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EBioMedicine. 2017 Sep;23:150-159. doi: 10.1016/j.ebiom.2017.08.015. Epub 2017 Aug 17.

Rapid Targeted Next-Generation Sequencing Platform for Molecular Screening and Clinical Genotyping in Subjects with Hemoglobinopathies.

Author information

1
Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Guangzhou, Guangdong, China; Guangdong Key Laboratory of Biological Chip, Guangzhou, Guangdong, China.
2
BGI-Shenzhen, Bei Shan Industrial Zone, Yantian District, Shenzhen, Guangdong, China.
3
Tianjin Medical Laboratory, BGI-Tianjin, BGI-Shenzhen, Tianjin, China; Binhai Genomics Institute, BGI-Tianjin, BGI-Shenzhen, Tianjin, China.
4
Department of Hematology, 303rd Hospital of the People's Liberation Army, Nanning, Guangxi, China.
5
The Second Department of Pediatrics, Affiliated Hospital of Zunyi Medical College, Zunyi, Guizhou, China.
6
Genetic Diagnosis Center, First People's Hospital of Yunnan Province, Medical School of Kunming University of Science and Technology, Kunming, Yunnan, China.
7
Department of Biochemistry and Molecular Biology, Hainan Medical College, Haikou, Hainan, China.
8
Department of Genetic and Metabolic Laboratory, Guangxi Zhuang Autonomous Region Women and Children Health Care Hospital, Nanning, Guangxi, China.
9
Department of Medical Genetics, Liuzhou Municipal Maternity and Child Healthcare Hospital, Liuzhou, Guangxi, China.
10
Maternity and Child Health Care Hospital of Foshan City, Foshan, Guangdong, China.
11
Guilin Women and Children health care hospital, Guilin, Guangxi, China.
12
Department of Clinical Laboratory, Zhuhai Municipal Maternal and Child Healthcare Hospital, Zhuhai Institute of Medical Genetics, Zhuhai, Guangdong, China.
13
Maternal and Child Health Hospital in Meizhou, Meizhou, Guangdong, China.
14
Department of Prenatal Diagnosis Center, Dong Guan Maternal and Child Health Hospital, Dongguan, Guangdong, China.
15
Baise Women and Children Care Hospital, Baise, Guangxi, China.
16
Genetic Laboratory, Qinzhou Maternaland Child Health Hospital, Qingzhou, Guangxi, China.
17
Women and Children's Health Hospital of Shaoguan, Shaoguan, Guangdong, China.
18
Department of Gynecology and Obstetrics, The People's Hospital of Yunfu City, Yunfu, Guangdong, China.
19
Pingguo Women and Children Care Hospital, Baise, Guangxi, China.
20
BGI Clinical Laboratories-Shenzhen, BGI-Shenzhen, Shenzhen, China.
21
Department of Paediatric, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia.
22
BGI-Shenzhen, Bei Shan Industrial Zone, Yantian District, Shenzhen, Guangdong, China; James D. Watson Institute of Genome Sciences, Hangzhou, Zhejiang, China.
23
School of Basic Medical Sciences, Zhejiang University, Hangzhou, Zhejiang, China; Center for Genetic & Genomic Medicine, Zhejiang University Medical School 1st Affiliated Hospital, James Watson Institute of Genome Sciences, Hangzhou, Zhejiang, China.
24
Departments of Molecular and Human Genetics, Baylor College of Medicine, Houston, USA.
25
BGI-Shenzhen, Bei Shan Industrial Zone, Yantian District, Shenzhen, Guangdong, China. Electronic address: maomao@genomics.cn.
26
Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Guangzhou, Guangdong, China; Guangdong Key Laboratory of Biological Chip, Guangzhou, Guangdong, China. Electronic address: xixm@smu.edu.cn.

Abstract

Hemoglobinopathies are among the most common autosomal-recessive disorders worldwide. A comprehensive next-generation sequencing (NGS) test would greatly facilitate screening and diagnosis of these disorders. An NGS panel targeting the coding regions of hemoglobin genes and four modifier genes was designed. We validated the assay by using 2522 subjects affected with hemoglobinopathies and applied it to carrier testing in a cohort of 10,111 couples who were also screened through traditional methods. In the clinical genotyping analysis of 1182 β-thalassemia subjects, we identified a group of additional variants that can be used for accurate diagnosis. In the molecular screening analysis of the 10,111 couples, we detected 4180 individuals in total who carried 4840 mutant alleles, and identified 186 couples at risk of having affected offspring. 12.1% of the pathogenic or likely pathogenic variants identified by our NGS assay, which were undetectable by traditional methods. Compared with the traditional methods, our assay identified an additional at-risk 35 couples. We describe a comprehensive NGS-based test that offers advantages over the traditional screening/molecular testing methods. To our knowledge, this is among the first large-scale population study to systematically evaluate the application of an NGS technique in carrier screening and molecular diagnosis of hemoglobinopathies.

KEYWORDS:

Clinical genotyping; Hemoglobinopathy; Molecular screening; Next-generation sequencing

PMID:
28865746
PMCID:
PMC5605365
DOI:
10.1016/j.ebiom.2017.08.015
[Indexed for MEDLINE]
Free PMC Article

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