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The Charcot-Marie-Toothtype 1A (CMT1 A) duplication was the first recurrent, large (>1 Mb), submicroscopic DNA duplication rearrangement found to be associated with a common auto-somal dominant trait. Mechanistic studies of the CMT1A duplication have set the paradigm for genomic disorders. The CMT1A-REP low-copy repeats (LCRs) were among the first identified nongenic genomic architectural features that could act as substrates for nonallelic homologous recombination (NAHR). Identification of the predicted reciprocal recombination product, the hereditary neuropathy with liability to pressure palsies (HNPP) deletion, resulted in a model for reciprocal duplication/deletion genomic disorders.

An approx 4-Mb genomic segment on chromosome 17p1 1.2 commonly deleted in 70-80% of patients with the Smith-Magenis syndrome (SMS) is flanked by large, complex, highly identical (approx 98.7%), and directly oriented, proximal (approx 256 kb) and distal (approx 176 kb) low-copy repeats (LCRs), termed SMS-REPs. These LCR copies mediate nonallelic homologous recombination (NAHR), resulting in both SMS deletion and the reciprocal duplication dup(17)(p1 1.2p1 1.2). A third copy, the middle SMS-REP (approx 241 kb) is inverted and located between them. Several additional large LCR17ps have been identified fomented by breakpoint mapping in patients with deletions ascertained because of an SMS phenotype. LCRs in proximal 17p constitute more than 23% of the analyzed genome sequence, approx fourfold higher than predictions based on virtual analysis of the entire human genome. LCRs appear to play a significant role not only in common recurrent deletions and duplications, but also in other rearrangements including unusual sized (i.e., uncommon, recurrent and nonrecurrent) chromosomal deletions, reciprocal translocations, and marker chromosomes. DNA sequence analysis from both common and unusual sized recurrent SMS deletions and common dup(17)(p1 1.2p1 1.2) reveals ′recombination hotspots′ or a remarkable positional preference for strand exchange in NAHR events. Large palindromic LCRs, mapping between proximal and middle SMS-REPs, are responsible for the origin of a recurrent somatic isochromosome i(17q), one of the most common recurrent structural abnormalities observed in human neoplasms, suggesting genome architecture may play arole in mitotic as well as meiotic rearrangements. LCRs in proximal 17p are also prominent features in the genome evolution of this region whereby several serial segmental duplications have played an important role in chromosome evolution accompanying primate speciation.

Meiotic unequal crossover events between blocks of low-copy repeats (LCRs) may lead to gene dosage imbalance resulting in genomic disorders. Genomic disorders are frequently associated with mental retardation or learning disabilities and mild to severe congenital anomalies. Chromosome 22q11.2 is particularly susceptible to chromosome rearrangements leading to several genomic disorders including velocardiofacial syndrome/DiGeorge syndrome (VCFS/DGS), der(22) syndrome, and cat-eye syndrome (CES), associated with a monosomy, trisomy, and tetrasomy of 22q11.2, respectively. Most VCFS/DGS patients have a similar hemizygous 3-Mb deletion mediated by meiotic interchromosomal homologous recombination events between LCRs termed LCR22s. The reciprocal duplication of the same interval, predicted on expected products of unequal crossover events, results in a more mild condition termed dup(22)(q11.2; q11.2) syndrome. In contrast to VCFS/DGS, dup(22)(q11.2; q11.2) and CES, der(22) syndrome is caused by a different molecular mechanism. Der(22) disorder arises in offspring of normal carriers of the constitutional t(1 1 ;22) (q23.3; q1 1.2) translocation by recombination between AT-rich (high AT sequence composition) palindromic sequences on 1 1q23.3 and 22q1 1.2. The palindromic sequence on 22q1 1.2 is within one of the LCR22s. Interestingly, both recurrent and novel breakpoints occur most often in LCR22s, making them an important architectural feature associated with susceptibility to genome rearrangements. To gain further insight into the mechanisms of how the LCR22s are involved in chromosome rearrangements, efforts are underway to determine the molecular evolution, structure, size, orientation, and their level of variability in humans.

Among genomic disorders, submicroscopic deletions underlying neurofibromatosis 1 (NF1) are unusual because they involve the deletion of a tumor suppressor gene (NF1), they show a different preference for low-copy repeats (LCR) as substrates for meiotic vs mitotic recombination events, and they account for only a small fraction of mutations that cause the disorder. The NF1 gene at chromosome 17q1 1.2 is flanked by two sets of LCRs in direct orientation that undergo paralogous recombination. A pair of NF1-REPs mediate the recurrent constitutional 1.4-Mb microdeletion that occurs preferentially during maternal meiosis, whereas a pair of JJAZ1 pseudogene and functional gene mediate the recurrent 1.2-Mb microdeletion that occurs preferentially during postzygotic mitosis in females. Breakpoints have been mapped at the nucleotide level for both deletions and sequence features that may contribute to the choice of discrete sites for strand exchange have been identified. NF1 -REP-mediated NF1 microdeletions involve 13 additional genes, whereas JJAZ1 -mediated microdeletions involve the same genes but one. NF1 microdeletions are of great interest because they predispose to a heavy tumor burden, malignancy, and possibly other severe manifestations.

Williams-Beuren syndrome (WBS; also called Williams syndrome) is a multisystem developmental disorder that is almost always associated with an approx 1.5-Mb deletion of chromosome 7q11.23 (OMIM no. 194050). The deletion was identified in 1993 based on the observation of phenotypic overlap with supravalvular aortic stenosis (SVAS), a distinct autosomal dominant disorder affecting the cardiovascular system (). It has since been shown that SVAS arises because of the disruption of one copy of the elastin gene, through either deletion, translocation or point mutation (–), but the genes contributing to the remaining aspects of WBS have not yet been definitively determined.

Sotos syndrome (SoS) is a well-known overgrowth syndrome with mental retardation, specific craniofacial features, and advanced bone age. Since NSD1 haploinsufficiency was proven to be the major cause of SoS in 2002, many intragenic mutations and chromosomal microdeletions (MDs) involving the entire NSD1 gene have been described. The sizes of most SoS MDs are identical and a specific genomic architecture around these MDs was found. Recently, precise analyses of the low-copy repeats (LCRs) flanking the SoS common deletion showed that the deletion arises through nonhomologous recombination (NAHR) utilizing the LCRs, and proved that SoS is a genomic disorder.

X chromosome rearrangements usually convey clinical manifestations in the hemizygous males and are, thus, readily ascertained. They are found in all parts of the X chromosome and are associated with more than 20 disorders. Some of the rearrangements are the results of homologous recombination between low-copy repeats (LCRs) on the X chromosome or between large homologous regions on the X and Y chromosome, whereas others are caused by nonhomologous end-joining (NHEJ). For most large deletions associated with contiguous gene syndromes, the deletion breakpoints remain uncharacterized. The deletions, as well as inversions and duplications on the X chromosome, occur mainly in male germ cells, indicating intrachromatid or sister chromatid exchange as the underlying mechanism.

Pelizaeus-Merzbacher disease () is a genomic disorder that is caused by altered dosage of a single gene, proteolipid protein 1 (). Either duplication or deletion of -containing genomic regions on chromosome Xq22.2 results in a severe leukodystrophy characterized by deficits of myelination in the central nervous system (). In this chapter, the molecular and genomic mechanisms for rearrangements causing PMD are reviewed, emphasizing differences in comparison to Charcot-Marie-Tooth disease type 1A () and hereditary neuropathy with liability to pressure palsies ()

Approximately 0.03% of men carry a Y-chromosomal defect that leads to azoospermia, the absence of sperm cells from semen. Deletion mapping of the Y chromosomes of azoospermic or oligozoospermic men suggested that loss of three nonoverlapping regions, AZFa, AZFb, and AZFc, could be responsible. When the finished Y-chromosomal reference sequence became available, the recurrent deletion of each of these intervals could be explained largely by non-allelic homologous recombination between direct repeats. However, in contrast to the conclusion from deletion mapping, AZFb deletions were found to overlap with AZFc deletions. In addition, a background level of nonhomologous recombination was found to generate a minority of deletions of these intervals. USP9Y appears to be the critical gene underlying the AZFa phenotype, but the critical genes lost in the AZFb and AZFc deletions have not yet been identified. Inspection of the sequence allowed additional duplications, inversions, and partial deletions of the AZF intervals to be anticipated, and many of the predicted structures have subsequently been identified in the population. The phenotypic consequences of these additional rearrangements of the AZFc region are unclear. High levels of gene conversion homogenize duplicated sequences in both direct and inverted orientations on the Y, which could potentiate subsequent rearrangements. The Y chromosome provides an excellent model for understanding genomic disorders; however, more finished sequences and new methodologies are needed.

A number of findings revealed that chromosome inversions are more frequent than deduced from classical cytogenetic studies. Indeed, some paracentric cryptic inversions have been found to be flanked by segmental duplications, either causing a Mendelian disease owing to the interruption of specific genes at inversion breakpoints or being present in the normal population as a polymorphism. In the latter case, in the heterozygous state they predispose to further unbalanced rearrangements such as inv dup rearrangements or simple deletions and duplications. The importance of this susceptibility factor has been well clarified with respect to some genomic disorders involving chromosome 8p and it is now emerging as a possible model that may explain the genetic basis of other recurrent chromosome rearrangements.