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Abstract

We identified complex genomic rearrangements consisting of intermixed duplications and triplications of genomic segments at the MECP2 and PLP1 loci. These complex rearrangements were characterized by a triplicated segment embedded within a duplication in 11 unrelated subjects. Notably, only two breakpoint junctions were generated during each rearrangement formation. All the complex rearrangement products share a common genomic organization, duplication-inverted triplication-duplication (DUP-TRP/INV-DUP), in which the triplicated segment is inverted and located between directly oriented duplicated genomic segments. We provide evidence that the DUP-TRP/INV-DUP structures are mediated by inverted repeats that can be separated by >300 kb, a genomic architecture that apparently leads to susceptibility to such complex rearrangements. A similar inverted repeat–mediated mechanism may underlie structural variation in many other regions of the human genome. We propose a mechanism that involves both homology-driven events, via inverted repeats, and microhomologous or nonhomologous events.

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Acknowledgements

We thank all of the families who participated in this study. We acknowledge P. Stankiewicz for helpful discussions. This work was supported in part by US National Institute of Neurological Disorders and Stroke (NINDS) grant R01 NS058529 to J.R.L., NINDS grant R01 HD053862 to H.Y.Z., US National Institute of General Medical Sciences (NIGMS) grant R01 GM064022 to P.J.H. and NINDS grant 5K08NS062711-03 to M.B.R. Lymphoblast cell lines were developed by the Baylor College of Medicine Intellectual and Developmental Disabilities Research Center cell culture core, which is funded by award P30HD024064 from the Eunice Kennedy Shriver US National Institute of Child Health and Human Development (NICHD). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NINDS, NIGMS, NICHD or the US National Institutes of Health. H.Y.Z. is an investigator of the Howard Hughes Medical Institute.

Author information

Author notes

    • Claudia M B Carvalho
    •  & Melissa B Ramocki

    These authors contributed equally to this work.

Affiliations

  1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.

    • Claudia M B Carvalho
    • , Davut Pehlivan
    • , Luis M Franco
    • , Claudia Gonzaga-Jauregui
    • , Ping Fang
    • , Daniela del Gaudio
    • , Marjorie Withers
    • , Pengfei Liu
    • , Sau Wai Cheung
    • , John W Belmont
    • , Huda Y Zoghbi
    • , P J Hastings
    •  & James R Lupski
  2. Department of Pediatrics, Division of Pediatric Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, Texas, USA.

    • Melissa B Ramocki
    •  & Huda Y Zoghbi
  3. Texas Children's Hospital, Houston, Texas, USA.

    • Melissa B Ramocki
    •  & James R Lupski
  4. Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.

    • Alanna McCall
    •  & James R Lupski
  5. Department of Pediatrics, Division of Clinical Genetics and Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, Tennessee, USA.

    • Eniko Karman Pivnick
  6. Nursing Administration, Division of Medical Genetics LeBonheur Children's Hospital, Memphis, Tennessee, USA.

    • Stacy Hines-Dowell
  7. Kapiolani Medical Specialists, Honolulu, Hawaii, USA.

    • Laurie H Seaver
    •  & Sansan Lee
  8. Children's Medical Associates, Alexandria, Virginia, USA.

    • Linda Friehling
  9. Division of Genetics, Department of Pediatrics, Maine Medical Center, Portland, Maine, USA.

    • Rosemarie Smith
  10. Department of Pediatrics, Division of Cardiology, Baylor College of Medicine, Houston, Texas, USA.

    • John W Belmont
  11. Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA.

    • Huda Y Zoghbi
  12. Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

    • Huda Y Zoghbi
  13. Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA.

    • Huda Y Zoghbi
  14. Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.

    • Luis M Franco
  15. Department of Pediatrics, John A. Burns School of Medicine, Honolulu, Hawaii, USA.

    • Laurie H Seaver

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Contributions

C.M.B.C. conducted high-density aCGH, FISH, breakpoint sequencing, Southern-blotting experiments and data analysis. M.B.R. coordinated human studies, recruited subjects and analyzed clinical data. D.P. and P.L. assisted with high-density aCGH and breakpoint sequencing. L.M.F. and J.W.B. conducted SNP genotyping. E.K.P., S.H.-D., L.S., L.F., S.L. and R.S. recruited and clinically characterized subjects. C.G.-J. assisted with data analysis. P.F. conducted the X-chromosome inactivation studies. A.M. and M.W. carried out cell culture. D.d.G. conducted MLPA. S.W.C. was involved in cytogenetic and clinical aCGH studies. J.R.L. and H.Y.Z. were involved in research design and data analyses. P.J.H. was involved in data analyses. C.M.B.C., M.B.R., P.J.H. and J.R.L. prepared the manuscript.

Competing interests

J.R.L. is on the scientific advisory board of Ion Torrent Systems, is a consultant for Athena Diagnostics and has stock ownership in 23andMe. P.F., D.d.G., S.W.C. and J.R.L. are based in the Department of Molecular and Human Genetics at Baylor College of Medicine, which derives clinical income from the application of high resolution human genome analyses.

Corresponding authors

Correspondence to Melissa B Ramocki or James R Lupski.

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DOI

https://doi.org/10.1038/ng.944

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