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Abstract
Genomic rearrangements can cause both Mendelian and complex disorders. Currently, several major mechanisms causing genomic rearrangements, such as non-allelic homologous recombination (NAHR), non-homologous end joining (NHEJ), fork stalling and template switching (FoSTeS), and microhomology-mediated break-induced replication (MMBIR), have been proposed. However, to what extent these mechanisms contribute to gene-specific pathogenic copy-number variations (CNVs) remains understudied. Furthermore, few studies have resolved these pathogenic alterations at the nucleotide-level. Accordingly, our aim was to explore which mechanisms contribute to a large, unique set of locus-specific non-recurrent genomic rearrangements causing the genetic neurocutaneous disorder neurofibromatosis type 1 (NF1). Through breakpoint-spanning PCR as well as array comparative genomic hybridization, we have identified the breakpoints in 85 unrelated individuals carrying an NF1 intragenic CNV. Furthermore, we characterized the likely rearrangement mechanisms of these 85 CNVs, along with those of two additional previously published NF1 intragenic CNVs. Unlike the most typical recurrent rearrangements mediated by flanking low-copy repeats (LCRs), NF1 intragenic rearrangements vary in size, location, and rearrangement mechanisms. We propose the DNA-replication-based mechanisms comprising both FoSTeS and/or MMBIR and serial replication stalling to be the predominant mechanisms leading to NF1 intragenic CNVs. In addition to the loop within a 197-bp palindrome located in intron 40, four Alu elements located in introns 1, 2, 3, and 50 were also identified as intragenic-rearrangement hotspots within NF1.
Keywords
DELETION BREAKPOINTS, PROBE AMPLIFICATION, STRUCTURAL VARIATION, MOLECULAR CHARACTERIZATION, HOMOLOGOUS RECOMBINATION, NONRECURRENT REARRANGEMENTS, DMD GENE, GENOMIC REARRANGEMENTS, HUMAN DYSTROPHIN GENE, SERIAL REPLICATION SLIPPAGE

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Citation

Please use this url to cite or link to this publication:

MLA
Hsiao, Meng-Chang et al. “Decoding NF1 Intragenic Copy-number Variations.” AMERICAN JOURNAL OF HUMAN GENETICS 97.2 (2015): 238–249. Print.
APA
Hsiao, M.-C., Piotrowski, A., Callens, T., Fu, C., Wimmer, K., Claes, K., & Messiaen, L. (2015). Decoding NF1 intragenic copy-number variations. AMERICAN JOURNAL OF HUMAN GENETICS, 97(2), 238–249.
Chicago author-date
Hsiao, Meng-Chang, Arkadiusz Piotrowski, Tom Callens, Chuanhua Fu, Katharina Wimmer, Kathleen Claes, and Ludwine Messiaen. 2015. “Decoding NF1 Intragenic Copy-number Variations.” American Journal of Human Genetics 97 (2): 238–249.
Chicago author-date (all authors)
Hsiao, Meng-Chang, Arkadiusz Piotrowski, Tom Callens, Chuanhua Fu, Katharina Wimmer, Kathleen Claes, and Ludwine Messiaen. 2015. “Decoding NF1 Intragenic Copy-number Variations.” American Journal of Human Genetics 97 (2): 238–249.
Vancouver
1.
Hsiao M-C, Piotrowski A, Callens T, Fu C, Wimmer K, Claes K, et al. Decoding NF1 intragenic copy-number variations. AMERICAN JOURNAL OF HUMAN GENETICS. 2015;97(2):238–49.
IEEE
[1]
M.-C. Hsiao et al., “Decoding NF1 intragenic copy-number variations,” AMERICAN JOURNAL OF HUMAN GENETICS, vol. 97, no. 2, pp. 238–249, 2015.
@article{7158499,
  abstract     = {Genomic rearrangements can cause both Mendelian and complex disorders. Currently, several major mechanisms causing genomic rearrangements, such as non-allelic homologous recombination (NAHR), non-homologous end joining (NHEJ), fork stalling and template switching (FoSTeS), and microhomology-mediated break-induced replication (MMBIR), have been proposed. However, to what extent these mechanisms contribute to gene-specific pathogenic copy-number variations (CNVs) remains understudied. Furthermore, few studies have resolved these pathogenic alterations at the nucleotide-level. Accordingly, our aim was to explore which mechanisms contribute to a large, unique set of locus-specific non-recurrent genomic rearrangements causing the genetic neurocutaneous disorder neurofibromatosis type 1 (NF1). Through breakpoint-spanning PCR as well as array comparative genomic hybridization, we have identified the breakpoints in 85 unrelated individuals carrying an NF1 intragenic CNV. Furthermore, we characterized the likely rearrangement mechanisms of these 85 CNVs, along with those of two additional previously published NF1 intragenic CNVs. Unlike the most typical recurrent rearrangements mediated by flanking low-copy repeats (LCRs), NF1 intragenic rearrangements vary in size, location, and rearrangement mechanisms. We propose the DNA-replication-based mechanisms comprising both FoSTeS and/or MMBIR and serial replication stalling to be the predominant mechanisms leading to NF1 intragenic CNVs. In addition to the loop within a 197-bp palindrome located in intron 40, four Alu elements located in introns 1, 2, 3, and 50 were also identified as intragenic-rearrangement hotspots within NF1.},
  author       = {Hsiao, Meng-Chang and Piotrowski, Arkadiusz and Callens, Tom and Fu, Chuanhua and Wimmer, Katharina and Claes, Kathleen and Messiaen, Ludwine},
  issn         = {0002-9297},
  journal      = {AMERICAN JOURNAL OF HUMAN GENETICS},
  keywords     = {DELETION BREAKPOINTS,PROBE AMPLIFICATION,STRUCTURAL VARIATION,MOLECULAR CHARACTERIZATION,HOMOLOGOUS RECOMBINATION,NONRECURRENT REARRANGEMENTS,DMD GENE,GENOMIC REARRANGEMENTS,HUMAN DYSTROPHIN GENE,SERIAL REPLICATION SLIPPAGE},
  language     = {eng},
  number       = {2},
  pages        = {238--249},
  title        = {Decoding NF1 intragenic copy-number variations},
  url          = {http://dx.doi.org/10.1016/j.ajhg.2015.06.002},
  volume       = {97},
  year         = {2015},
}

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