Over the past several years, the utility of microarray technology in delineating copy number changes has become well established. In the past 4 years, we have used the SNP array to detect and analyze allele ratios in 150 cases with 4-copy intervals, confirmed by FISH, offering insight into the underlying mechanisms of formation. These cases may be divided into 5 allele patterns - the first 4 of which involve a single homologue - as detected by the genotyping aspects of the microarray: (1) triplications combining homozygous and heterozygous alleles, with a 3:1 ratio of heterozygotes; (2) triplications with allele patterns combining homozygous and heterozygous alleles, with heterozygote ratios of both 3:1 and 2:2; (3) triplications that have homozygous alleles combined with only 2:2 heterozygous alleles; (4) triplications that are completely homozygous; and (5) homozygous duplications on each homologue with no heterozygous alleles. The implications of copy number variants with diverse allelic segregations are presented in this study.

Keywords:
Allele tracts, Chromosome microarray, Double duplication, Segmental UPD, Triplication
1.
Bonaglia MC, Giorda R, Massagli A, Galluzzi R, Ciccone R, Zuffardi O: A familial inverted duplication/deletion of 2p25.1-25.3 provides new clues on the genesis of inverted duplications. Eur J Hum Genet 17:179-186 (2009).
2.
Brady PD, Vermeesch JR: Genomic microarrays: a technology overview. Prenat Diagn 32:336-343 (2012).
3.
Buysse K, Antonacci F, Callewaert B, Loeys B, Fränkel U, et al: Unusual 8p inverted duplication deletion with telomere capture from 8q. Eur J Med Genet 52:31-36 (2009).
4.
Carvalho CM, Zhang F, Liu P, Patel A, Sahoo T, et al: Complex rearrangements in patients with duplications of MECP2 can occur by fork stalling and template switching. Hum Mol Genet 18:2188-2203 (2009).
5.
Carvalho CM, Ramocki MB, Pehlivan D, Franco LM, Gonzaga-Jauregui C, et al: Inverted genomic segments and complex triplication rearrangements are mediated by inverted repeats in the human genome. Nat Genet 43:1074-1081 (2012).
6.
Chabchoub E, Rodríguez L, Galán E, Mansilla E, Martínez-Fernandez ML, et al: Molecular characterisation of a mosaicism with a complex chromosome rearrangement: evidence for coincident chromosome healing by telomere capture and neo-telomere formation. J Med Genet 44:250-256 (2007).
7.
Derbyshire MK, Epstein LH, Young CSH, Munz PL, Fishel R: Nonhomologous recombination in human cells. Mol Cell Biol 14:156-169 (1994).
8.
Dittwald P, Gambin T, Gonzaga-Jauregui C, Carvalho CMB, Lupski JR, et al: Inverted low-copy repeats and genome instability - a genome-wide analysis. Hum Mutat 34:210-220 (2013).
9.
Hastings PJ, Lupski JR, Rosenberg SM, Ira G: Mechanisms of change in gene copy number. Nat Rev Genet 10:551-564 (2009).
10.
Knijnenburg J, van Haeringen A, Hansson KB, Lankester A, Smit MJ, et al: Ring chromosome formation as a novel escape mechanism in patients with inverted duplication and terminal deletion. Eur J Hum Genet 15:548-555 (2007).
11.
Lee JA, Carvalho CM, Lupski JR: A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell 131:1235-1247 (2007).
12.
Liehr T, Ewers E, Hamid AB, Kosyakova N, Voigt M, et al: Small supernumerary marker chromosomes and uniparental disomy have a story to tell. J Histochem Cytochem 59:842-848 (2011).
13.
Mantripragada KK, Buckley PG, Diaz de Stahl T, Dumanski JP: Genomic microarrays in the spotlight. Trends Genet 20:87-94 (2004).
14.
Mao Z, Bozzella M, Seluanov A, Gorbunova V: DNA repair by nonhomologous end joining and homologous recombination during cell cycle in human cells. Cell Cycle 7:2902-2906 (2008).
15.
Mitchell JJ, Vekemans M, Luscombe S, Hayden M, Weber B, et al: U-type exchange in a paracentric inversion as a possible mechanism of origin of an inverted tandem duplication of chromosome 8. Am J Med Genet 49:384-387 (1994).
16.
Papenhausen P, Schwartz S, Burnside R, Gadi I, Jaswaney V, et al: SNP microarray allele differentiation in 4-copy number intervals (abstract). 60th Annual Meeting of The American Society of Human Genetics, Washing- ton DC (2010). http://www.ashg.org/2010meeting/abstracts/fulltext/f22600.htm.
17.
Papenhausen P, Schwartz S, Risheg H, Keitges E, Gadi I, et al: UPD detection using homozygosity profiling with a SNP genotyping microarray. Am J Med Genet A 155:757-768 (2011).
18.
Redon R, Ishikawa S, Fitch KR, Feuk L, Perry GH, et al: Global variation in copy number in the human genome. Nature 444:444-454 (2006).
19.
Rowe LR, Lee JY, Rector L, Kaminsky EB, Brothman AR, et al: U-type exchange is the most frequent mechanism for inverted duplication with terminal deletion rearrangements. J Med Genet 46:694-702 (2009).
20.
Yu S, Graf WD: Telomere capture as a frequent mechanism for stabilization of the terminal chromosomal deletion associated with inverted duplication. Cytogenet Genome Res 129:265-274 (2010).
21.
Zuffardi O, Bonaglia M, Ciccone R, Giorda R: Inverted duplications deletions: underdiagnosed rearrangements? Clin Genet 75:505-513 (2009).
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2014
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