The Principles of Clinical Cytogenetics - Extra Materials - Springer

Structural Chromosome Rearrangements 165
INTRODUCTION
Structural Chromosome Rearrangements
Kathleen Kaiser-Rogers, PhD and Kathleen Rao, PhD
The subject of structural chromosome rearrangements is an immense one, to which entire catalogs
have been devoted. Indeed, there are theoretically an almost infinite number of ways in which chromosomes
can reconfigure themselves from the normal 23-pair arrangement with which we are familiar.
Although we tend to think of the resulting structural rearrangements in terms of chromosome
pathology, some rearrangements are fairly innocuous. In fact, a few such benign rearrangements
(such as certain pericentric inversions of chromosome 9) are seen frequently enough to be considered
polymorphic variants of no clinical significance.
In this chapter, we will discuss and provide examples of the ways in which chromosome rearrangements
can occur. We begin with an overview of general concepts that relate to all structural
rearrangements and their association with human pathology. Each category of structural rearrangement
is then dealt with as a unique entity in the second half of the chapter.
Mechanism of Formation
The exchange of genetic material between sister chromatids and homologous chromosomes is a
normal occurrence in somatic and germ cells. These types of exchange ensure mixing of the gene
pool and appear to be obligatory for normal cell division. It is only when exchanges occur between
nonallelic chromosomal regions that structural rearrangements result. Because chromosome breakage
can theoretically occur anywhere within the human genome and the involved chromosome(s) can
recombine in innumerable ways, the number of potential rearrangements that can result is immense.
In practice, however, there appear to be particular areas of the genome that are more susceptible to
breakage and rearrangement than others. The presence of a DNA sequence that is repeated elsewhere
in the genome, a fragile site (see Chapter 14) and/or a particular secondary DNA structure all appear
to influence the likelihood that a particular chromosome region is involved in a structural rearrangement
(1–6).
Numerous studies have shown that many rearrangements occur secondary to recombination
between nonallelic regions of homology. These regions of homology sometimes represent high-copynumber
repeats such as Alu or satellite DNA sequences. Recently, the role of low-copy repeats (LCRs)
in the formation of structural rearrangements has begun to be elucidated. There are now many
examples in the literature of recurring duplications, deletions, inversions, translocations, isochromosomes,
and marker chromosomes that form secondary to LCR-mediated nonallelic homologous recombination.
The LCRs that serve as substrates for these recombination events range in size from 1
to 500 kilobasepairs (kb) and share > 97% sequence identity. Although distributed throughout the
genome, LCRs might appear preferentially within pericentromeric chromosomal regions. The ultimate
size and types of rearrangement that result from these nonallelic homologous recombination
From: The Principles of Clinical Cytogenetics, Second Edition
Edited by: S. L. Gersen and M. B. Keagle © Humana Press Inc., Totowa, NJ
165
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