Emerging themes and new challenges in defining the role of structural variation in human disease

Abstract

The widespread use of array-comparative genomic hybridization (array-CGH) for the detection of copy number variants (CNVs) in both research and clinical laboratories has created a renaissance in the field of molecular cytogenetics, revealing that the human genome contains both a wealth of structural polymorphism and many novel genomic disorders. A new generation of experimental platforms enable structural variants to be identified with increasing resolution, and will require the development of more sophisticated methods to assess the pathogenic significance of novel structural variants if these technologies are to be of clinical utility. Indeed, we are now entering an era in which technologies to detect CNVs have advanced much faster than our understanding of the consequences of these variants on human phenotypes, and I argue that over the last few years the problem has now become one of interpretation rather than identification. This problem is made more complex by the realization that many genomic disorders show highly variable penetrance, blurring the boundary of how to define benign vs. pathogenic variants. I discuss insights from recent research which shed light on potential mechanisms that may underlie this phenomenon, and possible methods to determine the genetic elements that are responsible for the associated phenotype. Furthermore, there is now a growing appreciation that the underlying chromosomal architecture which catalyses many genomic disorders is polymorphic within the general population, and I discuss potential mechanisms by which inversion polymorphisms might create predispositions to genomic disorders.