Integrated small copy number variations and epigenome maps of disorders of sex development

Small copy number variations (CNVs) have typically not been analyzed or reported in clinical settings and hence have remained underrepresented in databases and the literature. Here, we focused our investigations on these small CNVs using chromosome microarray analysis (CMA) data previously obtained from patients with atypical characteristics or disorders of sex development (DSD). Using our customized CMA track targeting 334 genes involved in the development of urogenital and reproductive structures and a less stringent analysis filter, we uncovered small genes with recurrent and overlapping CNVs as small as 1 kb, and small regions of homozygosity (ROHs), imprinting and position effects. Detailed analysis of these high-resolution data revealed CNVs and ROHs involving structural and functional domains, repeat elements, active transcription sites and regulatory regions. Integration of these genomic data with DNA methylation, histone modification and predicted RNA expression profiles in normal testes and ovaries suggested spatiotemporal and tissue-specific gene regulation. This study emphasized a DSD-specific and gene-targeted CMA approach that uncovered previously unanalyzed or unreported small genes and CNVs, contributing to the growing resources on small CNVs and facilitating the narrowing of the genomic gap for identifying candidate genes or regions. This high-resolution analysis tool could improve the diagnostic utility of CMA, not only in patients with DSD but also in other clinical populations. These integrated data provided a better genomic-epigenomic landscape of DSD and greater opportunities for downstream research. Using a genome-wide analysis technique, researchers have identified genetic differences linked to disorders of sex development (DSD). DSD encompasses a wide-ranging group of rare conditions, the underlying genetic causes of most of which are poorly understood. Ina Amarillo and co-workers at Washington University in St. Louis DSD Team examined previously collected data generated by chromosome microarray analysis focusing on those unanalyzed and unreported small chromosomal deletions or duplications (“small copy number variations or CNVs”) detected in 334 genes associated with sex development. Many of the DSD-associated small CNVs were found to alter some of these genes or regulatory regions, providing a high-resolution analytical data for illuminating the genomic and epigenomic landscape of DSD. This approach will improve our understanding of DSD and other disorders, and facilitate further research on their biological causes.