syndrome (CAIS), where 46,XY individuals present as female, is caused by variants in the androgen receptor gene (AR). We analyzed the DNA of a patient with suspected CAIS using a targeted gene sequencing panel and whole exome sequencing (WES) but did not detect any small nucleotide variants in AR. Analysis of WES data using our bioinformatics pipeline designed to detect copy number variations (CNV) uncovered a rare duplication of exon 2 of AR. Using array comparative genomic hybridization, the duplication was found to span 43.6 kb and is predicted to cause a frameshift and loss of AR protein. We confirmed the power of our WES-CNV detection protocol by identifying pathogenic CNVs in FSHR and NR5A1 in previously undiagnosed patients with disorders of sex development. Our findings illustrate the usefulness of CNV analysis in WES data to detect pathogenic genomic changes that may go undetected using only standard analysis protocols.