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Adv Sci (Weinh). 2019 Apr 1;6(11):1802332. doi: 10.1002/advs.201802332. eCollection 2019 Jun 5.

A Cell-free DNA Barcode-Enabled Single-Molecule Test for Noninvasive Prenatal Diagnosis of Monogenic Disorders: Application to β-Thalassemia.

Yang X1,2,3,4, Zhou Q5,6, Zhou W1,2,4, Zhong M7, Guo X3, Wang X6, Fan X8, Yan S9, Li L7, Lai Y8, Wang Y6, Huang J1,2,4, Ye Y1,2,4, Zeng H6, Chuan J6, Du Y6, Ma C6, Li P10, Song Z6, Xu X1,2,4.

Author information

Department of Medical Genetics School of Basic Medical Sciences Southern Medical University Guangzhou Guangdong 510515 China.
Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases Guangzhou Guangdong 510515 China.
Affiliated Foshan Maternity & Child Healthcare Hospital Southern Medical University Foshan Guangdong 528000 China.
Guangdong Key Laboratory of Biological Chip Guangzhou Guangdong 510515 China.
The Center for Precision Medicine of First Affiliated Hospital Biomedical Translational Research Institute School of Pharmacy Jinan University Guangzhou Guangdong 510632 China.
Hunan Research Center for Big Data Application in Genomics Genetalks Inc. Changsha Hunan 410152 China.
Nanfang Hospital Southern Medical University Guangzhou Guangdong 510515 China.
Guangxi Zhuang Autonomous Region Women and Children Care Hospital Nanning Guangxi 530000 China.
Qinzhou Maternity & Child Healthcare Hospital Qinzhou Guangxi 535000 China.
Department of Genetics Yale University New Haven CT 06520 USA.


Noninvasive prenatal testing of common aneuploidies has become routine over the past decade, but testing of monogenic disorders remains a challenge in clinical implementation. Most recent studies have inherent limitations, such as complicated procedures, a lack of versatility, and the need for prior knowledge of parental genotypes or haplotypes. To overcome these limitations, a robust and versatile next-generation sequencing-based cell-free DNA (cfDNA) allelic molecule counting system termed cfDNA barcode-enabled single-molecule test (cfBEST) is developed for the noninvasive prenatal diagnosis (NIPD) of monogenic disorders. The accuracy of cfBEST is found to be comparable to that of droplet digital polymerase chain reaction (ddPCR) in detecting low-abundance mutations in cfDNA. The analytical validity of cfBEST is evidenced by a β-thalassemia assay, in which a blind validation study of 143 at-risk pregnancies reveals a sensitivity of 99.19% and a specificity of 99.92% on allele detection. Because the validated cfBEST method can be used to detect maternal-fetal genotype combinations in cfDNA precisely and quantitatively, it holds the potential for the NIPD of human monogenic disorders.


cell‐free DNA barcode‐enabled single‐molecule test (cfBEST); molecule counting system; monogenic disorders; noninvasive prenatal diagnosis (NIPD); β‐thalassemia

Conflict of interest statement

The authors declare no conflict of interest.

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