Chapter

The Origins and Consequences of Chromosome Pathology

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: http://dx.doi.org/10.1093/med/9780195375336.003.0003

Series: Oxford Monographs on Medical Genetics

The Origins and Consequences of Chromosome Pathology

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“WHAT WENT WRONG? And will it happen again?” These are the common questions from “chromosomal families” that bring people to the genetic clinic. We can recast these questions: “Did I, or one of us, produce an abnormal gamete? If so, why? What gamete might be produced next time? Or, if the chromosomes were normal at conception, what went wrong thereafter?” To deal intelligently with these questions, the counselor needs a broad knowledge of how gametes form, how chromosomes behave, and how the early conceptus grows. We consider the distinction between abnormality due to structural defect (full or segmental aneuploidy), the majority, and the small fraction due to functional defect (aberrant imprinting status). Most of the chromosome abnormalities in individuals that counselors see in the clinic will have arisen from errors during formation of the germ cells, and we focus particularly upon meiosis, the specialized cell division of gametogenesis. Chromosome defects can arise postzygotically, and abnormalities of mitotic cell division in the cleavage-stage embryo and in the embryo proper can produce chromosome mosaicism; we review the possible consequences of this. We refer in passing to the concept of dynamic mutation, but we leave its fuller discussion for the fragile X chapter (Chapter 15).

First, we look at etiology. We discuss three chromosomal settings within which genetic abnormality may arise, namely meiosis, mitosis, and genomic imprinting. Within each, we consider what types of abnormality may happen. In meiosis and mitosis, irregular segregation can produce aneuploidy for a whole chromosome, while asymmetric segregation of a structural rearrangement produces an incorrect amount of part of a chromosome (partial, or segmental aneuploidy). In genomic imprinting, the defect is qualitative, with abnormal expression of what can be a normal amount of chromosome. Sometimes there is overlap: for example, a meiotic error can subsequently lead to an abnormality of imprinting. Sometimes we cannot be sure which is the correct category: a supposed meiotic error, for example, could actually have arisen in a premeiotic mitosis. Nevertheless, this format is not too arbitrary, and it provides a useful framework within which the generality of chromosomal abnormality can be appreciated. Second, we consider pathogenesis: the process by which the underlying genetic defect then leads to phenotypic abnormality. Third, and with particular reference to the question of recurrence risk advice, we make some general comments about which categories of abnormality are likely to recur, or for which sporadic occurrence is the rule.

Chapter.  16748 words.  Illustrated.

Subjects: Clinical Genetics

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