Detection of maternal carriers of common α-thalassemia deletions from cell-free DNA

Abstract

α-Thalassemia is a common inherited blood disorder manifested mainly by the deletions of α-globin genes. In geographical areas with high carrier frequencies, screening of α-thalassemia carrier state is therefore of vital importance. This study presents a novel method for identifying female carriers of common α-thalassemia deletions using samples routinely taken for non-invasive prenatal tests for screening of fetal chromosomal aneuploidies. A total of 68,885 Vietnamese pregnant women were recruited and α-thalassemia statuses were determined by gap-PCR, revealing 5344 women (7.76%) carried deletions including αα/--^SEA (4.066%), αα/-α^3.7 (2.934%), αα/-α^4.2 (0.656%), and rare genotypes (0.102%). A two-stage model was built to predict these α-thalassemia deletions from targeted sequencing of the HBA gene cluster on maternal cfDNA. Our method achieved F1-scores of 97.14-99.55% for detecting the three common genotypes and 94.74% for detecting rare genotypes (-α^3.7/-α^4.2, αα/--^THAI, -α^3.7/--^SEA, -α^4.2/--^SEA). Additionally, the positive predictive values were 100.00% for αα/αα, 99.29% for αα/--^SEA, 94.87% for αα/-α^3.7, and 96.51% for αα/-α^4.2; and the negative predictive values were 97.63%, 99.99%, 99.99%, and 100.00%, respectively. As NIPT is increasingly adopted for pregnant women, utilizing cfDNA from NIPT to detect maternal carriers of common α-thalassemia deletions will be cost-effective and expand the benefits of NIPT.