Deciphering the pathogenic consequences of chromosomal aberrations in human genetic disease

Chromosomal aberrations include translocations, deletions, duplications, inversions, aneuploidies and complex rearrangements. They underlie genetic disease in roughly 15% of patients with multiple congenital abnormalities and/or mental retardation (MCA/MR). In genetic diagnostics, the pathogenicity of chromosomal aberrations in these patients is typically assessed based on criteria such as phenotypic similarity to other patients with the same or overlapping aberration, absence in healthy individuals, de novo occurrence, and protein coding gene content. However, a thorough understanding of the molecular mechanisms that lead to MCA/MR as a result of chromosome aberrations is often lacking. Chromosome aberrations can affect one or more genes in a complex manner, such as by changing the regulation of gene expression, by disrupting exons, and by creating fusion genes. The precise delineation of breakpoints by whole-genome sequencing enables the construction of local genomic architecture and facilitates the prediction of the molecular determinants of the patient’s phenotype. Here, we review current methods for breakpoint identification and their impact on the interpretation of chromosome aberrations in patients with MCA/MR. In addition, we discuss opportunities to dissect disease mechanisms based on large-scale genomic technologies and studies in model organisms. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13039-014-0100-9) contains supplementary material, which is available to authorized users.