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Genet Med. 2018 Jul;20(7):697-707. doi: 10.1038/gim.2017.170. Epub 2017 Nov 2.

Identification of balanced chromosomal rearrangements previously unknown among participants in the 1000 Genomes Project: implications for interpretation of structural variation in genomes and the future of clinical cytogenetics.

Dong Z1,2,3, Wang H1,3,4, Chen H2,5, Jiang H2,5, Yuan J2,5, Yang Z2,5, Wang WJ2,5, Xu F2,5,6, Guo X2,5, Cao Y1,3, Zhu Z2,5, Geng C2,5, Cheung WC1, Kwok YK1,3, Yang H2,5, Leung TY1,3,7, Morton CC8,9,10,11,12, Cheung SW13,14, Choy KW15,16,17.

Author information

1
Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong, China.
2
BGI-Shenzhen, Shenzhen, China.
3
Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China.
4
Department of Central Laboratory, Bao'an Maternity and Child Healthcare Hospital, Jinan University School of Medicine, Key Laboratory of Birth Defects Research, Birth Defects Prevention Research and Transformation Team, Shenzhen, China.
5
China National Genebank-Shenzhen, BGI-Shenzhen, Shenzhen, China.
6
Department of Biology, University of Copenhagen, Copenhagen, Denmark.
7
The Chinese University of Hong Kong-Baylor College of Medicine Joint Center For Medical Genetics, Hong Kong, China.
8
Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, Massachusetts, USA. cmorton@partners.org.
9
Harvard Medical School, Boston, Massachusetts, USA. cmorton@partners.org.
10
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. cmorton@partners.org.
11
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA. cmorton@partners.org.
12
Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester Academic Health Science Center, Manchester, UK. cmorton@partners.org.
13
The Chinese University of Hong Kong-Baylor College of Medicine Joint Center For Medical Genetics, Hong Kong, China. scheung@bcm.edu.
14
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA. scheung@bcm.edu.
15
Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong, China. richardchoy@cuhk.edu.hk.
16
Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China. richardchoy@cuhk.edu.hk.
17
The Chinese University of Hong Kong-Baylor College of Medicine Joint Center For Medical Genetics, Hong Kong, China. richardchoy@cuhk.edu.hk.

Abstract

PURPOSE:

Recent studies demonstrate that whole-genome sequencing enables detection of cryptic rearrangements in apparently balanced chromosomal rearrangements (also known as balanced chromosomal abnormalities, BCAs) previously identified by conventional cytogenetic methods. We aimed to assess our analytical tool for detecting BCAs in the 1000 Genomes Project without knowing which bands were affected.

METHODS:

The 1000 Genomes Project provides an unprecedented integrated map of structural variants in phenotypically normal subjects, but there is no information on potential inclusion of subjects with apparent BCAs akin to those traditionally detected in diagnostic cytogenetics laboratories. We applied our analytical tool to 1,166 genomes from the 1000 Genomes Project with sufficient physical coverage (8.25-fold).

RESULTS:

With this approach, we detected four reciprocal balanced translocations and four inversions, ranging in size from 57.9 kb to 13.3 Mb, all of which were confirmed by cytogenetic methods and polymerase chain reaction studies. One of these DNAs has a subtle translocation that is not readily identified by chromosome analysis because of the similarity of the banding patterns and size of exchanged segments, and another results in disruption of all transcripts of an OMIM gene.

CONCLUSION:

Our study demonstrates the extension of utilizing low-pass whole-genome sequencing for unbiased detection of BCAs including translocations and inversions previously unknown in the 1000 Genomes Project.

PMID:
29095815
PMCID:
PMC5932280
DOI:
10.1038/gim.2017.170
[Indexed for MEDLINE]
Free PMC Article

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