Universal Haplotype-Based Noninvasive Prenatal Testing for Single Gene Diseases

BACKGROUND: Researchers have developed approaches for the noninvasive prenatal testing of single gene diseases. One approach that allows for the noninvasive assessment of both maternally and paternally inherited mutations involves the analysis of single nucleotide polymorphisms (SNPs) in maternal plasma DNA with reference to parental haplotype information. In the past, parental haplotypes were resolved by complex experimental methods or inferential approaches, such as through the analysis of DNA from other affected family members. Recently, microfluidics-based linked-read sequencing technology has become available and allows the direct haplotype phasing of the whole genome rapidly. We explored the feasibility of applying this direct haplotyping technology in noninvasive prenatal testing. METHODS: We first resolved the haplotypes of parental genomes with the use of linked-read sequencing technology. Then, we identified SNPs within and flanking the genes of interest in maternal plasma DNA by targeted sequencing. Finally, we applied relative haplotype dosage analysis to deduce the mutation inheritance status of the fetus. RESULTS: Haplotype phasing and relative haplotype dosage analysis of 12 out of 13 families were successfully achieved. The mutational status of these 12 fetuses was correctly classified. CONCLUSIONS: High-throughput linked-read sequencing followed by maternal plasma-based relative haplotype dosage analysis represents a streamlined approach for noninvasive prenatal testing of inherited single gene diseases. The approach bypasses the need for mutationspecific assays and is not dependent on the availability of DNA from other affected family members. Thus, the approach is universally applicable to pregnancies at risk for the inheritance of a single gene disease

Parental decisions following prenatal diagnosis of sex chromosome aneuploidy in Hong Kong

Aim: According to the published work, pregnancy termination rates due to prenatal diagnosis of fetal sex chromosome aneuploidies (SCA) vary widely. Some potentially modifiable and non-modifiable factors have been reported to be associated with parental decision. This study aimed to evaluate the rate of pregnancy termination for fetal SCA and the factors influencing parents' decisions in Hong Kong. Methods: This was a 21-year retrospective cohort study of parents' decisions following prenatal diagnosis of SCA. Univariate and multivariate analyses for the association between demographic factors, prenatal factors, or counseling provided and decision-making were conducted. Results: The study included 399 pregnancies with prenatal diagnosis of SCA and the overall termination rate was 55.6% (91.7%, 48.0%, 23.4%, 4.8%, and 22.7% for 45,X, 47,XXY, 47,XXX, 47,XYY, and mosaicism, respectively). Pregnancies with ultrasound abnormalities were associated with higher termination rates than pregnancies with normal ultrasound findings (91.3% vs 28.3%, P < 0.0001). From multivariate regression analysis on 226 pregnancies with normal ultrasound examination, a higher likelihood to terminate was found in pregnancies affected by 45,X and 47,XXY (adjusted odds ratio, 4.72, P < 0.0001). Increased maternal age and history of infertility were associated with lower likelihood to terminate (adjusted odds ratio, 0.9, P = 0.012; and 5.12, P = 0.038, respectively). The pregnancy termination rate declined over time. Conclusion: A significant correlation was found between the termination of SCA-affected pregnancy and the presence of fetal sonographic abnormalities, type of SCA, maternal age, and presence of infertility. © 2017 Japan Society of Obstetrics and Gynecolog