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Figure 3.4 Trisomy 21. (A) Three copies of chromosome 21 are seen on a G-banded karyotype of a female with trisomy 21. (B) Schematic representation of results of fluorescent in situ hybridization (FISH) for interphase nuclei from a fetus with trisomy 21 using probes specific for the 13q14 and 21q22.13-q22.2 chromosomal regions. Redrawn and reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Genetics (Antonarakis et al. 2004), copyright 2004.

Figure 3.4 Trisomy 21. (A) Three copies of chromosome 21 are seen on a G-banded karyotype of a female with trisomy 21. (B) Schematic representation of results of fluorescent in situ hybridization (FISH) for interphase nuclei from a fetus with trisomy 21 using probes specific for the 13q14 and 21q22.13-q22.2 chromosomal regions. Redrawn and reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Genetics (Antonarakis et al. 2004), copyright 2004.

Box 3.4 Klinefelter syndrome and sex chromosome aneuploidy

Klinefelter syndrome (47,XXY) is the most common disorder affecting the sex chromosomes described in humans and occurs in one of every 500 male births. In 1942 Harry Klinefelter described a series of nine men with testicular abnormalities who failed to produce sperm and had enlargement of the breast (Klinefelter et al. 1942). This was found in 1959 to be the result of having an extra copy of the X chromosome (Jacobs and Strong 1959). Most affected individuals are infertile and have some reduction in speech and language ability. Other karyotypes have more recently been identified including 4 8, XX Y Y (one in 17 000 live male births) and 48,XXXY (one in 50 000) (Visootsak and Graham 2006). A translocation of Y material, which includes the key sex determining region, to the X chromosome during paternal meiosis means that the rarely occurring 46,XX males have normal male sexual development (Ferguson-Smith 1966).

stature in Turner syndrome (Rao et al. 1997). SHOK was identified by positional cloning (Box 2.5) among individuals with short stature and sex chromosome abnormalities. It is found in the pseudoautosomal region at the tips of the short arm of chromosomes X and Y, a region of sequence identity within which recombination and genetic exchange between sex chromosomes is restricted. Genes in this region are expressed in diploid dosage in males and females, making it a candidate region for genes underlying the Turner syndrome phenotype. Interestingly, while haploinsufficiency is associated with short stature, gene overdose seen in sex chromosome polyploidy is associated with tall stature (Ogata et al. 2001).

3.4 Translocations

Chromosomal breakage and rearrangement may result in a translocation event in which there is transfer of chromosomal regions between non-homologous chromosomes. This may be constitutional, involving for example recombination between mispaired chromosomes in the meiotic steps of gamete formation; or be acquired and arise in somatic cells secondary to exogenous or endogenous agents causing double-stranded DNA breaks. Such agents include ionizing radiation, oxygen free radicals, and enzymes of DNA metabolism. Somatic cell translocations may result in cancer through upregulation of proto-oncogenes or downregulation of tumour suppressor genes.

Constitutional translocations may be classified into reciprocal translocations, occurring between any two non-homologous chromosomes, or Robertsonian translocations, which are specific to whole arm exchanges between a subset of chromosomes distinguished by having as their normal state tiny short arms (chromosomes 13, 14, 15, 21, and 22) (Shaffer and Lupski 2000; Strachan and Read 2004) (Fig. 3.5). There may be a net loss or gain of genetic material making the translocation unbalanced, or there may be no overall loss or gain making a balanced translocation. Carriers of balanced translocations typically have no adverse effects except relating to reproduction where infertility, recurrent spontaneous abortion, and risk of chromosomal imbalance among offspring occur.

3.4.1 Reciprocal translocations

Reciprocal translocations are common, being present in about one in 625 people in the general population (Van Dyke et al. 1983), and may result from single breaks in any two non-homologous chromosomes. While the exchange of two acentric fragments leads to a stable reciprocal translocation, exchange of centric and acentric fragments leads to chromosomes with two or no centromeres which are lost (Fig. 3.5A). For those carrying a balanced reciprocal translocation, there are usually no phenotypic consequences for the individual but it may lead to reproductive problems for their offspring. After fertilization with a normal gamete, a normal baby,

Box 3.5 Turner syndrome

The characteristic clinical features were first described by Henry Turner in 1938 as a syndrome of infantilism, congenital webbed neck, and a deformity of the elbow (cubitus valgus) (Turner 1938). In 1959 Ford and colleagues described a female patient with Turner syndrome in which there was sex chromosome monosomy, in other words only one copy of the X chromosome (Ford et al. 1959).

Turner syndrome is the phenotype associated with the absence of all or part of one X chromosome. Like Down syndrome, it is a complex and variable pheno-type which includes short stature, ovarian failure, specific neurocognitive deficits, and anatomical abnormalities. The syndrome is found on average in one out of every 2500-3000 live female births.

a balanced carrier, or partial trisomies and monosomies may result (Fig. 3.6).

Translocation events involve the egg, sperm, or very early embryo and are almost always spontaneous, 'private' non-recurring rearrangements found only in a particular individual or family. Palindromic AT-rich repeat (PATRR) sequences are often found at breakpoints in translocations, including a recurrent reciprocal translocation involving chromosomes 11q23 and 22q11 (Box 3.6) (Inagaki et al. 2008). Elsewhere homologous clusters of olfactory receptor genes have been found on chromosomes 4p16 and 8p23 to contain breakpoints leading to t(4;8)(p16;p23) translocations, predisposed by mothers of cases having inversion polymorphisms in both the 4p and 8p regions (Section 5.5.1) (Giglio et al. 2002).

Rarely, reciprocal translocations can result in disease. For example, recurrent de novo reciprocal translocations have been reported involving the short arm of the X chromosome and a variety of different autosomes (including chromosomes 1, 3, 5, 6, 9, 11, 21) which result in the X-linked recessive disease Duchenne muscular dystrophy (Box 3.7) occurring in females where the normal X chromosome is inactivated, for example t(X;5)(p21.2;q31.2) (Greenstein et al. 1977; Nevin et al. 1986). This unusual scenario was seen to always involve the Xp21 region of the X chromosome and helped to define the likely site of the gene involved in causing the disease. A translocation involving chromosome 21, for example, allowed an elegant study in which probes could be designed based on the known ribosomal gene sequence found in the region of the translocation on chromosome 21 to clone the region spanning the breakpoint on the X chromosome (Ray et al. 1985).

3.4.2 Robertsonian translocations

Robertsonian translocations are the most common recurrent chromosomal rearrangement found in humans, occurring in about one in 1000 of the general population (Hamerton et al. 1975), and are restricted to chromosomes 13, 14, 15, 21, and 22. These 'acrocentric' chromosomes have very small short arms which comprise repeats of satellite DNA (very large arrays of tandemly repeated noncoding DNA) (Section 7.2) and ribosomal RNA genes (Page et al. 1996). In a Robertsonian translocation, breaks in the short arms near to the centromere leads to fusion of the remaining two long arms (Fig. 3.5B). This typically involves two different acrocentric chromosomes, or very rarely the same numbered chromosome, with one or both centromeres. As they are very close together, the two centromeres are functionally one, and the chromosome can segregate normally. There is a net loss of genetic material as the acentric fragment from the two short arms is lost, however this has little phenotypic effect and therefore it is regarded as a balanced translocation. The consequences of being a carrier of a balanced Robertsonian translocation can, however, be severe for future reproduction with the possibility, after fertilization with a normal gamete, of trisomy or monosomy of the chromosomes involved in the translocation (Fig. 3.7).

Approximately 85% of all Robertsonian translocations involve whole arm exchanges between chromosomes 13 and 14, or 14 and 21, which are denoted as rob(13q14q) and rob(14q21q) (Therman et al. 1989). For these translocations there is evidence that breakpoints recur in specific regions: between specific satellite DNA repeats for 14p, and between a satellite DNA and ribosomal DNA

(A) Reciprocal translocation

Chromosome 1

Chromosome 9

Chromosome 9

Stable reciprocal translocation

Acentric chromosome

Not stable in meiosis

Dicentric chromosome

(B) Robertsonian translocation %

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