Abstract
Duplicons, that is, DNA sequences with minimum length 10 kb and a high sequence similarity, are known to cause unequal homologous recombination, leading to deletions and the reciprocal duplications. In this study, we designed a Multiplex Amplifiable Probe Hybridisation (MAPH) assay containing 63 exon-specific single-copy sequences from within a selection of the 169 regions flanked by duplicons that were identified, at a first pass, in 2001. Subsequently, we determined the frequency of chromosomal rearrangements among patients with developmental delay (DD) and/or congenital malformations (CM). In addition, we tried to identify new regions involved in DD/CM using the same assay. In 105 patients, six imbalances (5.8%) were detected and verified. Three of these were located in microdeletion-related regions, two alterations were polymorphic duplications and the effect of the last alteration is currently unknown. The same study population was tested for rearrangements in regions with no known duplicons nearby, using a set of probes derived from 58 function-selected genes. The latter screening revealed two alterations. As expected, the alteration frequency per unit of DNA is much higher in regions flanked by duplicons (fraction of the genome tested: 5.2%) compared to regions without known duplicons nearby (fraction of the genome tested: 24.5–90.2%). We were able to detect three novel rearrangements, including the previously undescribed reciprocal duplication of the Williams Beuren critical region, a subduplicon alteration within this region and a duplication on chromosome band 16p13.11. Our results support the hypothesis that regions flanked by duplicons are enriched for copy number variations.
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Acknowledgements
We thank Hans Dauwerse, Kerstin Hansson, Jeroen Nijhuis for the FISH analysis, Yvonne Hilhorst for providing clinical information, Peter de Knijff for parental marker analysis. MK is funded by Zon-Mw (AGIKO fellowship 940-37-032), SW is funded by ZonMw (nr 912-04-047).
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† Leiden Muscular Dystrophy Pages, http://www.dmd.nl/DMD_MAPH.html
† Prophet (http://www.basic.nwu.edu/biotools/prophet.html)
† UCSC Genome Browser (http://genome.ucsc.edu/)
† Ensembl (http://www.ensembl.org)
† Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim
† Genome Variation Database, http://projects.tcag.ca/variation/.
Note added in proof
While this work was under review, another patient was described (Severe expressive-language delay related to duplication of the Williams-Beuren locus, MJ Somerville et al. N Engl J Med 2005; 353:1694–1701, October 20, 2005) with a duplication of the WBS region. We have assessed the phenotype of our patient in the light of the reported clinical features (language deficiency but good spatial abilities). Considering the age of our patient, we could not assess the spatial abilities, but our patient did present with (moderate) language disability.
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Kriek, M., White, S., Szuhai, K. et al. Copy number variation in regions flanked (or unflanked) by duplicons among patients with developmental delay and/or congenital malformations; detection of reciprocal and partial Williams-Beuren duplications. Eur J Hum Genet 14, 180–189 (2006). https://doi.org/10.1038/sj.ejhg.5201540
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DOI: https://doi.org/10.1038/sj.ejhg.5201540
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