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Hum Mutat. 2017 Feb;38(2):180-192. doi: 10.1002/humu.23146. Epub 2016 Dec 5.

Whole-Genome Sequencing of Cytogenetically Balanced Chromosome Translocations Identifies Potentially Pathological Gene Disruptions and Highlights the Importance of Microhomology in the Mechanism of Formation.

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Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden.
Center for Molecular Medicine, Karolinska Institutet, 171 76 Stockholm, Sweden.
Department of Clinical Genetics, Karolinska University Hospital, 171 76 Stockholm, Sweden.
Science for Life Laboratory, Karolinska Institutet Science Park, 171 21 Solna, Sweden.
Children's Hospital, Helsinki University Central Hospital and University of Helsinki, 00290 Helsinki, Finland.
Folkhälsan Institute of Genetics, 00290 Helsinki, Finland.
SciLifeLab, School of Biotechnology, KTH Royal Institute of Technology, 171 71 Stockholm, Sweden.
SciLifeLab, Department of Biochemistry and Biophysics, Stockholm University, 171 21 Stockholm, Sweden.
Department of Molecular and Human Genetics, Baylor College of Medicine, 77030 Houston TX, USA.
Texas Children's Hospital, 77030 Houston TX, USA.
Contributed equally


Most balanced translocations are thought to result mechanistically from nonhomologous end joining or, in rare cases of recurrent events, by nonallelic homologous recombination. Here, we use low-coverage mate pair whole-genome sequencing to fine map rearrangement breakpoint junctions in both phenotypically normal and affected translocation carriers. In total, 46 junctions from 22 carriers of balanced translocations were characterized. Genes were disrupted in 48% of the breakpoints; recessive genes in four normal carriers and known dominant intellectual disability genes in three affected carriers. Finally, seven candidate disease genes were disrupted in five carriers with neurocognitive disabilities (SVOPL, SUSD1, TOX, NCALD, SLC4A10) and one XX-male carrier with Tourette syndrome (LYPD6, GPC5). Breakpoint junction analyses revealed microhomology and small templated insertions in a substantive fraction of the analyzed translocations (17.4%; n = 4); an observation that was substantiated by reanalysis of 37 previously published translocation junctions. Microhomology associated with templated insertions is a characteristic seen in the breakpoint junctions of rearrangements mediated by error-prone replication-based repair mechanisms. Our data implicate that a mechanism involving template switching might contribute to the formation of at least 15% of the interchromosomal translocation events.


balanced chromosomal aberration; microhomology; nonhomologous end joining; reciprocal translocation; replication-based repair mechanisms; whole-genome sequencing

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