Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome

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Genomic disorders are characterized by the presence of flanking segmental duplications that predispose these regions to recurrent rearrangement. Based on the duplication architecture of the genome, we investigated 130 regions that we hypothesized as candidates for previously undescribed genomic disorders1. We tested 290 individuals with mental retardation by BAC array comparative genomic hybridization and identified 16 pathogenic rearrangements, including de novo microdeletions of 17q21.31 found in four individuals. Using oligonucleotide arrays, we refined the breakpoints of this microdeletion, defining a 478-kb critical region containing six genes that were deleted in all four individuals. We mapped the breakpoints of this deletion and of four other pathogenic rearrangements in 1q21.1, 15q13, 15q24 and 17q12 to flanking segmental duplications, suggesting that these are also sites of recurrent rearrangement. In common with the 17q21.31 deletion, these breakpoint regions are sites of copy number polymorphism in controls, indicating that these may be inherently unstable genomic regions.

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Figure 1: Detection of a previously unidentified recurrent microdeletion in 17q21.31 by targeted array CGH.
Figure 2: Structural resolution of a 1.5-Mb region of 17q21.31 (human genome May 2004 assembly (hg17), chr17:40,750,000–42,250,000) using high-density oligonucleotide arrays.
Figure 3: Photographs of individual 338H5 (del 17q21.31), age 4 years.
Figure 4: Structural resolution of five pathogenic rearrangements using high-density oligonucleotide arrays.

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The authors would like to thank all participating families and clinicians, particularly J. Flint, P. Bolton, A. Clarke, C. Fairhurst, T. Wolff, S. Mansour, S. Holder, R. Gibbons, L. Brueton, P. Day, F. Stewart, S. Keane, N. Meston, A. Seller, P. Clouston and K. Smith. This work was supported by grants from the US National Institutes of Health (NIH) (HD043569; E.E.E.), Merck Research Laboratories (A.J.S.), The Health Foundation (S.J.L.K.) and the Oxford Genetics Knowledge Park (S.J.L.K., R.R., C.G.). E.E.E. is an Investigator of the Howard Hughes Medical Institute.

Author information

This study was coordinated by A.J.S., P.S.E., S.S., S.J.L. and E.E.E.; the manuscript was written by A.J.S. and E.E.E.; experimental work was performed by A.J.S., S.H., R.R.S., R.R., C.A.F., R.S. and C.G.; clinical work was performed by J.A.H., H.S., S.M.P., E.B. and R.C.H.; computational analysis was performed by Z.C.; and array production was performed by T.A.R., D.G.A. and D.P.

Correspondence to Evan E Eichler.

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Competing interests

P.S.E., R.R.S. and T.A.R. are employees of NimbleGen Systems, Inc. and have stock options in the company.

Supplementary information

Supplementary Fig. 1

FISH validation of 13 rearrangements detected using the SD BAC array. (PDF 1361 kb)

Supplementary Fig. 2

Parental origin and inversion analysis of the 17q21.31 deletion in the family of IMR103. (PDF 1588 kb)

Supplementary Table 1

A non-redundant set of 130 potential rearrangement hotspots in the human genome. (PDF 46 kb)

Supplementary Table 2

Copy number variations detected in 269 HapMap samples and in 290 patients with mental retardation using the SD BAC array. (PDF 3016 kb)

Supplementary Table 3

Nine additional rearrangements, including seven of uncertain significance, detected using the SD BAC array in 290 patients with mental retardation. (PDF 16 kb)

Supplementary Table 4

Comparison of phenotypes between four of the five cases of del 17q21.31 ascertained using the SD BAC array and three previously reported overlapping deletions, plus phenotype details of six further pathogenic rearrangements ascertained using the SD BAC array. (PDF 16 kb)

Supplementary Table 5

Segmental duplication clusters at five rearragement breakpoints as defined by high-density oligonucleotide array analysis. (PDF 21 kb)

Supplementary Table 6

PCR primers used in this study. (PDF 8 kb)

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Sharp, A., Hansen, S., Selzer, R. et al. Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nat Genet 38, 1038–1042 (2006) doi:10.1038/ng1862

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