RT Journal
A1 Dittwald, Piotr
A1 Gambin, Tomasz
A1 Szafranski, Przemyslaw
A1 Li, Jian
A1 Amato, Stephen
A1 Divon, Michael Y.
A1 Rodríguez Rojas, Lisa Ximena
A1 Elton, Lindsay E.
A1 Scott, Daryl A.
A1 Schaaf, Christian P.
A1 Torres-Martinez, Wilfredo
A1 Stevens, Abby K.
A1 Rosenfeld, Jill A.
A1 Agadi, Satish
A1 Francis, David
A1 Kang, Sung-Hae L.
A1 Breman, Amy
A1 Lalani, Seema R.
A1 Bacino, Carlos A.
A1 Bi, Weimin
A1 Milosavljevic, Aleksandar
A1 Beaudet, Arthur L.
A1 Patel, Ankita
A1 Shaw, Chad A.
A1 Lupski, James R.
A1 Gambin, Anna
A1 Cheung, Sau Wai
A1 Stankiewicz, Pawel
T1 NAHR-mediated copy-number variants in a clinical population: Mechanistic insights into both genomic disorders and Mendelizing traits
JF Genome Research 
JO Genome Research 
YR 2013 
FD September 01 
VO 23 
IS 9 
SP 1395 
OP 1409 
DO 10.1101/gr.152454.112 
UL http://genome.cshlp.org/content/23/9/1395.abstract 
AB 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.