To evaluate the clinical performance of noninvasive prenatal screening (NIPS) for fetal sex chromosome aneuploidies (SCAs), pregnant women were recruited in this retrospective observational study. The NIPS test was undertaken using high-throughput gene sequencing. In total,50,301 pregnant women were analysed for demographic characteristics and medical history. Of them, 308 women (0.61%) had high risk for fetal SCAs, including 138 for 45,X, 111 for 47,XXY, 42 for 47,XXX, and 17 for 47,XYY. After the pre-test counselling, 182 participants chose to undergo invasive prenatal diagnosis, confirming 59 positive cases. The combined positive predictive value of NIPS was 32.42% (59/182), 18.39% (16/87), 44.4% (12/27), 39.29% (22/56), and 75% (9/12) for detecting SCAs, 45,X, 47,XXX, 47,XXY, and 47,XYY, respectively. NIPS can be a useful method to detect the fetal SCAs using high-throughput gene sequencing, though accuracy can still be improved, especially for 45,X. Although the value of NIPS compare favorably with those seen in traditional screening approaches for SCAs, it is important to highlight the limitations of NIPS while educating clinicians and patients.

BackgroundOur aim was to provide a theoretical basis for clinicians to conduct genetic counseling and choose further prenatal diagnosis methods for pregnant women who failed non-invasive prenatal screening (NIPS).MethodsA retrospective analysis was performed on pregnant women who had failed NIPS tests.ResultsAmong the 123,291 samples, 394 pregnant women did not obtain valid results due to test failures. A total of 378 pregnant women were available for follow-up, while 16 patients were lost to follow-up. Of these 378, 135 pregnant women chose further prenatal diagnosis through amniocentesis, and one case of dysplasia was recalled for postpartum chromosome testing. The incidence rate of congenital chromosomal abnormalities in those who failed the NIPS was 3.97% (15/378), which was higher than that of the chromosomal abnormalities in the common population (1.8%). Among the pregnant women who received prenatal diagnosis, the positive rates of chromosomal abnormalities in the chromosomal microarray analysis/copy number variation sequencing (CMA/CNV-seq) group and in the karyotyping group were 15.28 and 4.76%, respectively.ConclusionPrenatal diagnosis should be strongly recommended in posttest genetic counseling for pregnant women with NIPS failures. Further, high-resolution detection methods should be recommended for additional prenatal diagnoses.

Background: Complex chromosomal rearrangements (CCRs) are associated with high reproductive risk, infertility, abnormalities in offspring, and recurrent miscarriage in women. It is essential to accurately characterize apparently balanced chromosome rearrangements in unaffected individuals.Methods: A CCR young couple who suffered two spontaneous abortions and underwent labor induction due to fetal chromosomal abnormalities was studied using long-read sequencing(LRS), single-nucleotide polymorphism (SNP) array, G-banding karyotype analysis (550-band resolution), and Sanger sequencing.Results: SNP analysis of the amniotic fluid cells during the third pregnancy revealed a 9.9-Mb duplication at 7q21.11q21.2 and a 24.8-Mb heterozygous deletion at 13q21.1q31.1. The unaffected female partner was a carrier of a three-way CCR [46,XX,? ins(7;13)(q21.1;q21.1q22)t(2;13)(p23;q22)]. Subsequent LRS analysis revealed the exact breakpoint locations on the derivative chromosomes and the specific method of chromosome rearrangement, indicating that the CCR carrier was a more complex structural rearrangement comprising five breakpoints. Furthermore, LRS detected an inserted fragment of chromosome 13 in chromosome 7.Conclusions: LRS is effective for analyzing the complex structural variations of the human genome and may be used to clarify the specific CCRs for effective genetic counseling and appropriate intervention. K E Y W O R D Scomplex chromosomal rearrangements (CCRs), karyotype analysis of chromosome G-banding karyotype analysis (550 bands), long-read sequencing Oxford nanopore technology, thirdgeneration sequencing (TGS)