Deciphering the pathogenic consequences of chromosomal aberrations in human genetic disease.

Wigard P Kloosterman,Ron Hochstenbach

doi:10.1186/s13039-014-0100-9

Abstract

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 materialThe online version of this article (doi:10.1186/s13039-014-0100-9) contains supplementary material, which is available to authorized users.

Highlights

Structural genomic variations (SVs) are generally regarded as genetic changes with a size larger than 50 bp [1]
Large copy number changes are strongly enriched among patients with idiopathic multiple congenital abnormalities and/or mental retardation (MCA/Mental retardation (MR)) phenotypes compared to normal individuals [7]
In diagnostics of idiopathic MCA/MR, karyotyping would add less than 1% of pathogenic cases to those detected by microarray, as shown by a survey of 36,325 consecutive MCA/MR cases [11]

Summary

Introduction

Structural genomic variations (SVs) are generally regarded as genetic changes with a size larger than 50 bp [1]. In spite of the clear association between large (de novo) CNVs and other SVs (collectively known as chromosomal aberrations) with MCA/MR phenotypes [9], precise characterization of molecular mechanisms that cause disease in individual patients is often unknown This is largely a result of the complex effects of breakpoints on gene structure, function and expression. These technological breakthroughs provide unique opportunities to engineer specific chromosomal rearrangements that occur in patients with MCA/MR Such an approach circumvents measurement noise resulting from differences in genetic background, which has, for example, hampered the detection of gene-expression changes in case–control studies for various microdeletion or microduplication syndromes [57,59,101,102]. These selected examples demonstrate that zebrafish appears a very powerful model system to systematically dissect the functional consequences of chromosomal aberrations

Conclusions

21. Webber C

Findings

90. Williams NM