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Genet Med. 2016 Sep;18(9):940-8. doi: 10.1038/gim.2015.199. Epub 2016 Jan 28.

Low-pass whole-genome sequencing in clinical cytogenetics: a validated approach.

Dong Z1,2,3, Zhang J4, Hu P5, Chen H1, Xu J1, Tian Q4, Meng L5, Ye Y4, Wang J6, Zhang M6, Li Y6, Wang H2,3, Yu S1, Chen F1,7,8,9,10,11, Xie J12, Jiang H1,9,10, Wang W1,6,8,9,10, Choy KW2,3, Xu Z5.

Author information

1
BGI-Shenzhen, Shenzhen, China.
2
Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong, China.
3
Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China.
4
Department of Obstetrics, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
5
State Key Laboratory of Reproductive Medicine, Department of Prenatal Diagnosis, Nanjing Maternity and Child Health Care Hospital Affiliated to Nanjing Medical University, Nanjing, China.
6
Clinical Laboratory of BGI Health, BGI-Shenzhen, Shenzhen, China.
7
Shenzhen Birth Defect Screening Project Lab, BGI-Shenzhen, Shenzhen, China.
8
BGI-Nanjing, Nanjing, China.
9
The Guangdong Enterprise Key Laboratory of Human Disease Genomics, BGI-Shenzhen, Shenzhen, China.
10
Shenzhen Key Laboratory of Transomics Biotechnologies, BGI-Shenzhen, Shenzhen, China.
11
Section of Molecular Disease Biology, Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
12
Shenzhen Maternal and Child Health Care Hospital, Shenzhen, China.

Abstract

PURPOSE:

Chromosomal microarray analysis is the gold standard for copy-number variant (CNV) detection in prenatal and postnatal diagnosis. We aimed to determine whether next-generation sequencing (NGS) technology could be an alternative method for CNV detection in routine clinical application.

METHODS:

Genome-wide CNV analysis (>50 kb) was performed on a multicenter group of 570 patients using a low-coverage whole-genome sequencing pipeline. These samples were referred for chromosomal analysis; CNVs (i.e., pathogenic CNVs, pCNVs) were classified according to the American College of Medical Genetics and Genomics guidelines.

RESULTS:

Overall, a total of 198 abortuses, 37 stillbirths, 149 prenatal, and 186 postnatal samples were tested. Our approach yielded results in 549 samples (96.3%). In addition to 119 subjects with aneuploidies, 103 pCNVs (74 losses and 29 gains) were identified in 82 samples, giving diagnostic yields of 53.2% (95% confidence interval: 45.8, 60.5), 14.7% (5.0, 31.1), 28.5% (21.1, 36.6), and 30.1% (23.6, 37.3) in each group, respectively. Mosaicism was observed at a level as low as 25%.

CONCLUSIONS:

Patients with chromosomal diseases or microdeletion/microduplication syndromes were diagnosed using a high-resolution genome-wide method. Our study revealed the potential of NGS to facilitate genetic diagnoses that were not evident in the prenatal and postnatal groups.Genet Med 18 9, 940-948.

PMID:
26820068
DOI:
10.1038/gim.2015.199
[Indexed for MEDLINE]

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