Bp

Distal rearrangement breakpoint

Deletions 15q11-q13

Duplications 15q11-q13

Figure 5.4 Segmental duplications and chromosomal rearrangements at 15q11-q13. Schematic representation showing major interchromosomal and intrachromosomal duplications associated with breakpoints (BP) and chromosomal rearrangements. Common deletions and duplications are shown. AS, Angelman syndrome; PWS, Prader-Willi syndrome. Adapted and reproduced from Locke et al. (2004), copyright 2004, with permission from BMJ Publishing Group Ltd.

chromosome 3q29 microdeletion syndrome (OMIM 609425) (Willatt et al. 2005), chromosome 9q34.3 deletion syndrome (OMIM 610253) (Harada et al. 2004; Stewart et al. 2004b), and chromosome 22q13.3 deletion syndrome (OMIM 606232) (Flint et al. 1995; Wong et al. 1997). Detection of subtelomeric genomic imbalance can be achieved by a number of different approaches, such as fluorescence in situ hybridization (FISH) and array CGH, the latter including focused subtelomeric arrays (Knight and Regan 2006).

Other genetic diseases may also arise due to chromosomal rearrangements in subtelomeric regions, notably involving a tandem repeat at 4q35 in the subtelomeric region of chromosome 4q. This was found to cause a specific autosomal dominant disorder, fascioscapulohumeral muscular dystrophy (OMIM 158900), a neuromuscular disorder characterized by an asymmetrical weakness of facial, shoulder, and upper arm muscles (Wijmenga et al. 1992). Affected patients were found to have only one to ten 3.3 kb repeat units compared with normal individuals

Box 5.8 Terminal deletion of chromosome 1p36 syndrome (OMIM 607872)

Deletion at the telomeric end of the short arm of chromosome 1 occurs in about one in 5000 of the population. Deletion of 1p36 results in a characteristic syndrome including specific physical characteristics, psychomotor retardation, fits, delayed growth, and mental retardation (Shapira et al. 1997). Overall the syndrome is thought to account for 0.5-1.2% of idiopathic mental retardation.

Box 5.9 Cri du chat syndrome (OMIM 123450)

This syndrome was first described by Lejeune in 1963 (Lejeune et al. 1963). The incidence of the syndrome is between one in 20 000 and one in 50 000 births (Niebuhr 1978). Affected newborn babies have a diagnostic high pitched, cat-like cry. Young children show characteristic facial features, speech delay, and mental retardation and die early in childhood. The syndrome arises due to terminal, or less commonly interstitial, deletions in the short arm of chromosome 5. These can range from very small (5p15.2) to the whole short arm of the chromosome. Most arise de novo, while about 12% arise from unbalanced segregation of translocations or recombination events. The critical region underlying the characteristic cry was mapped to 5p15.3 and other features of the syndrome to 5p15.2 (Overhauser et al. 1994). More recent work has implicated haploinsufficiency of a specific gene involved in telomerase activity (TERT, encoding tel-omerase reverse transcriptase) located at 5p15.33 (Zhang et al. 2003). Within the critical region, the SEMA5A gene encoding a semaphorin protein, and the catenin gene CTNND2, are linked with cortical development and may play a role in the mental retardation seen among patients with this syndrome (Cerruti Mainardi 2006). Use of array CGH has allowed high resolution mapping and is facilitating genotype-phenotype associations with specific regions (Fig. 5.5).

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