Chao Chen1,2, Ru Li3, Jun Sun1,2, Yaping Zhu1,2, Lu Jiang1,2, Jian Li3, Fang Fu3, Junhui Wan3, Fengyu Guo1,2, Xiaoying An1,2, Yaoshen Wang1,2, Linlin Fan1,2, Yan Sun1,4, Xiaosen Guo1, Sumin Zhao1,2, Wanyang Wang1,2, Fanwei Zeng1, Yun Yang1,4,5, Peixiang Ni1,2, Yi Ding1,2, Bixia Xiang1, Zhiyu Peng6, Can Liao7. 1. BGI Genomics, BGI-Shenzhen, Shenzhen, 518083, China. 2. Tianjin Medical Laboratory, BGI-Tianjin, BGI-Shenzhen, Tianjin, 300308, China. 3. Department of Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China. 4. BGI-Wuhan Clinical Laboratories, BGI-Shenzhen, Wuhan, 490079, China. 5. Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China. 6. BGI Genomics, BGI-Shenzhen, Shenzhen, 518083, China. pengzhiyu@bgi.com. 7. Department of Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China. canliao6008@163.com.
Abstract
BACKGROUND: Noninvasive prenatal testing (NIPT) of recessive monogenic diseases depends heavily on knowing the correct parental haplotypes. However, the currently used family-based haplotyping method requires pedigrees, and molecular haplotyping is highly challenging due to its high cost, long turnaround time, and complexity. Here, we proposed a new two-step approach, population-based haplotyping-NIPT (PBH-NIPT), using α-thalassemia and β-thalassemia as prototypes. METHODS: First, we deduced parental haplotypes with Beagle 4.0 with training on a large retrospective carrier screening dataset (4356 thalassemia carrier screening-positive cases). Second, we inferred fetal haplotypes using a parental haplotype-assisted hidden Markov model (HMM) and the Viterbi algorithm. RESULTS: With this approach, we enrolled 59 couples at risk of having a fetus with thalassemia and successfully inferred 94.1% (111/118) of fetal alleles. We confirmed these alleles by invasive prenatal diagnosis, with 99.1% (110/111) accuracy (95% CI, 95.1-100%). CONCLUSIONS: These results demonstrate that PBH-NIPT is a sensitive, fast, and inexpensive strategy for NIPT of thalassemia.
BACKGROUND: Noninvasive prenatal testing (NIPT) of recessive monogenic diseases depends heavily on knowing the correct parental haplotypes. However, the currently used family-based haplotyping method requires pedigrees, and molecular haplotyping is highly challenging due to its high cost, long turnaround time, and complexity. Here, we proposed a new two-step approach, population-based haplotyping-NIPT (PBH-NIPT), using α-thalassemia and β-thalassemia as prototypes. METHODS: First, we deduced parental haplotypes with Beagle 4.0 with training on a large retrospective carrier screening dataset (4356 thalassemia carrier screening-positive cases). Second, we inferred fetal haplotypes using a parental haplotype-assisted hidden Markov model (HMM) and the Viterbi algorithm. RESULTS: With this approach, we enrolled 59 couples at risk of having a fetus with thalassemia and successfully inferred 94.1% (111/118) of fetal alleles. We confirmed these alleles by invasive prenatal diagnosis, with 99.1% (110/111) accuracy (95% CI, 95.1-100%). CONCLUSIONS: These results demonstrate that PBH-NIPT is a sensitive, fast, and inexpensive strategy for NIPT of thalassemia.
Authors: Imran S Haque; Gabriel A Lazarin; H Peter Kang; Eric A Evans; James D Goldberg; Ronald J Wapner Journal: JAMA Date: 2016-08-16 Impact factor: 56.272