PMID- 25640679
OWN - NLM
STAT- MEDLINE
DCOM- 20150409
LR  - 20200824
IS  - 1537-6605 (Electronic)
IS  - 0002-9297 (Print)
IS  - 0002-9297 (Linking)
VI  - 96
IP  - 2
DP  - 2015 Feb 5
TI  - Next-generation sequencing of duplication CNVs reveals that most are tandem and 
      some create fusion genes at breakpoints.
PG  - 208-20
LID - S0002-9297(14)00523-0 [pii]
LID - 10.1016/j.ajhg.2014.12.017 [doi]
AB  - Interpreting the genomic and phenotypic consequences of copy-number variation 
      (CNV) is essential to understanding the etiology of genetic disorders. Whereas 
      deletion CNVs lead obviously to haploinsufficiency, duplications might cause 
      disease through triplosensitivity, gene disruption, or gene fusion at 
      breakpoints. The mutational spectrum of duplications has been studied at certain 
      loci, and in some cases these copy-number gains are complex chromosome 
      rearrangements involving triplications and/or inversions. However, the 
      organization of clinically relevant duplications throughout the genome has yet to 
      be investigated on a large scale. Here we fine-mapped 184 germline duplications 
      (14.7 kb-25.3 Mb; median 532 kb) ascertained from individuals referred for 
      diagnostic cytogenetics testing. We performed next-generation sequencing (NGS) 
      and whole-genome sequencing (WGS) to sequence 130 breakpoints from 112 subjects 
      with 119 CNVs and found that most (83%) were tandem duplications in direct 
      orientation. The remainder were triplications embedded within duplications 
      (8.4%), adjacent duplications (4.2%), insertional translocations (2.5%), or other 
      complex rearrangements (1.7%). Moreover, we predicted six in-frame fusion genes 
      at sequenced duplication breakpoints; four gene fusions were formed by tandem 
      duplications, one by two interconnected duplications, and one by duplication 
      inserted at another locus. These unique fusion genes could be related to clinical 
      phenotypes and warrant further study. Although most duplications are positioned 
      head-to-tail adjacent to the original locus, those that are inverted, 
      triplicated, or inserted can disrupt or fuse genes in a manner that might not be 
      predicted by conventional copy-number assays. Therefore, interpreting the genetic 
      consequences of duplication CNVs requires breakpoint-level analysis.
CI  - Copyright (c) 2015 The American Society of Human Genetics. Published by Elsevier 
      Inc. All rights reserved.
FAU - Newman, Scott
AU  - Newman S
AD  - Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 
      30322, USA.
FAU - Hermetz, Karen E
AU  - Hermetz KE
AD  - Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 
      30322, USA.
FAU - Weckselblatt, Brooke
AU  - Weckselblatt B
AD  - Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 
      30322, USA.
FAU - Rudd, M Katharine
AU  - Rudd MK
AD  - Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 
      30322, USA. Electronic address: katie.rudd@emory.edu.
LA  - eng
SI  - GENBANK/KP007212
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SI  - GENBANK/KP007328
SI  - GENBANK/KP007329
SI  - GEO/GSE62657
GR  - R01 MH092902/MH/NIMH NIH HHS/United States
GR  - MH092902/MH/NIMH NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20150129
PL  - United States
TA  - Am J Hum Genet
JT  - American journal of human genetics
JID - 0370475
SB  - IM
MH  - Base Sequence
MH  - Chromosome Breakpoints
MH  - Chromosome Mapping
MH  - Comparative Genomic Hybridization/methods
MH  - DNA Copy Number Variations/*genetics
MH  - Gene Duplication/*genetics
MH  - Gene Fusion/*genetics
MH  - Genomics/methods
MH  - High-Throughput Nucleotide Sequencing/*methods
MH  - Humans
MH  - Molecular Sequence Data
PMC - PMC4320257
EDAT- 2015/02/03 06:00
MHDA- 2015/04/10 06:00
PMCR- 2015/08/05
CRDT- 2015/02/03 06:00
PHST- 2014/10/31 00:00 [received]
PHST- 2014/12/15 00:00 [accepted]
PHST- 2015/02/03 06:00 [entrez]
PHST- 2015/02/03 06:00 [pubmed]
PHST- 2015/04/10 06:00 [medline]
PHST- 2015/08/05 00:00 [pmc-release]
AID - S0002-9297(14)00523-0 [pii]
AID - 10.1016/j.ajhg.2014.12.017 [doi]
PST - ppublish
SO  - Am J Hum Genet. 2015 Feb 5;96(2):208-20. doi: 10.1016/j.ajhg.2014.12.017. Epub 
      2015 Jan 29.