NAHR-mediated copy-number variants in a clinical population: Mechanistic insights into both genomic disorders and Mendelizing traits

  1. Pawel Stankiewicz1,18
  1. 1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA;
  2. 2Institute of Informatics, University of Warsaw, 02-097 Warsaw, Poland;
  3. 3College of Inter-Faculty Individual Studies in Mathematics and Natural Sciences, University of Warsaw, 02-089 Warsaw, Poland;
  4. 4Institute of Computer Science, Warsaw University of Technology, 02-665 Warsaw, Poland;
  5. 5Genetics and Metabolism, Phoenix Children's Hospital, Phoenix, Arizona 85006, USA;
  6. 6Lenox Hill Hospital, New York, New York 10065, USA;
  7. 7Fundación Clínica Valle del Lili, Cali, 76001000, Colombia;
  8. 8Child Neurology, Pediatric Specialty Services, Austin, Texas 78723, USA;
  9. 9Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA;
  10. 10Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA;
  11. 11Signature Genomic Laboratories, PerkinElmer, Inc., Spokane, Washington 99207, USA;
  12. 12Department of Pediatrics and Neurology, Baylor College of Medicine, Houston, Texas 77030, USA;
  13. 13Cytogenetics Department, Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, Victoria 3052, Australia;
  14. 14Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA;
  15. 15Texas Children's Hospital, Houston, Texas 77030, USA;
  16. 16Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-106 Warsaw, Poland

    1. ↵17 These authors contributed equally to this work.

    Abstract

    We delineated and analyzed directly oriented paralogous low-copy repeats (DP-LCRs) in the most recent version of the human haploid reference genome. The computationally defined DP-LCRs were cross-referenced with our chromosomal microarray analysis (CMA) database of 25,144 patients subjected to genome-wide assays. This computationally guided approach to the empirically derived large data set allowed us to investigate genomic rearrangement relative frequencies and identify new loci for recurrent nonallelic homologous recombination (NAHR)-mediated copy-number variants (CNVs). The most commonly observed recurrent CNVs were NPHP1 duplications (233), CHRNA7 duplications (175), and 22q11.21 deletions (DiGeorge/velocardiofacial syndrome, 166). In the ∼25% of CMA cases for which parental studies were available, we identified 190 de novo recurrent CNVs. In this group, the most frequently observed events were deletions of 22q11.21 (48), 16p11.2 (autism, 34), and 7q11.23 (Williams-Beuren syndrome, 11). Several features of DP-LCRs, including length, distance between NAHR substrate elements, DNA sequence identity (fraction matching), GC content, and concentration of the homologous recombination (HR) hot spot motif 5′-CCNCCNTNNCCNC-3′, correlate with the frequencies of the recurrent CNVs events. Four novel adjacent DP-LCR-flanked and NAHR-prone regions, involving 2q12.2q13, were elucidated in association with novel genomic disorders. Our study quantitates genome architectural features responsible for NAHR-mediated genomic instability and further elucidates the role of NAHR in human disease.

    Footnotes

    • Received November 26, 2012.
    • Accepted April 30, 2013.

    This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported), as described at http://creativecommons.org/licenses/by-nc/3.0/.

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    1. Published in Advance May 8, 2013, doi: 10.1101/gr.152454.112 Genome Res. 23: 1395-1409 © 2013, Published by Cold Spring Harbor Laboratory Press

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