The Role of Large Genome Structural Variants in Human Health and Disease

Large and rare genome structural variants, such as chromosomal aneuploidy and large copy number variants - also known as microdeletions and microduplications - range from several hundred kilobases to megabases. These variants often alter the dosage of many genes and are implicated in human birth defects and developmental disorders. It has been proposed that the extent of dosage sensitivity of affected gene(s) is a major determinant of the pathogenicity of large genome structural variants. While an altered dose of a single gene could be tolerated, the dose alteration of multiple adjacent genes could lead to a combination of subtle deleterious effects that affect the transcriptome and disturb the precisely regulated development of key organs such as the heart and brain. Furthermore, these large variants could affect genome organization and stability, contributing to human diseases. Functional studies of large structural variants will provide a better understanding of the consequences for such rare variants; for example, Xq28 duplication, X-chromosome aneuploidy (e.g. XO Turner syndrome, XXY Klinefelter syndrome) and trisomy 21 (Down syndrome). Promisingly, this opens new avenues for therapy that may compensate for dosage anomalies in critical developmental genes. However, such studies have been limited due to a lack of resources and appropriate systems including patient-specific cell types relevant to phenotypes, early developmental windows, and appropriate controls.

Thus, this special Research Topic collection will highlight the latest important advances in our understanding of the role of large genome structural variants in human health and diseases. We will accept Research and Review manuscript submissions presenting outstanding contributions, including (but not limited to) the areas of:
• Functional studies of the effect of large genome structural variants on gene regulation and development using in vitro and in vivo models (e.g. primary cell lines/tissues, induced pluripotent stem cells, organoids, transgenic animals)
• Methods development, e.g. methods for prediction or identification of large genome structural variants and the extent of pathogenicity
• Studies exploring the new treatment of pathogenic genome structural variants and clinical applications.