Noninvasive detection of fetal subchromosomal abnormalities by semiconductor sequencing of maternal plasma DNA
| Autor: | Rachel Q. Xue, Huang Quanfei, Daniel Zhang, Yangyi Chen, Mindy Zhang, Jiexia Yang, Kang Zhang, Rui Hou, Chang Liu, Dong-hong Luo, Yiming Qi, Michael Ai, Ai-hua Yin, Jian Liu, Mingqin Mai, Lianghong Zheng, Hailiang Liu, Dongmei Wang, Michal Krawczyk, Bennett A. Caughey, Chun-fang Peng, Fangfang Guo, Michael Karin, Yunan Wang, Wei-wei Huang, Xin Zhao, Jing Wu |
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| Rok vydání: | 2015 |
| Předmět: |
Pathology
medicine.medical_specialty Aneuploidy Prenatal diagnosis Biology DNA sequencing Deep sequencing Fetus Pregnancy Prenatal Diagnosis Chromosome Duplication Gene duplication medicine Humans Chromosome Aberrations Comparative Genomic Hybridization Multidisciplinary Cell-Free System DNA Sequence Analysis DNA Ion semiconductor sequencing Biological Sciences medicine.disease Molecular biology Molecular Weight Semiconductors Cell-free fetal DNA Female Chromosome Deletion Comparative genomic hybridization |
| Zdroj: | Proceedings of the National Academy of Sciences. 112:14670-14675 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1518151112 |
| Popis: | Noninvasive prenatal testing (NIPT) using sequencing of fetal cell-free DNA from maternal plasma has enabled accurate prenatal diagnosis of aneuploidy and become increasingly accepted in clinical practice. We investigated whether NIPT using semiconductor sequencing platform (SSP) could reliably detect subchromosomal deletions/duplications in women carrying high-risk fetuses. We first showed that increasing concentration of abnormal DNA and sequencing depth improved detection. Subsequently, we analyzed plasma from 1,456 pregnant women to develop a method for estimating fetal DNA concentration based on the size distribution of DNA fragments. Finally, we collected plasma from 1,476 pregnant women with fetal structural abnormalities detected on ultrasound who also underwent an invasive diagnostic procedure. We used SSP of maternal plasma DNA to detect subchromosomal abnormalities and validated our results with array comparative genomic hybridization (aCGH). With 3.5 million reads, SSP detected 56 of 78 (71.8%) subchromosomal abnormalities detected by aCGH. With increased sequencing depth up to 10 million reads and restriction of the size of abnormalities to more than 1 Mb, sensitivity improved to 69 of 73 (94.5%). Of 55 false-positive samples, 35 were caused by deletions/duplications present in maternal DNA, indicating the necessity of a validation test to exclude maternal karyotype abnormalities. This study shows that detection of fetal subchromosomal abnormalities is a viable extension of NIPT based on SSP. Although we focused on the application of cell-free DNA sequencing for NIPT, we believe that this method has broader applications for genetic diagnosis, such as analysis of circulating tumor DNA for detection of cancer. |
| Databáze: | OpenAIRE |
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