Integration of targeted sequencing and pseudo-tetraploid genotyping into clinically assisted decision support for β-thalassemia invasive prenatal diagnosis

by Wenguang Jia, Jiying Shi, Hengying Zhu, Xiaojing Wu, Yayun Ling, Ping Chen

The high prevalence of β-thalassemia indicates the severe medical burden in Guangxi province in China. Millions of thousands of prenatal women with healthy or thalassemia-carrying fetuses received an unnecessary prenatal diagnosis. We designed a prospective single-center proof-of-concept study to evaluate the utility of a noninvasive prenatal screening method in the stratification of beta-thalassemia patients before invasive procedures.

Next-generation and optimized pseudo-tetraploid genotyping-based methods were utilized in preceding invasive diagnosis stratification to predict the mater-fetus genotype combinations in cell-free DNA, which is from maternal peripheral blood. Populational linkage disequilibrium information with additional neighboring loci to infer the possible fetal genotype. The concordance of the pseudo-tetraploid genotyping with the gold standard invasive molecular diagnosis was used to evaluate the effectiveness of this method.

127 β-thalassemia carrier parents were consecutively recruited. The total genotype concordance rate is 95.71%. The Kappa value was 0.8248 for genotype combinations and 0.9118 for individual alleles.

This study offers a new approach to picking out the health or carrier fetus before invasive procedures. It provides valuable novel insight into patient stratification management on β-thalassemia prenatal diagnosis.