Noninvasive prenatal testing of α-thalassemia and β-thalassemia through population-based parental haplotyping

• Main Authors: Chao Chen, Ru Li, Jun Sun, Yaping Zhu, Lu Jiang, Jian Li, Fang Fu, Junhui Wan, Fengyu Guo, Xiaoying An, Yaoshen Wang, Linlin Fan, Yan Sun, Xiaosen Guo, Sumin Zhao, Wanyang Wang, Fanwei Zeng, Yun Yang, Peixiang Ni, Yi Ding, Bixia Xiang, Zhiyu Peng, Can Liao
• Format: Article
• Language: English
• Published: BMC 2021-02-01
• Series: Genome Medicine
• Subjects: NIPT; Recessive monogenic diseases; Haplotypes; Population-based haplotyping; α-Thalassemia; β-Thalassemia
• Online Access: https://doi.org/10.1186/s13073-021-00836-8

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.