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

Andrew J. Sharp; Sierra Hansen; Rebecca R. Selzer; Ze Cheng; Regina Regan; Jane A. Hurst; Helen Stewart; Sue M. Price; Edward Blair; Raoul C. Hennekam; Carrie A. Fitzpatrick; Rick Segraves; Todd A. Richmond; Cheryl Guiver; Donna G. Albertson; Daniel Pinkel; Peggy S. Eis; Stuart Schwartz; Samantha J.L. Knight; Evan E. Eichler

doi:10.1038/ng1862

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

Andrew J. Sharp, Sierra Hansen, Rebecca R. Selzer, Ze Cheng, Regina Regan, Jane A. Hurst, Helen Stewart, Sue M. Price, Edward Blair, Raoul C. Hennekam, Carrie A. Fitzpatrick, Rick Segraves, Todd A. Richmond, Cheryl Guiver, Donna G. Albertson, Daniel Pinkel, Peggy S. Eis, Stuart Schwartz, Samantha J.L. Knight, Evan E. Eichler

Oral and Maxillofacial Surgery

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Abstract

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 disorders. 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.

Original language	English (US)
Pages (from-to)	1038-1042
Number of pages	5
Journal	Nature Genetics
Volume	38
Issue number	9
DOIs	https://doi.org/10.1038/ng1862
State	Published - Sep 4 2006

ASJC Scopus subject areas

Genetics

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Sharp, A. J., Hansen, S., Selzer, R. R., Cheng, Z., Regan, R., Hurst, J. A., Stewart, H., Price, S. M., Blair, E., Hennekam, R. C., Fitzpatrick, C. A., Segraves, R., Richmond, T. A., Guiver, C., Albertson, D. G., Pinkel, D., Eis, P. S., Schwartz, S., Knight, S. J. L., & Eichler, E. E. (2006). Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nature Genetics, 38(9), 1038-1042. https://doi.org/10.1038/ng1862

Sharp, AJ, Hansen, S, Selzer, RR, Cheng, Z, Regan, R, Hurst, JA, Stewart, H, Price, SM, Blair, E, Hennekam, RC, Fitzpatrick, CA, Segraves, R, Richmond, TA, Guiver, C, Albertson, DG, Pinkel, D, Eis, PS, Schwartz, S, Knight, SJL & Eichler, EE 2006, 'Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome', Nature Genetics, vol. 38, no. 9, pp. 1038-1042. https://doi.org/10.1038/ng1862

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title = "Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome",

abstract = "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 disorders. 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.",

author = "Sharp, {Andrew J.} and Sierra Hansen and Selzer, {Rebecca R.} and Ze Cheng and Regina Regan and Hurst, {Jane A.} and Helen Stewart and Price, {Sue M.} and Edward Blair and Hennekam, {Raoul C.} and Fitzpatrick, {Carrie A.} and Rick Segraves and Richmond, {Todd A.} and Cheryl Guiver and Albertson, {Donna G.} and Daniel Pinkel and Eis, {Peggy S.} and Stuart Schwartz and Knight, {Samantha J.L.} and Eichler, {Evan E.}",

note = "Funding Information: 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.",

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AU - Hurst, Jane A.

AU - Stewart, Helen

AU - Price, Sue M.

AU - Blair, Edward

AU - Hennekam, Raoul C.

AU - Fitzpatrick, Carrie A.

AU - Segraves, Rick

AU - Richmond, Todd A.

AU - Guiver, Cheryl

AU - Albertson, Donna G.

AU - Pinkel, Daniel

AU - Eis, Peggy S.

AU - Schwartz, Stuart

AU - Knight, Samantha J.L.

AU - Eichler, Evan E.

N1 - Funding Information: 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.

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N2 - 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 disorders. 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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Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome

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