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Am J Hum Genet. 2015 Aug 6;97(2):238-49. doi: 10.1016/j.ajhg.2015.06.002. Epub 2015 Jul 16.

Decoding NF1 Intragenic Copy-Number Variations.

Author information

1
Medical Genomics Laboratory, Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
2
Medical Genomics Laboratory, Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Faculty of Pharmacy, Medical University of Gdansk, 80-416 Gdansk, Poland.
3
Division of Human Genetics, Medical University Innsbruck, Peter-Mayr-Straße 1, 6020 Innsbruck, Austria.
4
Center for Medical Genetics, Ghent University Hospital, De Pintelaan, 185 9000 Gent, Belgium.
5
Medical Genomics Laboratory, Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA. Electronic address: lmessiaen@uabmc.edu.

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.

PMID:
26189818
PMCID:
PMC4573439
DOI:
10.1016/j.ajhg.2015.06.002
[Indexed for MEDLINE]
Free PMC Article

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