title: NAHR-mediated copy-number variants in a clinical population: mechanistic insights into both genomic disorders and Mendelizing traits.
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.
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors: Piotr
authors: P
authors: Dittwald
authors: Tomasz
authors: T
authors: Gambin
authors: Przemyslaw
authors: P
authors: Szafranski
authors: Jian
authors: J
authors: Li
authors: Stephen
authors: S
authors: Amato
authors: Michael Y
authors: MY
authors: Divon
authors: Lisa Ximena
authors: LX
authors: Rodríguez Rojas
authors: Lindsay E
authors: LE
authors: Elton
authors: Daryl A
authors: DA
authors: Scott
authors: Christian P
authors: CP
authors: Schaaf
authors: Wilfredo
authors: W
authors: Torres-Martinez
authors: Abby K
authors: AK
authors: Stevens
authors: Jill A
authors: JA
authors: Rosenfeld
authors: Satish
authors: S
authors: Agadi
authors: David
authors: D
authors: Francis
authors: Sung-Hae L
authors: SH
authors: Kang
authors: Amy
authors: A
authors: Breman
authors: Seema R
authors: SR
authors: Lalani
authors: Carlos A
authors: CA
authors: Bacino
authors: Weimin
authors: W
authors: Bi
authors: Aleksandar
authors: A
authors: Milosavljevic
authors: Arthur L
authors: AL
authors: Beaudet
authors: Ankita
authors: A
authors: Patel
authors: Chad A
authors: CA
authors: Shaw
authors: James R
authors: JR
authors: Lupski
authors: Anna
authors: A
authors: Gambin
authors: Sau Wai
authors: SW
authors: Cheung
authors: Pawel
authors: P
authors: Stankiewicz
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000483:Alleles; D001482:Base Composition; D002872:Chromosome Deletion; D025063:Chromosome Disorders / Q000235:genetics*; D058674:Chromosome Duplication; D003598:Cytoskeletal Proteins; D056915:DNA Copy Number Variations; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D015894:Genome, Human; D059765:Homologous Recombination; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D059372:Nucleotide Motifs; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C579167:Chrna7 protein, human; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; C108725:NPHP1 protein, human; D064569:alpha7 Nicotinic Acetylcholine Receptor
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