RT Journal
A1 Sobreira, Nara L.M.
A1 Gnanakkan, Veena
A1 Walsh, Michael
A1 Marosy, Beth
A1 Wohler, Elizabeth
A1 Thomas, George
A1 Hoover-Fong, Julie E.
A1 Hamosh, Ada
A1 Wheelan, Sarah J.
A1 Valle, David
T1 Characterization of complex chromosomal rearrangements by targeted capture and next-generation sequencing
JF Genome Research 
JO Genome Research 
YR 2011 
FD October 01 
VO 21 
IS 10 
SP 1720 
OP 1727 
DO 10.1101/gr.122986.111 
UL http://genome.cshlp.org/content/21/10/1720.abstract 
AB Translocations are a common class of chromosomal aberrations and can cause disease by physically disrupting genes or altering their regulatory environment. Some translocations, apparently balanced at the microscopic level, include deletions, duplications, insertions, or inversions at the molecular level. Traditionally, chromosomal rearrangements have been investigated with a conventional banded karyotype followed by arduous positional cloning projects. More recently, molecular cytogenetic approaches using fluorescence in situ hybridization (FISH), array comparative genomic hybridization (aCGH), or whole-genome SNP genotyping together with molecular methods such as inverse PCR and quantitative PCR have allowed more precise evaluation of the breakpoints. These methods suffer, however, from being experimentally intensive and time-consuming and of less than single base pair resolution. Here we describe targeted breakpoint capture followed by next-generation sequencing (TBCS) as a new approach to the general problem of determining the precise structural characterization of translocation breakpoints and related chromosomal aberrations. We tested this approach in three patients with complex chromosomal translocations: The first had craniofacial abnormalities and an apparently balanced t(2;3)(p15;q12) translocation; the second has cleidocranial dysplasia (OMIM 119600) associated with a t(2;6)(q22;p12.3) translocation and a breakpoint in RUNX2 on chromosome 6p; and the third has acampomelic campomelic dysplasia (OMIM 114290) associated with a t(5;17)(q23.2;q24) translocation, with a breakpoint upstream of SOX9 on chromosome 17q. Preliminary studies indicated complex rearrangements in patients 1 and 3 with a total of 10 predicted breakpoints in the three patients. By using TBCS, we quickly and precisely defined eight of the 10 breakpoints.