Developing and validating noninvasive prenatal testing for de novo autosomal dominant monogenic diseases in Vietnam.

Background: Over 60% of single-gene diseases in newborns are autosomal dominant variants. Noninvasive prenatal testing for monogenic conditions (NIPT-SGG) is cost-effective and timesaving, but not widely applied. This study introduces and validates NIPT-SGG in detecting 25 monogenic conditions. Methods: NIPT-SGG with a 30-gene panel applied next-generation sequencing and trio assays to confirm de novo variants. Diagnostic tests confirmed NIPT-detected cases. Results: Among 93 pregnancies with ultrasound findings, 11 (11.8%) fetuses were screened and diagnosed with monogenic diseases, mostly with Noonan syndrome. NIPT-SGG determined >99.99% of actual positive and negative cases, confirmed by diagnostic tests. No false-negatives or false-positives were reported. Conclusion: NIPT-SGG effectively identifies the fetuses affected with monogenic diseases, which is a promisingly safe and timely antenatal screening option for high-risk pregnancies.

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

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/-α3.7 (2.934%), αα/-α4.2 (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 (-α3.7/-α4.2, αα/--THAI, -α3.7/--SEA, -α4.2/--SEA). Additionally, the positive predictive values were 100.00% for αα/αα, 99.29% for αα/--SEA, 94.87% for αα/-α3.7, and 96.51% for αα/-α4.2; 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.