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

Piotr Dittwald, Tomasz Gambin, Przemyslaw Szafranski, Jian Li, Stephen Amato, Michael Y. Divon, Lisa Ximena Rodríguez Rojas, Lindsay E. Elton, Daryl A. Scott, Christian P. Schaaf, Wilfredo Torres-Martinez, Abby K. Stevens, Jill A. Rosenfeld, Satish Agadi, David Francis, Sung Hae L. Kang, Amy Breman, Seema R. Lalani, Carlos A. Bacino, Weimin BiAleksandar Milosavljevic, Arthur L. Beaudet, Ankita Patel, Chad A. Shaw, James R. Lupski, Anna Gambin, Sau Wai Cheung, Pawel Stankiewicz

Research output: Contribution to journalArticlepeer-review

98 Scopus citations

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 59-CCNCCNTNNCCNC-39, 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.

Original languageEnglish (US)
Pages (from-to)1395-1409
Number of pages15
JournalGenome Research
Volume23
Issue number9
DOIs
StatePublished - Sep 2013
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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