Ypr

Chromosome 15

Stable Robertsonian translocation

Lost

Figure 3.5 Reciprocal (A) and Robertsonian (B) translocations. Schematic representation of the processes involved in the two major classes of translocation. Redrawn and adapted with permission from Strachan and Read (2004).

Stable Robertsonian translocation

Lost

Figure 3.5 Reciprocal (A) and Robertsonian (B) translocations. Schematic representation of the processes involved in the two major classes of translocation. Redrawn and adapted with permission from Strachan and Read (2004).

Gametes

Chromosome 1

Chromosome 9

Fertilization by normal gamete

Zygotes

Normal

Balanced carrier

Partial trisomy chromosome 1

Partial monosomy chromosome 9

Partial monosomy chromosome 1

Partial trisomy chromosome 9

Figure 3.6 Meiosis in a carrier of a balanced reciprocal translocation. Partial monosomy or partial trisomy may result from unbalanced gametes of a carrier of a balanced reciprocal translocation. Redrawn and adapted with permission from Strachan and Read (2004).

Box 3.6 Palindromic AT-rich repeats and recurrent reciprocal translocation

The most common recurrent reciprocal translocation found in man involves breakpoints on chromosomes 11q23 and 22q11. This translocation is denoted t(11;22)(q23;q11) and has been reported in more than 160 unrelated families. The propensity for such recurrent events was resolved to specific PATRR sequences found at the chromosomal breakpoints resulting in unstable secondary structures (Edelmann et al. 2001; Kurahashi and Emanuel 2001; Kurahashi et al. 2004, 2007). PATRRs associated with translocation comprise several hundred bases of DNA of a near perfect palindrome (sequence reading the same in either direction) with an AT-rich centre and another flanking AT-rich region; they can self pair leading to hairpin or cruciform structures which are unstable and hotspots for recombination. Among healthy individuals, the size of the PATRR at 11q23 varies significantly and was an important determinant of rates of de novo translocations in sperm (Kato et al. 2006). The risk for balanced carriers of the t(11;22)(q23;q11) translocation is of the supernumerary der(22)t(11;22) syndrome or Emanuel syndrome (OMIM 609029) (Zackai and Emanuel 1980) occurring in their children due to a 3 : 1 meiotic non-disjunction event (Shaikh et al. 1999). The risk of such an unbalanced event occurring is highest for female heterozygotes (estimated at 10% risk). Affected individuals show a characteristic syndrome of mental retardation, craniofacial abnormalities, and congenital heart defects. Chromosome 22q11 is a region prone to non-allelic homologous recombination and recurrent genomic rearrangements (reviewed in Section 5.2.2).

Box 3.? Duchenne muscular dystrophy (OMIM 310200)

This devastating neuromuscular disorder affects one in 3300 male live births with a progressive muscular dystrophy. The mean age at diagnosis is between 4 and 6 years, the ability to walk is generally lost at 8-10 years of age, with death in the late teens or early twenties through respiratory and cardiac failure (Biggar et al. 2002). Skeletal and cardiac muscle is affected with defective membrane stability; necrosis and regeneration of muscle fibres is seen (Deconinck and Dan 2007). About

30% of cases arise due to spontaneous mutations, the remainder show X-linked recessive inheritance. Affected individuals lack dystrophin, in about 70% of cases due to deletions of one or multiple exons of the dystrophin (DMD) gene at Xp21; about 20% are due to small deletions, insertions, or point mutations (Hoffman et al. 1987; Koenig et al. 1987; Davies et al. 1988; Aartsma-Rus et al. 2006). DMD is a remarkably large gene spanning 2.3 Mb with 79 exons and at least seven promoters.

(rDNA) for 13p and 21p (Page et al. 1996; Bandyopadhyay et al. 2002). It may be that the particular sequence or genomic architecture in these regions predisposes to this, with translocations then resulting from meiotic mispair-ing between two non-homologous chromosomes and recombination involving specific highly homologous sequences found on the short arms (Bandyopadhyay et al. 2002). Such events occur predominantly during oogenesis; overall 93% of Robertsonian translocations are maternal in origin (Bandyopadhyay et al. 2002).

3.5 Chromosomal rearrangements

3.5.1 Large scale structural variation resulting from intrachromosomal rearrangements

Within a single chromosome, or homologous pair of chromosomes, a number of cytogenetically visible variants have been identified. These may be classified into interstitial and terminal deletions, interstitial and terminal duplications, marker chromosomes, inversions, and isochromosomes (Fig. 3.8) (Shaffer and Lupski 2000). A deletion or duplication is considered interstitial if there is exchange within a chromosomal arm, and the original telomere is retained. Interstitial deletions and duplications are thought to occur in at least one in 4000 of the

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