Figure 5-8 Incidence of chromosome abnormalities in newborn surveys, based on chromosome analysis of over 68,000 newborns. See Sources & Acknowledgments.

Chromosome abnormalities are described by a standard set of abbreviations and nomenclature that indicate the nature of the abnormality and (in the case of analyses performed by FISH or microarrays) the technology used. Some of the more common abbreviations and examples of abnormal karyotypes and abnormalities are listed in Table 5-1.


Some Abbreviations Used for Description of Chromosomes and Their Abnormalities, with Representative Examples


Abbreviations from Shaffer LG, McGowan-Jordan J, Schmid M, editors: ISCN 2013: an international system for human cytogenetic nomenclature, Basel, 2013, Karger.

Gene Dosage, Balance and Imbalance

The central concept for thinking about chromosome and genomic disorders is that of gene dosage and its balance or imbalance. As we shall see in later chapters, this same concept applies generally to considering some single-gene disorders and their underlying mutational basis (see Chapters 7, 11, and 12); however, it takes on uniform importance for chromosome abnormalities, where we are generally more concerned with the dosage of genes within the relevant chromosomal region than with the actual normal or abnormal sequence of those genes. Here, the sequence of the genes is typically quite unremarkable and would not lead to any clinical condition except for the fact that their dosage is incorrect.

Most genes in the human genome are present in two doses and are expressed from both copies. Some genes, however, are expressed from only a single copy (e.g., imprinted genes and X-linked genes subject to X inactivation; see Chapter 3). Extensive analysis of clinical cases has demonstrated that the relative dosage of these genes is critical for normal development. One or three doses instead of two is generally not conducive to normal function for a gene or set of genes that are typically expressed from two copies. Similarly, abnormalities of genomic imprinting or X inactivation that cause the anomalous expression of two copies of a gene or set of genes instead of one invariably lead to clinical disorders.

Predicting clinical outcomes for chromosomal and genomic disorders can be an enormous challenge for genetic counseling, particularly in the prenatal setting. Many such diagnostic dilemmas will be presented throughout this section and in Chapters 6 and 17, but there are a number of general principles that should be kept in mind as we explore specific types of chromosome abnormality in the sections that follow (see Box).


Unbalanced Karyotypes and Genomes in Liveborns

General Guidelines for Counseling

Monosomies are more deleterious than trisomies. Complete monosomies are generally not viable, except for monosomy for the X chromosome. Complete trisomies are viable for chromosomes 13, 18, 21, X, and Y.

The phenotype in partial aneuploidy depends on a number of factors, including the size of the unbalanced segment, which regions of the genome are affected and which genes are involved, and whether the imbalance is monosomic or trisomic.

Risk in cases of inversions depends on the location of the inversion with respect to the centromere and on the size of the inverted segment. For inversions that do not involve the centromere (paracentric inversions), there is a very low risk for an abnormal phenotype in the next generation. But, for inversions that do involve the centromere (pericentric inversions), the risk for birth defects in offspring may be significant and increases with the size of the inverted segment.

For a mosaic karyotype involving any chromosome abnormality, all bets are off! Counseling is particularly challenging because the degree of mosaicism in relevant tissues or relevant stages of development is generally unknown. Thus there is uncertainty about the severity of the phenotype.

Abnormalities of Chromosome Number

Triploidy and Tetraploidy


Trisomy can exist for any part of the genome, but trisomy for a whole chromosome is only occasionally compatible with life. By far the most common type of trisomy in liveborn infants is trisomy 21, the chromosome constitution seen in 95% of patients with Down syndrome (karyotype 47,XX,+21 or 47,XY,+21) (Fig. 5-9). Other trisomies observed in liveborns include trisomy 18 and trisomy 13. It is notable that these autosomes (13, 18, and 21) are the three with the lowest number of genes located on them (see Fig. 2-7); presumably, trisomy for autosomes with a greater number of genes is lethal in most instances. Monosomy for an entire chromosome is almost always lethal; an important exception is monosomy for the X chromosome, as seen in Turner syndrome (Case 47). These conditions are considered in greater detail in Chapter 6.


Figure 5-9 Chromosomal and genomic approaches to the diagnosis of trisomy 21. A, Karyotype from a male patient with Down syndrome, showing three copies of chromosome 21. B, Interphase fluorescence in situ hybridization analysis using locus-specific probes from chromosome 21 (red, three spots) and from a control autosome (green, two spots). C, Detection of trisomy 21 in a female patient by whole-genome chromosomal microarray. Increase in the fluorescence ratio for sequences from chromosome 21 are indicated by the red arrow. D, Detection of trisomy 21 by whole-genome sequencing and overrepresentation of sequences from chromosome 21. Normalized sequence representation for individual chromosomes (± SD) in chromosomally normal samples is indicated by the gray shaded region. A normalized ratio of approximately 1.5 indicates three copies of chromosome 21 sequences instead of two, consistent with trisomy 21. See Sources & Acknowledgments.

Although the causes of aneuploidy are not fully understood, the most common chromosomal mechanism is meiotic nondisjunction. This refers to the failure of a pair of chromosomes to disjoin properly during one of the two meiotic divisions, usually during meiosis I. The genomic consequences of nondisjunction during meiosis I and meiosis II are different (Fig. 5-10). If the error occurs during meiosis I, the gamete with 24 chromosomes contains both the paternal and the maternal members of the pair. If it occurs during meiosis II, the gamete with the extra chromosome contains both copies of either the paternal or the maternal chromosome. (Strictly speaking, these statements refer only to the paternal or maternal centromere, because recombination between homologous chromosomes has usually taken place in the preceding meiosis I, resulting in some genetic differences between the chromatids and thus between the corresponding daughter chromosomes; see Chapter 2.)


Figure 5-10 The different consequences of nondisjunction at meiosis I (center) and meiosis II (right), compared with normal disjunction (left). If the error occurs at meiosis I, the gametes either contain a representative of both members of the chromosome 21 pair or lack a chromosome 21 altogether. If nondisjunction occurs at meiosis II, the abnormal gametes contain two copies of one parental chromosome 21 (and no copy of the other) or lack a chromosome 21.

Proper disjunction of a pair of homologous chromosomes in meiosis I appears relatively straightforward (see Fig. 5-10). In reality, however, it involves a feat of complex engineering that requires precise temporal and spatial control over alignment of the two homologues, their tight connections to each other (synapsis), their interactions with the meiotic spindle, and, finally, their release and subsequent movement to opposite poles and to different daughter cells. The propensity of a chromosome pair to nondisjoin has been strongly associated with aberrations in the frequency or placement, or both, of recombination events in meiosis I, which are critical for maintaining proper synapsis. A chromosome pair with too few (or even no) recombinations, or with recombination too close to the centromere or telomere, may be more susceptible to nondisjunction than a chromosome pair with a more typical number and distribution of recombination events.

In some cases, aneuploidy can also result from premature separation of sister chromatids in meiosis I instead of meiosis II. If this happens, the separated chromatids may by chance segregate to the oocyte or to the polar body, leading to an unbalanced gamete.

Nondisjunction can also occur in a mitotic division after formation of the zygote. If this happens at an early cleavage division, clinically significant mosaicism may result (see later section). In some malignant cell lines and some cell cultures, mitotic nondisjunction can lead to highly abnormal karyotypes.

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Nov 27, 2016 | Posted by in GENERAL & FAMILY MEDICINE | Comments Off on Abnormalities

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