Structural rearrangements

R. J. McKinlay Gardner, Grant R. Sutherland and Lisa G. Shaffer

in Chromosome Abnormalities and Genetic Counseling

Fourth edition

Published on behalf of Oxford University Press

Published in print November 2011 | ISBN: 9780195375336
Published online October 2012 | e-ISBN: 9780199975174 | DOI:

Series: Oxford Monographs on Medical Genetics

Structural rearrangements

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IN THIS CHAPTER we consider the circumstance of parents, themselves typically karyotypically normal, who have had a child in whom a structural chromosome rearrangement has been identified. Under this heading, we distinguish in particular deletions (partial monosomy) and duplications (partial trisomy). If the rearrangement occurs during meiosis, or at a postzygotic mitosis, we generally assume a recurrence risk no different from the general population. These cases arise anew—de novo—with the affected child. If, however, the rearrangement arises at a premeiotic mitosis, the parent would be a gonadal mosaic, and an increased risk for recurrence, for a second child with the same abnormality, could in theory apply. Usually, no prior distinction between these two possibilities can be made, although how often a rearrangement is observed (unique/nonrecurrent, or commonly seen/recurrent) may suggest the site of generation (see later). Here we consider those deletions and duplications in which cytogenetic or molecular cytogenetic techniques are important in demonstrating the defect, and which are generally thought of as being chromosomal conditions. In some, and more particularly those now coming to light through the microarray, there is a possibility that a parent might be a carrier, and so our focus is not exclusively on de novo defects.

Some of these deletions and duplications occur sufficiently frequently, and/or present a sufficiently distinctive phenotype, that they have acquired syndrome status. The classical route whereby a chromosomal syndrome came to be established followed the recognition of a group of patients with a very similar clinical picture, often with a characteristic dysmorphology: “phenotype-first.” Subsequent cytogenetic studies revealed the underlying chromosomal basis in common (in the case of Down syndrome, this took nearly a century). Nowadays, the typical approach is “genotype-first,” or “reverse dysmorphology” (Shaffer et al., 2007; van Ravenswaaij-Arts and Kleefstra, 2009). Subtle deletions and duplications may not present a distinctive enough phenotype that would allow the clinician to “call” a syndrome. But in the laboratory, recurrent rearrangements, whether seen in house, or in collaboration with other cytogenetic services, nationally or internationally, can be collected. It is then up to the clinicians to draw together the observations from the patients thus identified and to construct the core features of the new syndrome. This new approach of identifying the chromosomal abnormality first can reveal the natural clinical variation of the genomic rearrangements, which might never have been possible with the traditional phenotype-first approach.

Chapter.  23560 words.  Illustrated.

Subjects: Clinical Genetics

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