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

Piotr Dittwald , Tomasz Gambin , Przemysław Szafranski , Jian Li , Stephen Amato , Michael Y. Divon , Lisa Ximena Rodriguez 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 Bi , Aleksandar Milosavljevic , Arthur L. Beaudet , Ankita Patel , James R. Lupski , Chad A. Shaw , Anna Gambin , Sau Wai Cheung , Pawel Stankiewicz


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 dataset 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.
Author Piotr Dittwald - [Baylor College of Medicine]
Piotr Dittwald,,
, Tomasz Gambin (FEIT / IN)
Tomasz Gambin,,
- The Institute of Computer Science
, Przemysław Szafranski - [Baylor College of Medicine]
Przemysław Szafranski,,
, Jian Li - [Baylor College of Medicine]
Jian Li,,
, Stephen Amato - [Phoenix Children's Hospital]
Stephen Amato,,
, Michael Y. Divon
Michael Y. Divon,,
, Lisa Ximena Rodriguez Rojas
Lisa Ximena Rodriguez Rojas,,
, Lindsay E. Elton - [Child Neurology]
Lindsay E. Elton,,
, Daryl A. Scott - [Baylor College of Medicine]
Daryl A. Scott,,
, Christian P. Schaaf - [Baylor College of Medicine]
Christian P. Schaaf,,
et al.`
Journal seriesGenome Research, ISSN 1088-9051
Issue year2013
Publication size in sheets0.3
ASJC Classification2716 Genetics(clinical); 1311 Genetics
Languageen angielski
Score (nominal)50
Score sourcejournalList
ScoreMinisterial score = 50.0, 27-08-2020, ArticleFromJournal
Ministerial score (2013-2016) = 50.0, 27-08-2020, ArticleFromJournal
Publication indicators WoS Citations = 71; Scopus Citations = 72; GS Citations = 113.0; Scopus SNIP (Source Normalised Impact per Paper): 2013 = 2.868; WoS Impact Factor: 2013 = 13.852 (2) - 2013=14.927 (5)
Citation count*115 (2020-08-30)
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* presented citation count is obtained through Internet information analysis and it is close to the number calculated by the Publish or Perish system.
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